GB2560712A

GB2560712A - A monitoring system

Info

Publication number: GB2560712A
Application number: GB1704300.1A
Authority: GB
Inventors: T O'connell Mark
Original assignee: Probe Scient Ltd
Current assignee: Probe Scient Ltd
Priority date: 2017-03-17
Filing date: 2017-03-17
Publication date: 2018-09-26
Also published as: GB201704300D0

Abstract

A delivery system 1 and method comprises: a receptacle 2 for containing a fluid, adapted to allow the fluid to flow from the receptacle; a molecular exchange area 4; and a supply conduit 3 defining a fluid path between from the receptacle to the molecular exchange area, wherein the receptacle is positioned above the other components such that the fluid is transported by the action of gravity. In a further embodiment the system and method is a monitoring system and method, further comprising an outlet conduit 5 defining a fluid path from the molecular exchange area to a sensor unit 10. The systems may comprise one or more attachments to hold one or more of the components of the system in position (e.g. a stand, pole, and/or wall mount), and may also comprise one or more means to control the flow rate of the fluid (e.g. a constriction element, moving the height of the receptacle with respect to the molecular exchange area, altering the size or internal cross sectional area of the supply conduit). The sensor unit may comprise an electrochemical or optical sensor, with an electroanalytical component (e.g. a potentiostat, coulometer or voltmeter), or a recognition substrate.

Description

(71) Applicant(s):

Probe Scientific Limited (Incorporated in the United Kingdom)

The Venture Centre, Sir William Lyons Road, COVENTRY, CV4 7EZ, United Kingdom (72) Inventor(s):

Mark T O'Connell (56) Documents Cited:

GB 1457848 A WO 2010/078404 A1 US 5368725 A1 (58) Field of Search:

EP 0118735 A2 CN 204016966 U

INT CLA61B, A61M, B01D, G01N Other: WPI, EPODOC, Patent Fulltext (74) Agent and/or Address for Service:

Forresters IP LLP

Sherborne House, 119-121 Cannon Street, LONDON, EC4N 5AT, United Kingdom (54) Title of the Invention: A monitoring system

Abstract Title: A system suitable for dialysis, ultra-filtration and drug delivery without using pumps (57) A delivery system 1 and method comprises: a receptacle 2 for containing a fluid, adapted to allow the fluid to flow from the receptacle; a molecular exchange area 4; and a supply conduit 3 defining a fluid path between from the receptacle to the molecular exchange area, wherein the receptacle is positioned above the other components such that the fluid is transported by the action of gravity. In a further embodiment the system and method is a monitoring system and method, further comprising an outlet conduit 5 defining a fluid path from the molecular exchange area to a sensor unit 10. The systems may comprise one or more attachments to hold one or more of the components of the system in position (e.g. a stand, pole, and/or wall mount), and may also comprise one or more means to control the flow rate of the fluid (e.g. a constriction element, moving the height of the receptacle with respect to the molecular exchange area, altering the size or internal cross sectional area of the supply conduit). The sensor unit may comprise an electrochemical or optical sensor, with an electroanalytical component (e.g. a potentiostat, coulometer or voltmeter), or a recognition substrate.

This print incorporates corrections made under Section 117(1) of the Patents Act 1977.

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Figure 6b

Title: Gravity feed monitoring system

Description of Invention

The present invention relates to a monitoring system, delivery system and methods of monitoring and delivering molecules. In particular, the present invention relates to a monitoring system, delivery system and methods of monitoring and delivering molecules having a gravity feed and a molecular exchange device for use with a sensor unit.

Monitoring systems are known that utilise molecular exchange devices to detect substances and amounts of substances in a specific environment.

In known molecular exchange devices, there is generally a fluid passageway that carries fluid from one end of the device to the other, which enables fluid to be supplied to the device and fluid to flow out of the device in a desired direction. Such molecular exchange devices generally include a porous membrane past which a fluid is supplied and removed. Molecules from the fluid can pass through the membrane into the subject and vice versa. In the latter case, analysis can be carried out using internal or external apparatus to ascertain the presence of certain molecules and their amounts/concentrations. These known molecular exchange devices are used in conjunction with a pump. The pump is required to introduce fluid into the molecular exchange device, push or pull or push and pull the fluid along the fluid passageway, and remove the fluid from the device.

In these known molecular exchange devices, due to their construction, there are generally tight bends or constrictions in the fluid passageways of the device. In particular, with the concentric arrangement, there is an outer tube having a lumen with a circular cross-section and an intra-luminal tube also having a circular cross-section positioned centrally within the outer tube, forming an inner and an outer fluid passageway. The outer tube having a permeable membrane across which molecular exchange can take place. In such an arrangement fluid may be passed into and along the inner/outer fluid passageway and drawn along and out of the other fluid passageway. This arrangement creates a back-pressure within the fluid passageway of the molecular exchange device where there is a constriction, bend or other obstacle in the fluid passageway carrying fluid into and out of the device. A pump is required to overcome the back pressure and move fluid through the molecular exchange device.

In a monitoring system that utilizes a pump, or other powered or energized action, it has been found that the pumps are prone to errors. The quality of the pump is usually dependent on the materials used. For example, a high end stepper motor driven pump works well when glass syringes are used. However, glass syringes are expensive and costly to maintain. To address the problem, plastic syringes have been utilized in such pumps. The drawback of this arrangement is that a seal is required to maintain the integrity of the fluid compartment, and damage can occur when the seal experiences friction as it moves down the barrel of the syringe. Another problem with such pumps is that they provide a source of error due to inconsistent flow. In an attempt to make the pumps more accurate and address health and safety concerns, pumps with high precision and capable of pumping at the desired flow rates have been developed. However, these high precision pumps are expensive and require maintenance. This increases the overall cost of any monitoring system utilizing these pumps. The high cost of the pumps and their running costs is a particular disadvantage for continuous monitoring systems.

The known monitoring systems that utilise a pump are also not appropriate in situations, such as in developing countries, when there is no access to electricity for running the pump, and/or a pump and battery are not affordable.

It is an object of the present invention to provide a monitoring system that overcomes or mitigates some or all of the above disadvantages.

Definitions

For the avoidance of doubt, the following terms are intended to have the definitions as outlined below:

Molecular exchange is the selective exchange of any suitable molecule or composition, including but not limited to dialysis, ultra-filtration, drug delivery etc., from the device to the external environment and vice versa.

The casing is constructed from any suitable material, such that the substantial flow of fluid or molecules is prevented through its walls in the environment within which it is intended to be used. Hence, in biological applications where the molecular exchange device is intended to be inserted in a human or animal body, the casing is made of a material that is resistant to a biological biocompatible environment and prevents substances from penetrating through the casing. The material of the casing must also be rigid enough to ensure the device is not easily damaged during insertion, but flexible enough to allow a degree of bending of the device during use. Preferably, the casing is constructed from high density polyethylene (HDPE), polyamide, carbon fibre, stainless steel or similar material.

The distal end of the casing is the end of the device that is intended to be inserted into the environment in which molecular exchange is desired.

The proximal end of the casing is the end of the device that is not intended to be inserted into the environment in which molecular exchange is desired. The distal and proximal ends of the casing are adapted to allow the insertion/withdrawal of perfusion fluid to/from the fluid passageways.

The distal and proximal ends are also adapted to allow insertion/withdrawal of additional components, such as probes, sensors, connectors to monitoring/analysing systems etc.

The at least one exchange aperture is a portion of the casing that exposes the adjacent portion of the fluid passageway. The exchange aperture may be an opening in the external wall of the cavity. Alternatively, the exchange aperture may be a porous area that permits the exchange of selected molecules to/from the fluid passageways from/to the environment external to the device.

The porous portions are porous to the extent that they permit the selective exchange of molecules across the fluid passageway and/or casing. A skilled person would appreciate that different sized molecules will require different porosities to permit the selective exchange of molecules.

A flow chamber provides the passage of fluid from at least one fluid passageway to another at least one fluid cavity. For example, the flow chamber may provide passage of fluid from one fluid passage way to another fluid passageway through, for example, a connecting tube or an open chamber.

Analyte or plurality of analytes is any component, substance or chemical or biological constituent that is of interest to be detected and/or the amount measured.

An electrical contact and/or connection is an electrically conductive material, usually metal, which can pass an electrical current when touching another electrical contact. The electrical contact can have one or more connections that touch the electrical connections of a respective electrical contact to form electrical communication.

Electroanalytical component controls an electrochemical sensor. For example, the electroanalytical component is a potentiostat, coulometer or a voltmeter.

Electrochemical sensor is a detector that measures the concentration of a target analyte or plurality of analytes by oxidizing or reducing the target analyte or plurality of analytes at an electrode and measuring the resulting current. The electrochemical sensor has a reference electrode and at least one working electrode. Advantageously, the electrochemical sensor may further comprise one or more auxiliary electrodes. The electrochemical sensor may comprise one, two, three, four, five, six, seven, eight, nine, ten or more working electrodes.

An electrode may be a working electrode, an auxiliary electrode, or a reference electrode. The reference electrode is an electrode which has a stable and well-known electrode potential; and establishes the electrical potential against which other potentials may be measured. The working electrode is the electrode on which the reaction of interest is occurring. The auxiliary electrode, along with the working electrode, provides a circuit over which current is either applied or measured. The potential of the auxiliary electrode is usually not measured and is adjusted so as to balance the reaction occurring at the working electrode. This configuration allows the potential of the working electrode to be measured against a known reference electrode without compromising the stability of that reference electrode by passing current over it. The auxiliary electrode can provide stability to the system.

The sensor unit or monitoring unit has electrical components, such as an electroanalytical component, such as a potentiostat in the form of a PCB, a rechargeable battery, an EEPROM (Electrically Erasable Programmable Read-Only Memory) unit for caching data, a component for transmitting the data wirelessly (e.g. via Bluetooth®) to an external control unit, such as a personal computer, tablet or smartphone. In embodiments of the invention, these electrical components are sealed in a casing. The electroanalytical component is connected to a first electrical contact for connecting to the second electrical contact of the sensor unit. The rechargeable battery is connected to a third electrical contact for connecting to the fourth electrical contact of the battery charging unit.

An optical sensor, the sensor has a light source for emitting illuminating light, such as LEDs or OLEDs, and a light receiving unit, such as a photodiode which feeds back to a voltmeter. In these embodiments the electrical contact provides power for the setting of the voltage, provides power for the light source to emit light, and collects the information from the photodiode. The light source has a gating arrangement to achieve the desired wavelength for the analyte of interest. The gating arrangement zones out wavelengths not required. Alternatively, a laser can be used as the light source. Optical sensors have excellent long term stability.

The porous area of a molecular exchange device is porous to the extent that the selective exchange of molecules across the fluid passageway is permitted. A skilled person would appreciate that different sized molecules will require different porosities to permit the selective exchange of the desired molecule,

i.e. analyte or plurality of analytes.

A perfusate is the fluid before it has passed through the molecular exchange areas. In contrast, a dialysate a fluid that has passed through the molecular exchange area and comprises any selected exchange materials.

Sensor arrangement comprises an electrochemical sensor or an optical sensor. These are well known in the art.

The subject is any suitable environment in which the device may be applied. For example, the subject can be a human or animal body. Alternatively, the subject could be part of a industrial, chemical or fermentation process.

Summary of the invention

In a first aspect of the invention, there is a monitoring system comprising a receptacle for containing a fluid and adapted to allow the fluid to flow from the receptacle by the action of gravity; a molecular exchange area; a supply conduit defining a fluid path from the receptacle to a molecular exchange area; and an outlet conduit defining a fluid path from the molecular exchange area to an outlet port, wherein, in use, the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the outlet port by the action of gravity.

The main advantage provided by the monitoring system in accordance with the present invention is that, during use, the gravity feed of the fluid through the system avoids the need for a powered or motorised action to transport the fluid through the monitoring system. This provides a simple and cost effective monitoring system, which does not require any additional arrangements to use the monitoring system. In particular, no expensive pumps, electricity, or other powered or motorised arrangements are required to transport fluid through the system. This simplifies the requirements and reduces the cost of manufacturing the monitoring system, and reduces the cost of running and maintaining the monitoring system. It can also improve the safety of the monitoring system.

The system can provide a continuous flow of fluid through the molecular exchange area.

In a second aspect of the invention, there is a delivery system comprising a receptacle for containing a fluid and adapted to allow the fluid to flow from the receptacle by the action of gravity; a molecular exchange area; a supply conduit defining a fluid path from the receptacle to a molecular exchange area; and an outlet conduit defining a fluid path from the molecular exchange area to an outlet port, wherein, in use, the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the outlet port by the action of gravity.

The main advantage provided by the delivery system in accordance with the present invention is that, during use, the gravity feed of the fluid through the system avoids the need for a powered or motorised action to transport the fluid through the delivery system. This provides a simple and cost effective delivery system, which does not require any additional arrangements to use the delivery system. In particular, no expensive pumps, electricity, or other powered or motorised arrangements are required to transport fluid through the system. This simplifies the requirements and reduces the cost of manufacturing the delivery system, and reduces the cost of running and maintaining the delivery system. It can also improve the safety of the delivery system.

The delivery system can deliver any desired fluid across the molecular exchange area. The system can provide a continuous flow of fluid through the molecular exchange area.

In advantageous embodiments, the volume of the receptacle may be 0.0005 to 10 litres, 0.0005 to 0.75 litres, 0.25 to 8 litres, or 0.5 to 4 litres. In some embodiments, the volume of the receptacle may will be 0.005, 0.1,0.02, 0.05, 0.1,0.2, 0.25, 0.5, 0.75, 1,2, 3, 4, 5, 6, 7, 8, 9, 10 litres.

In preferred embodiments, the receptacle is positioned at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50 60, 70, 80, 90 centimetres, 1, 2, 3, 4, 5, or more meters above the molecular exchange area.

Advantageously the systems further comprise one or more attachments to hold one or more of the receptacle(s), supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position. In a preferred embodiment the attachment is a stand, pole, and/or wall mountable arrangement. Advantageously, the attachment is extendable and/or retractable to move the position of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit.

In some embodiments, the systems further comprise one or more means to control the flow rate. The means may be selected from: a constriction element; moving the height of the receptacle with respect to the molecular exchange area; altering the size of the supply conduit, altering the internal cross-sectional area of the supply conduit. In some arrangements, the means are an adaptor that changes the size of the internal cross-sectional area of the supply conduit.

In an advantageous embodiment, the flow rate is 0.01 to 150pl/min and preferably 30 to 150pl/min. The flow rate may be 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,

0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 150pl/miη

In a preferred embodiment, the supply conduit and/or the outlet conduit is in the form of tubing. The tube can have a uniform cross-section and/or uniform wall thickness. The tube may have a a circular cross-section; and optionally have an internal diameter of 0.01 to 0.5 mm, or 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5 mm; and /or an external diameter of 0.02 to 7mm, or 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mm.

In a preferred embodiment, the systems further comprise a sensor unit. The sensor may be connected to the outlet port, or positioned between the molecular exchange area and the outlet port. In this arrangement the outlet conduit is in two parts; one part linking the molecular exchange area and the sensor unit, and the other part linking the sensor unit and the outlet port.

In some embodiments, the sensor unit comprises one, two, three, four, five, six, seven, eight, nine or more sensor arrangements. The sensor unit comprises at least one, two or more flow cells; and each of the flow cells comprises one or more sensor arrangements.

Advantageously, the sensor arrangement comprises an electrochemical sensor or an optical sensor. The electrochemical sensor comprises one, two, three, four, five, six, seven, eight, nine, ten or more working electrodes.

In an advantageous embodiment, the sensor unit further comprises an electroanalytical component. The electroanalytical component is a potentiostat, coulometer or a voltmeter

In an alternative embodiment, the sensor arrangement is an optical sensor having a light source and a receiving unit.

In an advantageous embodiment, the sensing arrangement comprises a recognition substrate that has selective recognition of the analyte of interest. The recognition substrate binds to the analyte of interest directly or indirectly. The recognition substrate may bind to a converted product of the analyte of interest. Advantageously, the sensor arrangement may further comprise an immobilised enzyme reactor (IMER). The recognition substrate may be selected from an enzyme, an antibody, an aptamer, and/or material imprinted polymers (MIPS).

In an advantageous embodiment, the molecular exchange area is a fluid conduit having porous area. Advantageously, the molecular exchange area comprises at least one fluid passageway supported by a casing, and comprising at least one exchange aperture wherein a portion of at least one of the fluid passageways exposed by the exchange aperture is porous

In some aspects of the invention there are two or more fluid passageways. In some embodiments of the invention, the two or more fluid passageways each run from the inlet to the outlet of the molecular exchange area. One or more of the fluid passageways has an exchange aperture. In addition to or alternatively, one exchange aperture expose two or more fluid passageways and allows molecular exchange to occur from/to each of the fluid passageways.

In an alternative embodiment of the invention, the molecular exchange area is a molecular exchange device.

The molecular exchange device comprising a casing, extending from a proximal end to a distal end, supporting at least two fluid passageways extending from the proximal end to the distal end; the casing comprising at least one exchange aperture between the distal end and the proximal end, wherein a portion of the fluid passageway exposed by the exchange aperture is porous.

In an advantageous embodiment of the present invention, a separator extends along the casing for at least the length of the exchange aperture, separating the at least two fluid passageways. In a further advantageous embodiment, the separator extends along substantially the entire length of the casing, from the distal end to the proximal end, separating the at least two fluid passageways. Preferably, the separator extends along the central axis of the casing. The separator provides the advantage of ensuring that there is no exchange of fluid between two or more fluid passageways, thereby improving dialysis efficiency. The separator also provides support to the two or more fluid passageways, particularly at the porous portion of the passageway. The separator may or may not be integral with the casing.

Advantageously, the two fluid passageways may be arranged on aligning sides of the central separator. Advantageously, two or more fluid passageways may be arranged around the central separator. Preferably pairs of fluid passageways in fluid communication with one another may be arranged around the central separator to permit multiple sets of molecular exchange in one device. The molecular exchange may be for analysis, dialysis, delivery, recovery and extraction of substances etc.. During use in a subject, for example, one set of fluid passageways may deliver a drug to the external environment of the device, whereas another set of fluid passageway may be used for recovery, extraction or analysis of a substance from the environment surrounding the device into the passageway to measure the overall drug content. It is envisaged that each set of fluid passageways will be selected for a particular function.

In an advantageous embodiment the at least two fluid passageways are at least partially defined by the casing and/or separator. Alternatively, the at least two fluid passageways are not at least partially defined by the casing and/or separator. For example, the fluid passageways are at least one tube held within the casing. In one embodiment of the invention the porous region of the fluid passage way is a porous membrane bonded within the casing at the proximal and distal ends of the exchange aperture. Preferably, the at least one tube is a porous membrane. More preferably, the porous membrane is a dialysis membrane.

In an embodiment of the invention, substantially the entire area of the tube is porous. In this embodiment, the tube can be made of a single type of material, which obviates the need for forming a separate porous portion in the conduit adjacent to the exchange aperture and makes the molecular exchange device even cheaper to manufacture. This embodiment also provides the advantage that the porous portion does not need to be carefully aligned with the at least one exchange aperture of the casing. As the hollow tube is only exposed to the external environment at the exchange aperture of the casing, molecular exchange will only occur at these desired points of the casing.

In a preferred embodiment the at least one tube extends from the proximal end to the distal end of the casing, folds back on itself at the distal end and extends from the distal end to the proximal end of the casing, providing two fluid passageways.

Advantageously, the at least one tube has a circular or non-circular shaped cross section. This enables the hollow tube to be positioned in the correct orientation within the casing. For example, the cross section may have one or more straight edges or be D-shaped or be profiled to orientate the hollow tube in such a way as to optimise its efficiency for exchange.

In preferred embodiments the fluid may be supplied to one of the fluid passageways and drawn from other fluid passageway to ensure flow of fluid within the device.

Advantageously, the exchange aperture is an opening in the casing, preferably formed by removing, such as by cutting, an area of the casing. In an alternative embodiment, the exchange aperture is a porous area, preferably formed by treating the casing to render a portion of the casing porous.

In a preferred embodiment, more than one exchange aperture exposes the same fluid passageway.

In one embodiment, the porous portions of the more than one exchange aperture have different porosities. The porosity of each porous portion will depend upon the intended function of the specific porous portion.

In a preferred embodiment having two or more of fluid passageways or two or more porous portions on one fluid passageway, the porous portions have different porosities from one another. The use of porous portions and/or fluid passageways having different porosities enables different selections of molecular exchange at different exchange apertures along the casing.

For example, when the device is being used to deliver a drug into the bloodstream of a subject and monitor the concentration of the drug in the bloodstream, at least one porous portion will require a porosity that enables the drug to pass through the porous area into the bloodstream and at least one porous portion that has a porosity allowing the drug bound to a carrier, such as a plasma protein, for example albumin, to pass through the hollow area into the respective fluid passageway. The latter porous portion, located further downstream to other porous portion with respect to the flow of fluid within the at least two fluid passageways, will need to have a porosity that allows the passage of larger particles, i.e. the drug bound to a carrier as opposed to the drug alone. A skilled person will appreciate that the desired porosity of the porous portion of a fluid passageway will depend upon the size of the molecule that is intended to be exchanged across the porous portion adjacent to the exchange aperture. This arrangement will enable both the free (unbound to carrier) concentration and the total (unbound and bound to carrier) concentration of the drug to be determined.

In a preferred embodiment, the at least two fluid passageways have aligned exchange apertures. In use, an exchange aperture may rest against the internal walls of the vessel preventing access to the porous portion of the fluid passageway adjacent to the exchange aperture, as it is often the case that the device is not inserted into centre of the vessel. By providing aligned exchange apertures, it is more likely that at least one of the exchange apertures will be in contact with the flow of fluid within the vessel.

Alternatively, the exchange apertures may be positioned along the respective fluid passageway so that the apertures are not aligned. Such an arrangement is advantageous when the exchange apertures are intended to be used for different purposes.

In a preferred embodiment, the casing supports the at least two fluid passageways in the form of a tube, which are separated by the central separator along the length of the exchange aperture. The separator provides support to the tubing, whilst enabling a substantially large extent of exposure to the fluid passageway. In such an embodiment exchange of molecules may occur over substantially the entire circumference of the exposed tube, thereby providing a maximum surface area and increasing the efficiency of the exchange of molecules.

In a preferred embodiment, the at least two fluid passageways are held away from the separator in the porous section as a consequence of the hollow tubes being sealed where they enter and exit the porous section, thereby enabling substantially 100% of the circumference of the porous portion of the fluid passageway to be exposed. This provides the advantage of maximising the surface area of the porous region in contact with the environment external to the device. Preferably, the at least two fluid passageways are sealed by glue.

Advantageously, the distal end of the device comprises a plug in the end of the casing. More advantageously in this embodiment, the separator extends to the distal end of the casing and contains a fluid aperture to allow flow from one of the fluid passageway to another fluid passageway.

Alternatively, the distal end of the casing is formed as a tip containing a flow chamber to allow flow from the end of at least one of the fluid passageways into the end of another fluid passageway. Advantageously, the ends of the fluid passageways are within the flow chamber, such that any bond between the end of the fluid passageway and the distal end of the casing is remote from the exchange aperture to avoid fragmentation of the tube/porous membrane attached to the inside of the casing.

In an arrangement, the flow chamber has a sensor arrangement for detecting a substance. For example, the sensor arrangement is a fibre optic and a reflector, wherein the fibre optic and reflector are positioned at the distal end of the device to enable spectrological measurements, for example, spectrophotometric measurement. Alternatively the sensor arrangement is a wave guide, conductor, photoelectric, electro-active or electrochemical sensor.

In an advantageous embodiment, the fluid transported along the at least one of the fluid passageways carries a composition, such as a drug, to be delivered; and it is delivered via molecular exchange across the exchange aperture. However, in some embodiments, the molecular exchange device further comprises a channel leading from the proximal end of the casing to the distal end of the casing to provide additional materials to the interior and/or exterior of the distal end of the casing. Preferably, the channel is integral with the separator. More preferably, the channel is formed within the central axis of the separator.

The channel may supply fluid through to the distal end of the casing, in particular, into the flow chamber. In such an embodiment, the fluid can then pass into one or more of the fluid passageways. Of course, the reverse is possible, with fluids being passed along the fluid passageways into the distal end of the casing and then drawn out through the channel to the proximal end of the casing.

In an advantageous embodiment, the channel delivers a composition to activate a particular drug being administered by the device.

The channel may also be used to receive an additional component. For example, a guide wire may be inserted for positioning the molecular exchange device into the desired position within a subject. Advantageously, a probe may be provided within the channel, such as electrical, sonic or optical probes, that may be used for detection and/or analysis. In a preferred embodiment, the channel may be exposed to the environment external to the device, to enable such a probe to have direct contact with the external environment. For example, a fibre optic or light source could be provided at the distal end of the molecular exchange device to allow guidance of the device during insertion into a subject.

Preferably, the proximal end of the casing is adapted for attachment to a catheter or cannular, to accommodate insertion of the molecular exchange device into the subject. Insertion of the device using a catheter or cannular is a minimally invasive procedure.

More preferably, the proximal end of the casing is a lockable-mating arrangement or anchoring member for connecting to an invasive port. In a medical application, it is possible that the subject will already have an existing invasive port inserted. Therefore, preferably, the proximal end is a lockablemating arrangement or anchoring member for connecting to an existing invasive port, which reduces damage caused by insertion of the molecular exchange device into the subject.

More preferably, the proximal end of the casing is adapted for attachment to a pump. The pump allows fluid to be pumped into the fluid passageways and/or drawn from the fluid passageways, to ensure flow of the fluid through the device. Fluid may flow in both directions through the fluid passageways of the device. The intended use of the individual fluid passageway will determine whether the pump provides fluid flow through the fluid passageway in one direction or both directions. As will be appreciated, when the device has two or more of fluid passageways, the supply to and/or return of fluid from each of the fluid passageways will depend upon its required function.

Advantageously, the proximal end of the casing is adapted for attachment to an external device. More advantageously, the proximal end of the casing is adapted for attachment to two or more of external devices. The one or more external devices may be attached directly to the ends of the fluid passageways at the proximal ends of the device or indirectly attached to the fluid passageways via connecting tubing.

In a preferred embodiment, the external devices analyse the composition of the fluid drawn from one or more of the fluid passageways. Advantageously, the external device determines the presence of one or more molecules in the fluid from the fluid passageways and/or measures the amount/concentration of one or more molecules in the fluid. More advantageously, the external devices control delivery of a drug into the patient through the molecular exchange device.

In an advantageous embodiment, the device can provide a self-maintaining mechanism for drug delivery, to maintain the concentration of the drug at a predetermined level.

Advantageously, the systems further comprise a second receptacle. The second receptacle can be attached to the outlet port. A sensor unit may be positioned between the first receptacle and the molecular exchange area and/or a second sensor unit may be positioned between the molecular exchange area and the second receptacle.

In an advantageous embodiment, the receptacle comprises two compartments that are fluidly sealed from one another; each receptacle compartment contains a fluid and provides the fluid to the molecular exchange area of the system by the action of gravity. The compartments may be integral with one another or separate to one another. The first compartment contains a perfusion fluid and the second receptacle compartment contains oil.

The invention further provides a method of monitoring for the presence of a molecule, the method comprising providing a receptacle containing a fluid and adapted to allow the fluid to flow from the receptacle; providing a molecular exchange area; and providing a supply conduit defining a fluid path from the container to a molecular exchange area; wherein the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the outlet port by the action of gravity; and molecular exchange occurs across the molecular exchange area such that the presence of a molecule can be detected. The method can use any of the monitoring systems described herein.

The invention further provides a method of delivering a molecule, the method comprising providing a receptacle containing a fluid and adapted to allow the fluid to flow from the receptacle; providing a molecular exchange area; providing a supply conduit defining a fluid path from the container to a molecular exchange area; and providing an outlet conduit defining a fluid path from the molecular exchange area to an outlet port; wherein the receptacle is positioned above the supply conduit and molecular exchange area such that the fluid is transported from the receptacle to the molecular exchange area by the action of gravity; and molecular exchange occurs across the molecular exchange area to deliver a molecule. The method can use any of the delivery systems described herein.

Figures

In order that the present invention may be more readily understood, nonlimiting examples thereof will now be described, by way of example, with reference to the accompanying drawings.

Figure 1 is an overall illustration of a first embodiment of a monitoring system in accordance with the present invention;

Figure 2 is an overall illustration of a second embodiment of a monitoring system in accordance with the present invention, where the molecular exchange area is a molecular exchange device;

Figure 3 is an overall illustration of a first embodiment of a delivery system in accordance with the present invention;

Figure 4 is an illustration of a cut away view of a molecular exchange area in the form of a medical device;

Figure 5 is an illustration of a cut away view of a molecular exchange area;

Figure 6a and 6b are illustrations of a third embodiment of a monitoring system in accordance with the present invention, where the system comprises two receptacles, and two sensor units.

Specific description

In a first aspect of the invention, there is a monitoring system comprising a receptacle for containing a fluid and adapted to allow the fluid to flow from the receptacle by the action of gravity; a molecular exchange area; a supply conduit defining a fluid path from the receptacle to a molecular exchange area; and an outlet conduit defining a fluid path from the molecular exchange area to an outlet port, the outlet port adapted to be connected to a sensing arrangement; wherein, in use, the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the sensor unit by the action of gravity.

To achieve the flow of fluid through the system by the action of gravity, the receptacle providing the fluid to the rest of the system must be in an elevated position compared to the other components of the system. This would be appreciated by those of skill in the art.

Receptacle

The receptacle can be in any form that allows fluid to flow from the receptacle by the action of gravity. The receptacle could be a glass bottle, plastic bottle or a bag. The receptacle may be formed from an elastomeric material, such as rubber, plastic, silicon or other suitable material that can be filled with a volume of fluid. For example, the receptacle could be an elastomeric bag, such as standard fusion/IV bag that are normally utilised for intravenous medical use. Such bags are usually formed from two heat sealed sheets of an elastomeric material. If the receptacle is not formed from an elastomeric material, a vent will be required to equalise the pressure within the receptacle.

In an aspect of the invention, the receptacle is a closed receptacle. The receptacle may be prefilled and/or re-fillable. The receptacle may further comprise a valve that allows the receptacle to be refilled with fluid. The receptacle may be sterile or non-sterile depending on its intended utility. For a re-fillable receptacle, it may be necessary to control sterility in the environment in a different way.

In an aspect of the invention, the volume of the receptacle may be 0.0005 to 10 litres, 0.0005 to 0.75 litres, 0.25 to 8 litres, or 0.5 to 4 litres. The volume of the receptacle may be 0.005, 0.1,0.02, 0.05, 0.1,0.2, 0.25, 0.5, 0.75, 1,2, 3, 4, 5, 6, 7, 8, 9, 10 litres (I). The actual volume of the receptacle will depend on the intended utility of the device. For example, for drug delivery, a volume of 0. 5I may be sufficient. In contrast, for use on a production line to monitor analytes for quality control purposes a receptacle with a 2I volume may be appropriate.

The receptacle must be positioned above the molecular exchange area during use, to ensure that there is a proper elevation to provide consistent pressure for the supply of the fluid into the supply conduit. This allows the monitoring system to work by gravity feed of the fluid to the molecular exchange area.

In one aspect of the invention, the receptacle is positioned at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90 centimeters, 1, 2, 3, 4, 5, or more meters above the molecular exchange area.

The exact elevation of the receptacle with respect to the molecular exchange area will depend on many factors such as the cross-sectional area of the fluid path of the supply conduit, the thickness of the walls defining the fluid path of the supply conduit, the volume of the fluids being supplied and the desired flow rate of the fluid through the system/molecular exchange area. Moreover, the required elevation will depend on the intended utility of the monitoring system.

Stationary/portable device

In one aspect of the invention, the monitoring system may further include one or more attachments to hold one or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position. One of the attachments may hold two or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position relative to one or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position. Two or more attachments may hold two or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position with respect to one or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position.

The attachment may be a stand, pole, and/or wall mountable arrangement. The attachment, such as a stand, pole or wall mounted, may be moveable from one position to the other. The attachment, such as a stand or pole, may be extendable/retractable to allow the position of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit to be moved. For example, the receptacle may be held by an extendable/retractable attachment that changes the height of the receptacle with respect to the molecular exchange area. This arrangement would allow different flow rates to be achieved and/or accommodate different utilities of the monitoring system.

In some aspects of the invention, at least one of the one or more attachments is adapted to be portable from one location to different location. For example the attachment, such as a pole or a stand can be on wheels.

Flow rate

In one aspect of the invention, during use, it is preferable that the supply conduit is maintained in a fixed position to provide a constant perfusion rate. In some aspects of the invention, this is achieved by using an attachment, such as a pole or stand that maintains the position of the supply conduit during use.

In some aspects of the invention, the flow rate of the fluid through the molecular exchange area can be altered by constricting the receptacle. This creates a pressure within the receptacle and forces the fluid out of the receptacle. The receptacle may be constricted by hand and/or by placing a constriction element around the receptacle to create pressure within the receptacle.

In, some aspects of the invention, the flow rate of the fluid through the molecular exchange area can be altered by moving the height of the receptacle with respect to the molecular exchange device.

In some aspects of the invention, the flow rate can be altered by altering the size of the supply conduit.

In some aspects of the invention, the flow rate is 0.01 to 150pl/min and preferably 30 to 150pl/min. The flow rate may be 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5,

5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 150pl/min.

The supply and outlet conduits

The supply conduit defines a fluid path from the receptacle to a molecular exchange area. The outlet conduit defines a fluid path from the molecular exchange area to the outlet port. The supply and outlet conduits can be any arrangement that can carry fluid (by the action of gravity) from the receptacle to the molecular exchange area or the molecular exchange area to the outlet port. For example, the supply and/or outlet conduits may be in the form of tubing. The tube can have a uniform cross-section and/or uniform wall thickness. The tube can have a circular cross-section, or any other shaped cross-section that allows the passage of a fluid along the tubing. A tube with a circular cross section may, for example, have an internal diameter of 0.01 to 0.5 mm, or approximately 0.25mm. The internal diameter of the tubing may be 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5 mm. The tubing may have an external diameter of 0.02 to 7mm or approximately 1mm. The tubing may have an external diameter 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,

6.5, 7 mm.

In some aspects of the invention, the supply conduit and/or outlet conduit may be standard IV drip tubing.

In some aspects of the invention, the rate of flow of the fluid can be controlled by changing the internal cross-sectional area of the supply conduit. In an aspect of the invention, a plurality of supply conduits having different internal cross-sectional areas can be provided and/or utilised within the same monitoring system. This can be utilized alone to control the flow rate or in combination with the receptacle being constricted to create pressure within the receptacle, either by hand, placing a constriction element around the receptacle and/or or using an infusion pump to create pressure within the receptacle.

An adaptor may be provided that can allow supply conduits having different internal cross-sectional areas to be used with the same molecular exchange area of the monitoring system. For example the adaptor may be circular in shape with a plurality of openings around the external periphery of the adaptor. The adaptor can be rotated so that each of the openings is positioned over the inlet of the molecular exchange device, and a supply conduit having the desired cross-sectional area can be attached to the molecular exchange area via the adaptor.

In some aspects of the invention, the monitoring system may further comprise a valve arranged to occlude the supply conduit. The valve for example may be a roller valve or a pinch valve. When the valve is closed it occludes the supply conduit it prevents fluid being transported along the supply conduit to the molecular exchange device. When the valve is open it allows fluid to be transported from the receptacle to the sensor unit.

The supply conduit may have a first port connected to the receptacle and a second port. The second port may be used to introduce an additional fluid into the molecular exchange area.

Sensor unit

In some aspects of the invention, the sensor unit is positioned in an outlet of the outlet conduit, a container, for example a bucket or toilet bowl, and/or a sensor apparatus.

In some aspects of the invention, the analyte(s) to be detected and/or quantified may be detected on site (online). In addition to or alternatively, the analyte may be detected or quantified off site (offline). For example, the fluid may be collected in a container and taken to a laboratory for the analysis to be completed. It may be that the analysis is carried out online and offline for quality control purposes.

In the online arrangement, the sensor may be connected to the outlet port, or positioned between the molecular exchange area and the outlet port. In the latter arrangement the outlet conduit is in two parts; one part linking the molecular exchange area and the sensor unit, and the other part linking the sensor unit and the outlet port.

In some aspects, a second receptacle may be present after the online sensor unit, after the molecular exchange area, and/or a second sensor unit may be present before the molecular exchange area. In such an arrangement, there would exist a first receptacle to allow a fluid to flow through the first sensor unit, and then on to the molecular exchange area and from there through the second sensor unit and into a second receptacle. In such a manner, the presence of the analyte can be measured in the perfusate and dialysate and the difference between these two represents the effect of the environment. In such an arrangement, the flow can be reversed by lifting the second receptacle above the molecular exchange area, and lower the first receptacle to promote flow through the molecular exchange area by the action of gravity.

The arrangement having two sensor units can be utilised to determine the difference in the concentration of an analyte

In preferred embodiments of the invention, the sensor unit has a sensor arrangement. In some embodiments, the sensor unit comprises a flow cell having a sensor arrangement. In preferred embodiments, the sensor arrangement includes an electrochemical sensor or an optical sensor.

In one embodiment, the electrochemical sensor has a base material, such as a ceramic chip or a plastic polymer substrate, having at least two electrodes; a reference electrode and at least one working electrode. The sensor may also have one or more auxiliary electrodes.

The sensor may have two, three, four, five, six, seven, eight, nine, ten or more electrodes. For example, there may be a reference electrode, a working electrode, and optionally an auxiliary electrode. In a preferred embodiment, a working electrode may be used in conjunction with an auxiliary electrode, and a reference electrode in a three electrode system.

The reference electrode is an electrode which has a stable and well-known electrode potential; and establishes the electrical potential against which other potentials may be measured. The working electrode is the electrode on which the reaction of interest is occurring. The auxiliary electrode, along with the working electrode, provides a circuit over which current is either applied or measured. The potential of the auxiliary electrode is usually not measured and is adjusted so as to balance the reaction occurring at the working electrode. This configuration allows the potential of the working electrode to be measured against a known reference electrode without compromising the stability of that reference electrode by passing current over it. The auxiliary electrode can provide stability to the system.

There may be one, two, three, four, five, six, seven, eight, nine, ten or more working electrodes. The working electrode may comprise a gold, platinum, glassy carbon, or diamond doped carbon surface. A recognition substrate can be attached to the working electrode, either directly or indirectly; or positioned close by such that the electrode can register a change in the current due to the presence of the analyte of interest in the flow cell. Alternatively, no recognition substrate is attached to the working electrode and the surface of the electrode is oxidised by the analyte of interest and the change in current is registered. In this arrangement, a certain voltage can be applied to select for the analyte of interest.

The recognition substrate may be any substrate that has selective recognition for the analyte of interest (i.e. the analyte being detected). The recognition substrate may bind to the analyte of interest directly or indirectly. Alternatively, the recognition substrate may bind to a converted product of the analyte of interest. Again, the recognition substrate may bind to directly or indirectly to the converted product. The converted product may be produced by any means known in the art. In some embodiments, the sensor arrangement includes an immobilised enzyme reactor (IMER). The IMER acts to convert the analyte to an electroactive product that can be oxidised or reduced, which changes the current. The change in current can be detected and enables the presence and/or amount of analyte to be determined.

The recognition substrate can be selected from an enzyme, an antibody, an aptamer, and/or material imprinted polymers (MIPS). The recognition substrate can break away from the surface of the electrode, which can affect the sensitivity of the sensor. The sensor arrangement can be recalibrated by inserting a known concentration of the analyte (such as glucose), or a known concentration of the analyte can be inserted simply to determine that the sensor arrangement is functioning/working.

The enzyme is immobilised onto an electrode, and the function of the electrode is essentially connected with the catalytic activity of the immobilised enzyme. The electrochemical response of the electrode is based on the enzymic generation of electroactive species or on the electrochemical communication of the enzyme with the electrode. For example, in a glucose sensor, glucose oxidase is entrapped on the electrode by a dialysis membrane. The decrease in measured oxygen is proportional to the glucose concentration.

For repeated use of enzymes on such sensors, there are numerous techniques in the art for holding the enzymes in place such a providing a number of membrane layers.

In an alternative embodiment, the sensor arrangement may have one or more membrane layers on the surface of the working electrode to retain the recognition substrate in contact with the surface of the electrode. One, two, three, four, five, six, seven, or more membrane layers can be placed on top of the electrode surface. The recognition substrate is captured in the one or more layers of membrane. The membrane can act to retain the recognition substrate in place and prevent/reduce damage to the recognition substrate during use. The membrane can also act as a filter to ensure that only the desired analyte/converted product can contact the recognition substrate. The one or more layers may be cross-linked to the surface of the electrode. One or more of the layers may include a mediator material that enhances detection of the analyte. For example, if the analyte to be detected is glucose, the layer can include nation, which creates a charged surface that allows neutral substrates such as glucose to be absorbed, but repels charged substrates. In this arrangement, the sensor arrangement can also be recalibrated by inserting a known concentration of the analyte (such as glucose), or a known concentration of the analyte can be inserted simply to determine that the sensor arrangement is functioning/working.

In an alternative arrangement, glucose can be converted by glucose oxidase to produce hydrogen peroxide. The hydrogen peroxide can be converted by the voltage to produce hydrogen, oxygen and water. This can be achieved with a membrane arrangement on top of the working electrode, such that the first membrane provides a selective layer for selecting glucose from the perfusion fluid. The glucose binds to the recognition substrate, for example glucose oxidase, which is retained on a second membrane/layer. The glucose oxidase catalyses the oxidation of the glucose, and one of the resulting products is hydrogen peroxidase. The resulting hydrogen peroxidase passes to a third membrane/layer where it is oxidised at the working electrode by the current set by the potentiostat. The change in current is detected by the potentiostat. In this arrangement, the third membrane/layer is on top of the working electrode, the second membrane/layer is on top of the third layer, and the first membrane/layer is on top of the second membrane/layer. In this arrangement, the layers can be over one of the working electrodes only, or on top of some or all of the other electrodes.

The electrochemical sensor arrangement of the above embodiments must have a reference electrode and one or more working electrodes. The plurality of working electrodes can detect the same and/or different analytes. Each working electrode (and the reference and auxiliary electrodes) requires a channel connected to an electric connector that can be connected to an electrical connector of the monitoring unit. Each channel can connect to an individual electrical connector. Such sensors arrangements may be prepared using Thick-Film Technology for example. The sensor unit can have multiple sensor arrangements, channels and electric connectors.

In one arrangement the multiple sensors arrangements can detect different analytes. In another embodiment, some of the sensor arrangements detect different analytes and some of the sensors detect the same analyte. In another arrangement, the multiple sensor arrangements detect the same analyte. In embodiments where some or all of the sensor arrangements detect the same analyte, this embodiment can be utilised to determine if one of the sensor arrangements is not working properly. If all but one of the sensor arrangements provide the same result, then it can be determined that the sensor arrangement detecting a different result is not functioning correctly. This sensor arrangement can be ignored or turned off.

In the embodiments in which the sensor arrangement is an optical sensor, the sensor has a light source for emitting illuminating light, such as LEDs or OLEDs, and a light receiving unit, such as a photodiode which feeds back to a voltmeter. In these embodiments the electrical contact provides power for the setting of the voltage, provides power for the light source to emit light, and collects the information from the photodiode. The light source has a gating arrangement to achieve the desired wavelength for the analyte of interest. The gating arrangement zones out wavelengths not required. Alternatively, a laser can be used as the light source. Optical sensors have excellent long term stability. Optical sensors can be utilised in colorimetric assays.

In an advantageous embodiment, all or some of the flow cell containing the sensor arrangement is visible from the outside of the sensor unit. This means a visual check of the sensor arrangement can be made. Microfluidic devices, such as a flow cell, often have bubbles of gas travelling through the device. If such bubbles were to accumulate on the one or more of the electrodes and/or recognition substrates, it could affect the accuracy of the sensor arrangement. It will also be possible to visual any discoloration of the sensor arrangement that would suggest there is a problem with the sensor arrangement.

During use, a perfusion fluid is passed into the flow cell by the action of gravity feed unit. The fluid travels across the sensor arrangement, and the electrochemical or optical sensor detects any target analyte in the perfusion fluid.

The sensor unit can further comprise an electroanalytical component. In an alternative arrangement, the sensor unit can be electrically connected to a monitoring unit that comprises the electroanalytical component. In particular, the sensor unit may have an electrical contact for electrical communication with respective electrical contact of a monitoring unit. This data is transmitted to the monitoring unit via the respective first and second electrical contact of the sensing unit and the monitoring unit.

The electroanalytical component, such as a potentiostat or coulometer, determines the presence and/or amount of an analyte by measuring the potential and/or current in a sensor arrangement of the sensor unit containing the analyte. In a preferred embodiment, the electroanalytical component is a potentiostat.

A potentiostat is a device that controls the potential between two or more electrodes while measuring the resulting current flow. In the present invention, the electrodes form part of the sensor arrangement of the sensor unit.

In an embodiment of the present invention, the analyte binds to a recognition substrate on the electrochemical sensor arrangement, which results in a change in the current. The potentiostat records the change in current, which can be used to determine the presence of an analyte in the fluid sample passing though the sensor unit. The magnitude of the change in current can be used to determine the amount of the analyte present in the fluid sample passing through the sensor unit. Alternatively, a coulometer could be utilised. Coulometers determine the presence and/or amount of an analyte by measuring the electric charge (in coulombs) passing through an electrochemical sensor arrangement. The amount of the analyte present can be determined based on the amount of a substance that accumulates on the electrodes. Again, in the present invention the electrodes from which this measurement is taken form part of the sensor arrangement of the sensor unit.

In a preferred embodiment, the electroanalytical component is a potentiostat in the form of a PCB having electrical contact pads for connection with contact pads on the sensor unit. Data is cached onto EEPROM (Electrically

Erasable Programmable Read-Only Memory) unit. The data can be transmitted to an external control unit, such as a personal computer, tablet or smartphone. The data is transmitted wirelessly to the control unit, such as via Bluetooth® The external control unit allows data to be stored and analysed effectively, rapidly, and accurately. The sensor unit and/or the monitoring unit are powered by a rechargeable battery.

In an arrangement of the sensor unit having an optical sensor, the electroanalytical component is a voltmeter in the form of a PCB having electrical contact pads for connection with contact pads of the sensor unit. Data is cached onto EEPROM (Electrically Erasable Programmable ReadOnly Memory) unit. The data can be transmitted to an external control unit, such as a personal computer, tablet or smartphone. The data is transmitted wirelessly to the control unit, such as via Bluetooth®. The external control unit allows data to be stored and analysed effectively, rapidly, and accurately. The sensor unit and/or monitoring unit are powered by a rechargeable battery.

In an embodiment of the invention having the electroanalytical component in a monitoring unit, the monitoring unit can have a top and a bottom surface and a substantially perpendicular side surface extending from the top surface to the bottom surface; wherein the monitoring unit has a recess found in the bottom surface and the side surface so that a sensor unit can be received in the recess; and a retaining arrangement that prevents the sensor unit being unintentionally removed from the recess by being lifted directly away from the bottom surface of the recess and prevents the sensor being withdraw from the side surface of the recess; wherein the recess has a base wall and side walls that do not include any sharp internal angles so that all parts of the recess can be accessed and cleaned when the sensor unit is not positioned within the recess.

The arrangement of the recess being open on the bottom and the side surface, in combination with the recess having no internal angles, allows the device to be readily cleaned by manual cleaning such as wiping. This reduces the risk of contamination/cross-contamination and the costs associated with cleaning the device.

The recess is provided in the bottom and side surface of the two part moulding. The recess houses the electric contact pad of the monitoring unit, which provides the electrical connection to the electric contact pad of the sensor unit. The first and second electrical contacts of the two units are in direct contact with one another. In a preferred embodiment the electrical contact of the monitoring unit has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more electric connectors connected to the electroanalytical component.

The first electrical contacts of the monitoring unit are well known in the art, such as electrical connectors having male and female parts that connect to one another to establish electrical connection. Also known in the art are electric contacts in the form of a flat plate and/or a spring connector. In some embodiment, a single flat plate has one or more spring connectors for electrical connection with a respective electrical connector of the sensor unit or monitoring unit. In an arrangement with multiple electric connectors, each electrical connectors of the sensor unit can have a separate channel providing connection between each of the electrodes to an individual connector.

In an advantageous embodiment, the monitoring unit is formed of a two part moulding having a top surface, a bottom surface and a side surface extending between top and the bottom surfaces. The electronic components of the monitoring unit are fully encapsulated in the two part moulding to ensure that no fluid can ingress the unit, which mitigates cross-contamination. In a preferred embodiment, the casing provides a sealed unit. In such an arrangement, the unit cannot be opened without breaking the seal and damaging the unit.

In preferred embodiments, the width of the casing is from 50 to 100mm, and preferably 60 to 70mm; the depth of the casing is from 30 to 50mm, and preferably 40 to 45mm; and the height of the casing is from 4 to 8mm, and preferably 6 to 7mm. In preferred embodiments, the width of the recess is from 8 to 25mm, and preferably 11 to 20mm; the depth of the recess is from 12 to 20 mm, and preferably 14 to 16mm; and the height of the recess is from 3 to 5mm, and preferably 3 to 4mm.

The battery can be recharged using a standard external battery charger, such as a USB or microUSB connector. However, such connectors provide a cavity in the monitoring unit that cannot be readily cleaned. Therefore, alternative charging means are preferred, such as inductive charging or electrical contacts, connectable to a mains electrical charging unit, on the external surface of the monitoring unit. These arrangements allow the external surfaces of the monitoring unit to be cavity and crevice free.

In a preferred embodiment, the electrical contacts of the monitoring unit for connection to the battery charging unit are positioned in the recess. This arrangement means that the sensor unit cannot be held in the attached configuration with the monitoring unit when the battery is charging. This is advantageous when the sensor unit is connected to a molecular exchange device that is position in a human or animal subject. Hence, the battery cannot be charged when the monitoring system is being used, i.e. when the system is connected to a molecular exchange device positioned in a subject. This mitigates the small risk that a current could be passed down the perfusate fluid (a salt solution) that passes from the sensor unit to the molecular exchange device along microfluidic tubing, and into the subject.

The charging electrical contact of the battery can be one or more electrical connectors that form an electrical connection with respective one or more electric connectors of the electrical contact of the battery charging unit. The one or more electrical connectors of the monitoring unit for providing the electrical connection to the battery charging unit can be the same type of electrical connectors as the electrical connectors that provide electrical connection to the sensor unit. Alternatively, different types of electrical connectors can be utilised for each of these purposes. The monitoring unit may have a series of electrical connectors for electrical connection with the electrical connectors of the battery charging unit, and a further series of electrical connectors for electrical connection with the electrical connectors of the sensor unit.

In the embodiment in which the electrical contact of the monitoring unit for electrical connection to the battery charging unit are positioned in the recess, it is advantageous for the (first) electrical contact of the monitoring unit for electrical connection with the sensor unit to be positioned in the recess such that the (third) electrical contact of the battery charging unit will not pass over them when being position in the recess for charging the battery. This will mitigate the risk of the electrical contact of the battery charging unit providing a current to this electrical contact and causing damage.

In a preferred embodiment, the monitoring unit (third) electrical contact for the battery charging unit are positioned closer to the outer edge of the recess that the monitoring unit (first) electrical contact for the sensor unit. This arrangement means that the electrical contact of the battery charging unit will not need to pass over the monitoring unit (first) electrical contact when being placed into position in the recess for charging.

In an alternative arrangement, the monitoring unit (first) electrical contact for the battery charging unit are positioned on one side of the recess and the monitoring unit (third) electrical contact for the sensor unit are positioned on the other side of the recess; such that the electrical contact of the battery charging unit will not need to pass over the monitoring unit (first) electrical contact when being placed into position in the recess for charging.

In such arrangements, the battery charging unit can have a different configuration to the sensor unit. However, it is envisaged that the battery charging unit and the sensor unit will have similar shapes and configurations to ensure allow them to form similar cooperating attachment arrangements with the monitoring unit.

The battery charging unit can be fixed to a standard wall plug for charging. Alternatively, the battery charging unit can have a standard connection, such as a micro USB or USB socket for connection to a standard medical grade charger.

In an advantageous embodiment, the monitoring unit has an operating button to turn the unit on/off and/or control the stop/start of the electrochemical sensor. This arrangement provides an independent capability to test whether the monitoring unit is on/off. In a preferred embodiment, the button is position beneath an elastic membrane bonded to the casing of the monitoring unit, so that the button can be pressed without breaking the seal of the casing, i.e. prevent an access point for fluid to enter the unit and reduce the risk of crosscontamination. In a preferred embodiment, the operating button is position on the bottom surface of the monitoring unit to prevent unintended use.

In an alternative embodiment the monitoring unit is turned on/off and/or the electrochemical sensor is turned on/off remotely by a control unit that is wirelessly connected to the monitoring unit.

In an advantageous embodiment, the monitoring unit has a visible signal, such as one or more LEDs, and/or an audible signal that can indicate various aspects of the functioning of the device. The various aspects can be an indication that the monitoring unit and/or sensor unit is on or off, that the device is taking measurements, that the device is transferring data, that the device is transferring a data dump and/or that battery needs charged or is fully charged. The indication may distinguish between different levels of data transfer, i.e. the data is being transferred at different time intervals and/or amounts. For example, the indictor may indicate that the data is being transferred every two seconds or that five data points are being transferred every ten seconds. The visible signal for each indicator may be one or more of a different coloured LEDs and/or flashing LEDs, wherein the flashing LEDs have different flashing sequences.

The top surface of the monitoring unit may be a simple plastic surface, or it can be a display illustrating the results of the analysis.

Additional sensor unit and/or flow cells

In some embodiments, the monitoring system can have one or more sensor units; and each sensor unit can have one or more flow cells.

In an embodiment of the invention, the sensor unit has two flow cells. In this arrangement, the fluid is transported by gravity from the receptacle into the first flow cell and across the sensor arrangement(s). The fluid exiting the first flow cell is transported to the molecular exchange area. Within the molecular exchange area, there is a selective transfer of materials; and the perfusion fluid containing the selected materials will then be transported from the molecular exchange area to the second flow cell of the sensor unit. The fluid flows over the sensor arrangement(s) of the second flow cell. The fluid exiting the second flow cell can be collected in in a waste receptacle. In these embodiments, the electroanalytical component of the sensor unit (or a monitoring unit electrically connected to the sensor unit) can detect the difference in the readings of the target analyte(s) between the two flow cells. In these embodiments, the first flow cell and fluidic tubing should be sterile if the fluid is introduced into a human or animal subject when it flows through the molecular exchange area. The second flow cell and any fluidic tubing taking the fluid away from the molecular exchange device does not need to be sterile, provided the fluid will not be reintroduced into the first flow cell.

In an alternative embodiment, the monitoring system has two sensor units of the invention described herein. Each sensor unit can be in direct electrical contact with a monitoring unit as described above. Alternatively, each sensor unit can be in direct electrical contact with the same monitoring unit. In this arrangement, a first receptacle is fluidly connected to a first sensor unit, the first sensor unit is fluidly connected to a molecular exchange device as described above. Gravity transports the perfusion fluid from the first receptacle to the first sensor unit, and across the sensor arrangement(s). The fluid exiting the first sensor unit is then transported to the molecular exchange area by gravity. Within the molecular exchange area, there is a selective transfer of materials; and the perfusion fluid containing the selected materials will then be transported by gravity from the molecular exchange area to the second sensor unit. The fluid flows over the sensor arrangement(s) of the second sensor unit.

The first sensor unit will determine the amount of analyte present in the fluid before the fluid is reintroduced into the molecular exchange device, and the second sensor unit can detect the change in the amount with respect to the first sensor unit. The monitoring unit(s) can then look at the difference in the readings of the target analyte(s) between the two sensor units. This can provide a more sensitive reading.

Optionally, the fluid exiting the second sensor unit can be transported by gravity to a second receptacle. The second receptacle can be switched with the first receptacle (i.e. positioned at a height above the other components of the system). This arrangement allows the same perfusion fluid to be used.

In embodiments in which the molecular exchange area is positioned in a human or animal subject, the sensor unit and fluidic tubing must be sterile because the fluid is introduced into the subject when it flows through the molecular exchange area. The second sensor unit and any fluidic tubing need to be sterile, because it is being reintroduced into the first sensor unit.

It is advantageous to have a sensor unit that is releasable from the monitoring unit, it means that the sensor unit can be disposed of after a single use to mitigate any contamination, or it can be reused.

The flow cell of the sensor unit ensures that measurements can be derived from a flowing measurement driven by gravity, rather than through capillary action. This ensures that a continuous reading of the analyte concentration in a subject can be achieved if desired.

The main advantage provided by gravity feed of the fluid through the sensor unit avoids the need for a powered or motorized action to transport the fluid through the monitoring or deliver systems. This provides a simple and cost effective system, which does not require any additional arrangements to use the system. In particular, no expensive pumps, electricity, or other powered or motorized arrangements are required to transport fluid through the system. This simplifies the requirements and reduces the cost of manufacturing the system, and reduces the cost of running and maintaining the monitoring device. It can also improve the safety of the system.

Continuous monitoring includes continuous measurements being taken, or measurements taken at regular intervals. For example, continuous monitoring may mean that measurements are taken every 30 seconds, one minute, two minutes, etc. In some embodiments, the measurements will be taken at regular intervals with a flushing of the sensor between some or all of the measurements.

In an embodiment of the delivery system, a sensor unit is positioned after the molecular exchange area. A known concentration of a composition, such as a drug, can be introduced into the receptacle. The composition is carried from the receptacle to the drug via the supply conduit. The composition is then delivered across the molecular exchange area. The sensor unit can measure the amount of the composition in the fluid being carried from the molecular exchange area. The difference between the measure amount and the known concentration of the composition can be utilised to determine the amount of the composition that has been delivered.

Molecular exchange area

The molecular exchange area is any arrangement that enables the selective exchange of material from a subject. For example, the molecular exchange area may be a fluid conduit having porous area across which selective molecular exchange can take place. This may be a hollow fibre in a casing having a porous area. Alternatively, the molecular exchange area may be part of a molecular exchange device, such as the device described in PCT publication W02008038015. The molecular exchange device is a device that is implanted in a subject, which selects exchange material from the subject. When the subject is a human or animal, the molecular exchange device is a sterile device. The exchange material passes may pass over a porous area of the molecular exchange device. The selected exchange material may include the target analyte(s).

The sensor unit is connected to the molecular exchange device via a fluidic connection, such as tubing. The sensor unit is not inserted into the subject, which means that it can be non-sterile. During use, the perfusate fluid, transporting the selected exchange material, travels from the molecular exchange device into the sensor unit, such as a flow cell, such that the fluid passes over one or more sensor arrangements.

The selected exchange material may include solute fractions present in blood that have diffused across the semi-permeable membrane of the molecular exchange device.

In some aspects of the invention, the molecular exchange area comprises at least one fluid passageway supported by a casing, and comprising at least one exchange aperture wherein a portion of at least one of the fluid passageways exposed by the exchange aperture is porous.

The casing supports and protects the fluid passageways. The casing further ensures that the porous portion of the passageway will not fragment in use, whilst ensuring that the passageway maintains its shape and maximises the flow of fluid therein.

The inlet to the molecular exchange area is attached to the supply conduit and the outlet of the molecular exchange area is attached to the outlet conduit.

In an advantageous embodiment of the invention, the molecular exchange area is a hollow fibre in a casing having a porous area along the casing.

In a preferred embodiment of the invention, the at least two fluid passageways are held away from the separator in the porous section as a consequence of the hollow tubes being sealed where they enter and exit the porous section, thereby enabling substantially 100% of the circumference of the porous portion of the fluid passageway to be exposed. This provides the advantage of maximising the surface area of the porous region in contact with the environment external to the device. Preferably, the at least two fluid passageways are sealed by glue.

In an advantageous embodiment, the fluid transported along the at least one of the fluid passageways carries a composition, such as a drug, to be delivered; and it is delivered via molecular exchange across the exchange aperture. Advantageously, the molecular exchange device further comprises a channel leading from the proximal end of the casing to the distal end of the casing to provide additional materials to the interior and/or exterior of the distal end of the casing. Preferably, the channel is integral with the separator. More preferably, the channel is formed within the central axis of the separator.

Fluid

The monitoring and delivery systems have a fluid path from the receptacle to the supply conduit, into the molecular exchange area, into the outlet conduit to the sensor unit.

For molecular exchange a perfusion fluid is used. A perfusion fluid may be a sterile and/or isotonic fluid. The exact form of the perfusion fluid will depend upon the intended use of the system.

One benefit of using molecular exchange utilising perfusion fluid in the monitoring system is that it is a transparent/clear fluid. This enables analytes to be drawn from the external environment and collected in the sensor unit. The analyte can then be detected and/or quantified by standard colour change technology. This is advantageous when the analyte has been taken from a coloured fluid, such as blood, when such standard colour change tests could not be utilised.

In another arrangement of the invention, the system has a receptacle having first and second compartments which are fluidly sealed from one another; each compartment contains a fluid and provides the fluid to the molecular exchange area of the system by the action of gravity. The compartments can be integral with one another or separate to one another. The first compartment contains a perfusion fluid and the second compartment contains oil. In this arrangement, the flow rate of each fluid is controlled so that each fluid is introduced as continuously flowing droplets. Each fluid droplet has a fixed volume. The fluids have a reciprocal arrangement that allows them to feel into the molecular exchange device and subsequently the sensor unit in a desired arrangement, i.e. one droplet of oil followed by one droplet of perfusion fluid etc. This arrangement disperses the perfusion fluid and allows rapid detection of an analyte in the perfusion fluid. Alternating aqueous and oil droplets allows for sample segregation and later on allows reaction substances to the added to one or other drop so, for example, a colour reaction can occur and be detected by an optical system.

Additional receptacles

In some embodiments, the monitoring system further comprises one or more additional receptacles. In a preferred arrangement, the monitoring system has two receptacles. The first receptacle contains a fluid and is adapted to allow the fluid to flow from the first receptacle to a molecular exchange area, via the supply conduit; and from the molecular exchange area to the second receptacle, via the outlet conduit. The second receptacle is connected to the outlet port. The first receptacle is positioned above the supply conduit, molecular exchange area, outlet conduit, and second receptacle such that the fluid is transported from the first receptacle to the second receptacle by the action of gravity. In an alternative arrangement, the second receptacle is positioned above the supply conduit, molecular exchange area, outlet conduit, and first receptacle such that the fluid is transported from the second receptacle to the first receptacle by the action of gravity. The elevation of first and second receptacles can be switched between the two arrangements.

In an advantageous arrangement, the system further comprises a first and second sensor unit. The first sensor unit position between the first receptacle and molecular exchange area. The second sensor unit position between the molecular exchange area and the second receptacle. The first sensor detects one or more analytes present in the fluid transported from the first receptacle to the molecular exchange device; or the fluid transported from the molecular exchange area to the first receptacle. The second sensor detects one or more analytes present in the fluid transported from the molecular exchange area to the second receptacle; or the fluid transported from the second receptacle to the molecular exchange device.

In the molecular exchange area, selective transfer of materials can occur across the porous area. In the arrangement in which the first receptacle is elevated, the first sensor unit determines the amount of analyte present in the fluid before the fluid is introduced into the molecular exchange area, and the second sensor unit determines the amount of analyte present in the fluid after the fluid has travelled through the molecular exchange area. The difference in the readings of the target analyte(s) between the two sensor units can be utilised to determine the change in the amount of the analyte.

In the arrangement in which the first receptacle is elevated, i.e. the second receptacle has been switched with the first receptacle, the second sensor unit determines the amount of analyte present in the fluid before the fluid is introduced into the molecular exchange area, and the second sensor unit determines the amount of analyte present in the fluid after the fluid has travelled through the molecular exchange area. The difference in the readings of the target analyte(s) between the two sensor units can be utilised to determine the change in the amount of the analyte.

This arrangement allows the same fluid to be utilised to monitor a change in the amount of an analyte in the subject in which the molecular exchange area is positioned.

In some embodiments, the system can comprise additional receptacles that the collect the fluid that has been transported through the system. The receptacle can then be removes so that the collected fluid can be analysed and/or otherwise disposed of.

Examples of use

The monitoring system of the invention, as described above, can be utilized in a wide variety of environments and for a wide number of purposes.

The monitoring system of the invention can be used to analyze water quality, for example in a factory setting. The factory water, for example, can switch from hard to soft, which may require changes to other parameters within the factory. It is known to use water cartridges to control the amount of calcium in water. Water cartridges are expensive and are thrown away after a defined volume (for example, 10,000 litres) of water have gone through them. This safety mechanism ensures that the filter is thrown away before it stops functioning correctly. To get as much use out of the filter as possible, the monitoring system of the invention can be used to measure the amount of calcium in the water that has passed through the filter. If the amount of calcium increases, this indicates that the filter is not functioning correctly and the filter can be replaced. This allows an accurate assessment of the functioning of the filter rather than a simply basing it on the volume of water that has flown through the filter. The monitoring system of the invention may also be used to detect a faulty filter, so it can be fixed or replaced.

The delivery system of the invention can be used to deliver perfusion drugs to a human or animal subject. This is of maximum benefit in situations when a pump to deliver a perfusion drug is too expensive and./or there is no power to drive the pump.

The delivery system of the invention can be used to deliver drugs into solid tumour. The selective transfer of the drug into the tumour can reduce the potential damage caused to cells in the surrounding environment.

The monitoring system of the invention can be used for quality control purposes, for example on a production line in a factory or other environment. The monitoring system can detect and/or quantify the amount of any substance that can cross membrane. For example, in a production line utilizing milk, the monitoring system can be uses to detect the lactate concentration to ascertain if the milk has gone off.

The monitoring system of the invention can be used to determine if a cow, or other milk producing mammal, is pregnant. The monitoring system can measure leutinising hormone in combination with estradiol in cow’s milk to determine if the cow is pregnant. This is currently achieved by taking a blood sample. The molecular exchange area of the monitoring system of the invention can be dipped into the milk to be tested.

The monitoring system of the invention can be used in a medical/domestic facility. For example, the monitoring system can be used to detect for the presence of an analyte in urine. In this arrangement, the molecular exchange area can be positioned in the toilet bowl (or other container) and the sensor unit and/or monitoring unit can wirelessly transmit the data to an external control unit, such as via Bluetooth©. The external control unit, such as a mobile phone, may be programmed to turn the sensor and/or monitoring unit on when it is in close proximity. The perfusate fluid is well buffered so flushing or cleaning the toilet bowl will have no detrimental effect to the molecular exchange. For example, the monitoring system can be used to test for diabetes or pregnancy. When testing for diabetes, for example in a diabetes clinic, the analyte detected by the sensor unit is glucose. When testing for pregnancy, for example in a doctors’ surgery, maternity unit or in at home, the analyte to be detected is beta subunit of human chorionic gonadotropin; or leutinising hormone in combination with estradiol.

The monitoring system of the present invention can also be used for a colorimetric assay to detect an analyte present in a non-transparent fluid. Colorimetric assays use reagents that undergo a measurable color change in the presence of the analyte. However, colorimetric assays cannot usually be used if the analyte is present in a non-transparent fluid, because the colour change may not be visible. For example, a colour change cannot readily be determined when the fluid is liquid or blood. However, perfusion fluid is transparent, si the analyte of interest can be selected from the subject and a colorimetric assay can be used. Colorimetric tests are well known in the art. These could be used to test for toxicity, such as aspirin or paracetamol, present in blood or urine, or simply used in a setting where there is not sufficient funding for a pump or battery, such as a developing country.

The delivery system can be used to deliver any components, such as a drug, to the environment in which the molecular exchange area is positioned.

Examples

As illustrated in figure 1, there is a first embodiment of a monitoring system (1) comprising a receptacle (2) for containing a fluid and adapted to allow the fluid to flow from the receptacle (2); a molecular exchange area(4); a supply conduit (3) defining a fluid path from the receptacle (2) to a molecular exchange area (4); and an outlet conduit (5) defining a fluid path from the molecular exchange area (2) to an outlet port (6), the outlet port (6) adapted to be connected to a sensor unit; wherein, in use, the receptacle (2) is positioned above the supply conduit (3), molecular exchange area (4), and outlet conduit (5) such that the fluid is transported from the receptacle (2) to the sensor unit by the action of gravity.

In use, fluid contained in the receptacle (2) will be transported to the supply conduit, by the action of gravity, to provide a continuous flow of fluid to the molecular exchange area. The molecular exchange area has an exchange aperture (7) having a porous membrane across which the analyte to be detected will cross from the external environment into the molecular exchange area. The fluid will be transported from the molecular exchange area (4) to the outlet (6) of the outlet conduit (5), and into the sensor unit. The sensor unit may be any form of arrangement that enables detection of the analyte.

As illustrated in figure 2, there is a second embodiment of a monitoring system where the molecular exchange area (4) is in the form of a molecular device. The monitoring system (1) comprises a receptacle (2) for containing a fluid and adapted to allow the fluid to flow from the receptacle (2) by the action of gravity; a molecular exchange area(4); a supply conduit (3) defining a fluid path from the receptacle (2) to a molecular exchange area (4); and an outlet conduit (5) defining a fluid path from the molecular exchange area (2) to an outlet port (6), the outlet port (6) adapted to be connected to a sensor unit; wherein, in use, the receptacle (2) is positioned above the supply conduit (3), molecular exchange area (4), and outlet conduit (5) such that the fluid is transported from the receptacle (2) to the sensor unit by the action of gravity.

The molecular exchange area in the form of a device has a casing (14) supporting two fluid passageways (13a, 13b) extending from the proximal end to the distal end; two aligned exchange apertures, between the proximal end and the distal end of the casing, exposing the fluid passageways (13a, 13b). The portion of the fluid passageways (13a, 13b) exposed by the opposed exchange apertures are porous. The fluid passageways (13a, 13b) provide a single path of fluid through the device.

In use, fluid contained in the receptacle (2) will be transported to the supply conduit by the action of gravity to provide a continuous flow of fluid to the molecular exchange area. The fluid flows from the supply conduit (3) into the fluid passageway (13a) from the proximal end to the distal end; and returns from the distal end to the proximal end through fluid passageway (13b) to the outlet conduit (5).

The molecular exchange device has an exchange aperture (7a, 7b) that expose the fluid passageways (13a, 13b) across which the analyte to be detected will cross from the external environment into the molecular exchange area (2). The fluid will be transported from the molecular exchange area (4) to the outlet (6) of the outlet conduit (5), and into the sensor unit. The sensor unit may be any form of arrangement that enables detection of the analyte.

As illustrated in figure 3, there is a first embodiment of a delivery system (12) comprising a receptacle (2) for containing a fluid and adapted to allow the fluid to flow from the receptacle (2) by the action of gravity; a molecular exchange area (4); and a supply conduit (3) defining a fluid path from the receptacle (2) to a molecular exchange area (4); wherein, in use, the receptacle (2) is positioned above the supply conduit (3) and molecular exchange area (4) such that the fluid is transported from the receptacle (2) to the sensor unit by the action of gravity.

In use, fluid contained in the receptacle (2) will be transported to the supply conduit by the action of gravity to provide a continuous flow of fluid to the molecular exchange area. The molecular exchange area has an exchange aperture (7) across which the substance to be delivered will cross from molecular exchange area into the external. The exchange aperture (7) is porous to allow the transfer of a substance from the molecular exchange area (4) into the external environment.

Figure 4 illustrates an embodiment of a molecular exchange area in the form of a device that may be part of the monitoring system or the delivery system discussed above. The molecular exchange device has a casing (14) supporting two fluid passageways (13a, 13b) extending from the proximal end to the distal end; two aligned exchange apertures, between the proximal end and the distal end of the casing, exposing the fluid passageways (13a, 13b). The portion of the fluid passageways (13a, 13b) exposed by the opposed exchange apertures are porous. The fluid passageways (13a, 13b) provide a single path of fluid through the device.

Figure 5 illustrates an embodiment of a molecular exchange area that may be part of the monitoring system or the delivery system discussed above. The molecular exchange device has a casing (14) supporting a fluid passageways (13) extending through the molecular exchange area, such that one end can connect to the supply conduit and the other end can connect to the outlet conduit; and an exchange aperture exposing the fluid passageway (13). The portion of the fluid passageway (13) exposed by the opposed exchange apertures are porous. The fluid passageway (13) provides a single path of fluid through the molecular exchange area.

Figure 6 and figure 6b illustrates an embodiment of the monitoring system (1) comprising a first receptacle (2) for containing a fluid and adapted to allow the fluid to flow from the receptacle (2); a molecular exchange area(4); a supply conduit (3) defining a fluid path from the receptacle (2) to a molecular exchange area (4); and an outlet conduit (5) defining a fluid path from the molecular exchange area (2) to an outlet port (6), the outlet port (6) connected to a second receptacle (8). There is a first sensor unit (9) connected to a monitoring unit (not shown), which is positioned between the first receptacle (2) and the molecular exchange area (4); connected via the supply conduit (3). There is a second sensor unit (10) connected to a monitoring unit (not shown), which is positioned between the molecular exchange area (4) and a second receptacle (8); connected via the outlet conduit (5). The second receptacle (8) is attached to the outlet port (6).

In the arrangement shown in figure 6a, the first receptacle (2) is in an elevated position with respect to the other components of the system. The fluid can flow from the first receptacle (2) along the supply conduit (3), through the sensor unit (9), and from the first sensor unit (9) to the molecular exchange area (4) via the supply conduit (3); through the molecular exchange area (4); where selective transfer of materials can occur across the porous exchange aperture (7); and the fluid containing the selected materials is then taken through the second sensor unit (10) to the second receptacle (8) via the outlet conduit (5). The transport of the fluid is driven by gravity.

In the arrangement of figure 6a, the first sensor unit (9) determines the amount of analyte present in the fluid before the fluid is introduced into the molecular exchange area (4), and the second sensor unit (10) determines the amount of analyte present in the fluid after the fluid has travelled through the molecular exchange area (4). The difference in the readings of the target analyte(s) between the two sensor units (9; 10) can be utilised to determine the change in the amount of the analyte.

In the arrangement shown in figure 6b, the second receptacle (8) has been switched with the first receptacle (2), in that the second receptacle (8) is in an elevated position with respect to the other components of the system. The same fluid can flow from the second receptacle (8) along the outlet conduit (5) (acting as a supply conduit), through the second sensor unit (10), and from the sensor unit (10) to the molecular exchange area (4) via the outlet conduit (5); through the molecular exchange area (4), where selective transfer of materials can occur across the porous exchange aperture (7); and the fluid containing the selected materials is then taken through the first sensor unit (9) to the first receptacle (2) via the inlet conduit (3) (acting as an outlet conduit). The transport of the fluid is driven by gravity.

In the arrangement of figure 6b, the second sensor unit (10) determines the amount of analyte present in the fluid before the fluid is introduced into the molecular exchange area (4), and the second sensor unit (9) determines the amount of analyte present in the fluid after the fluid has travelled through the molecular exchange area (4). The difference in the readings of the target analyte(s) between the two sensor units (10; 9) can be utilised to determine the change in the amount of the analyte. This arrangement allows the same fluid to be utilised to monitor a change in the amount of an analyte in the subject in which the molecular exchange area (4) is positioned.

When used in this specification and claims, the terms comprises and there 5 is a selective transfer of materials; and the perfusion fluid containing the selected materials will then be transported by gravity from comprising and variations thereof mean that the specified features, steps or integers are included. The terms are not to be interpreted to exclude the presence of other features, steps or components.

The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

Claims

1. A monitoring system comprising:

a receptacle for containing a fluid and adapted to allow the fluid to flow from the receptacle;

a molecular exchange area;

a supply conduit defining a fluid path from the container to a molecular exchange area; and an outlet conduit defining a fluid path from the molecular exchange area to an outlet port, the outlet port adapted to be connected to a sensor unit;

wherein, in use, the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the sensor unit by the action of gravity.

2. A delivery system comprising:

a receptacle for containing a fluid and adapted to allow the fluid to flow from the receptacle on drop at a time;

a molecular exchange area; and a supply conduit defining a fluid path from the container to a molecular exchange area;

wherein, in use, the receptacle is positioned above the supply conduit and molecular exchange area such that the fluid is transported from the receptacle to the molecular exchange area by the action of gravity.

3. A system according to any one of claims 1 to 2, wherein the volume of the receptacle may be 0.0005 to 10 litres, 0.0005 to 0.75 litres, 0.25 to 8 litres, or 0.5 to 4 litres.

4. A system according to any one of claims 1 to 3, wherein the volume of the receptacle may will be 0.005, 0.1,0.02, 0.05, 0.1,0.2, 0.25, 0.5, 0.75, 1,2,3, 4, 5, 6, 7, 8,9,10 litres.

5. A system according to any one of the preceding claims, wherein the receptacle is positioned at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50 60, 70, 80, 90 centimetres, 1,2, 3, 4, 5, or more meters above the molecular exchange area.

6. A system according to any one of the preceding claims, further comprising one or more attachments to hold one or more of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit in position.

7. A system according to claim 6, wherein the attachment is a stand, pole, and/or wall mountable arrangement.

8. A system according to any one of claims 6 to 7, wherein the attachment is extendable and/or retractable to move the position of the receptacle, supply conduit, molecular exchange area, outlet conduit and/or the sensor unit.

9. A system according to any one of the preceding claims, further comprising one or more means to control the flow rate.

10. A system according to claim 9, wherein the means are selected from: a constriction element; moving the height of the receptacle with respect to the molecular exchange area; altering the size of the supply conduit, altering the internal cross-sectional area of the supply conduit.

11. A system according to claim 9, wherein the means are an adaptor that changes the size of the internal cross-sectional area of the supply conduit.

12. A system of any preceding claim, wherein the flow rate is 0.01 to 150pl/min and preferably 30 to 150pl/min. The flow rate may be 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5,

4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50,

55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135,

140, 145 150pl/min

13. A system of any preceding claim, wherein the supply conduit and/or the outlet conduit is in the form of tubing.

14. A system of any preceding claim, wherein the tube has a uniform cross-section and/or uniform wall thickness.

15. A system of any one of claims 13 to 14, wherein the tube has a circular cross-section; and optionally has an internal diameter of 0.01 to 0.5 mm, or 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5 mm; and /or an external diameter of 0.02 to 7mm, or 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2,

2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mm.

16. A system according to any one of the preceding claims, further comprising a sensor unit.

17. A system according to claim 16, wherein the sensor unit comprises one, two, three, four, five, six, seven, eight, nine or more sensor arrangements.

18. A system according to any one of claims 16 to 17, wherein the sensor unit comprises at least one, two or more flow cells; and each of the flow cells comprises one or more sensor arrangements.

19. A system according to any one of claims 17 to 18, wherein the sensor arrangement comprises an electrochemical sensor or an optical sensor.

20. A system according to claim 19, wherein the electrochemical sensor comprises one, two, three, four, five, six, seven, eight, nine, ten or more working electrodes.

21. A system according to any one of claims 16 to 20, wherein the sensor unit further comprises an electroanalytical component.

22. A system according to any one of claim 21, wherein the electroanalytical component is a potentiostat, coulometer or a voltmeter

23. A system according to claim 19, wherein the sensor arrangement is an optical sensor having a light source and a receiving unit.

24. A system according to any one of claims 17 to 23, wherein the sensing arrangement comprises a recognition substrate that has selective recognition of the analyte of interest.

25 A system according to claim 24, wherein the recognition substrate binds to the analyte of interest directly or indirectly.

26. A system according to claim 25, wherein the recognition substrate binds to a converted product of the analyte of interest.

27. A system according to any one of claims 16 to 26, wherein the sensor arrangement further comprises an immobilised enzyme reactor (IMER).

28. A system according to claim 25, wherein the recognition substrate is selected from an enzyme, an antibody, an aptamer, and/or material imprinted polymers (MIPS).

29. A system according to any one of the preceding claims, wherein the molecular exchange area is a fluid conduit having porous area.

30. A system according to any one of the preceding claims, wherein the molecular exchange area comprises at least one fluid passageway supported by a casing, and comprising at least one exchange aperture wherein a portion of at least one of the fluid passageways exposed by the exchange aperture is porous

31. A system according to any one of the preceding claims, further comprising a second receptacle.

32. A system according to claim 31, wherein the second receptacle is attached to the outlet port

33. A system according to any one of claims 31 to 32, further comprising a sensor unit positioned between the first receptacle and the molecular exchange area and/or a second sensor unit positioned between the molecular exchange area and the second receptacle.

34. A system according to any one of the preceding claims, wherein the receptacle comprises two compartments that are fluidly sealed from one another; each receptacle compartment contains a fluid and provides the fluid to the molecular exchange area of the system by the action of gravity.

35. A system according to claim 34, wherein the compartments are integral with one another or separate to one another.

36. A system according to any one of claims 34 to 35, wherein the first compartment contains a perfusion fluid and the second receptacle compartment contains oil.

37. A method of monitoring for the presence of a molecule, the method comprising:

providing a receptacle containing a fluid and adapted to allow the fluid to flow from the receptacle;

providing a molecular exchange area; and providing a supply conduit defining a fluid path from the container to a molecular exchange area;

wherein the receptacle is positioned above the supply conduit, molecular exchange area, and outlet conduit such that the fluid is transported from the receptacle to the sensor unit by the action of gravity; and molecular exchange occurs across the molecular exchange area such that the presence of a molecule can be detected.

38. A method of claim 37, wherein the method uses the system of any one of claims 1 and 2 to 36.

39. A method of delivering a molecule, the method comprising: providing a receptacle containing a fluid and adapted to allow the fluid to flow from the receptacle;

providing a molecular exchange area;

providing a supply conduit defining a fluid path from the container to a molecular exchange area; and providing an outlet conduit defining a fluid path from the molecular exchange area to an outlet port;

5 wherein the receptacle is positioned above the supply conduit and molecular exchange area such that the fluid is transported from the receptacle to the molecular exchange area by the action of gravity; and molecular exchange occurs across the molecular exchange area to deliver a molecule.

10

40. A method of claim 39, wherein the method uses the system of any one of claims 2 to 36.

Intellectual

Property

Office

Application No: GB1704300.1 Examiner: Laura Goacher