HK1152214A - Gas sensor - Google Patents

Description

Gas sensor

The present invention relates to sensors for detecting gaseous substances, in particular for detecting substances present in a gas stream exhaled by a patient or subject. The sensor is particularly suitable for, but not limited to, analysis of carbon dioxide and/or water content of a gas stream. The sensor finds particular use as a capnographic sensor (capnographic sensor) for detecting and measuring the concentration of a gas, such as carbon dioxide, in exhaled breath of humans and animals, thereby providing an indication of the respiratory condition of a patient or subject and aiding in the identification and diagnosis of a respiratory disorder or disease. In a particularly preferred embodiment, the sensor is used to determine the water vapour content of the airflow exhaled by the subject and the results thereof are used to indicate the lung function of the subject.

Analysis of carbon dioxide content of exhaled breath from humans or animals is a valuable tool for assessing the health of a subject. In particular, the measurement of carbon dioxide concentration allows to assess the extent and/or progression of various pulmonary and/or respiratory diseases, in particular asthma and Chronic Obstructive Pulmonary Disease (COPD).

Carbon dioxide can be detected using a variety of analytical techniques and instruments. The most practical and widely used analyzer uses spectroscopic infrared absorption (spectroscopic infra-red absorption) as a detection method, but can also detect gases using mass spectrometry, gas chromatography, thermal conductivity, and the like. Although most analytical instruments, techniques and sensors for carbon dioxide measurement are based on the physicochemical properties of the gas, new techniques utilizing electrochemistry are being developed and a class of electrochemical methods has been proposed. However, direct electrochemical techniques for measuring carbon dioxide (CO) have not been available₂) Gas dissolution of the gas in the electrolyte and subsequent change in electrolyte pH, an indirect method was devised. Other electrochemical methods utilize high temperature catalytic reduction of carbon dioxide. However, these methods are often very expensive, inconvenient to use and often exhibit very low sensitivity and slow response times. These disadvantages render them inadequate for the analysis of breath samples, particularly in tidal breathing (tidal breathing) analysis.

A more recently adopted technique consists in monitoring specific chemical reactions in an electrolyte containing suitable organometallic ligands that chemically interact after pH changes caused by the dissolution of carbon dioxide gas. The pH change then disturbs a series of reactions and then indirectly estimates the carbon dioxide concentration in the atmosphere from the change in acid-base chemistry.

Carbon dioxide is an acid gas and interacts with water and other (protic) solvents. For example, carbon dioxide is dissolved in an aqueous solution according to the following reaction:

it is understood that as more carbon dioxide dissolves, hydrogen ions (H) are dissolved⁺) The concentration of (c) is increased.

The detection of carbon dioxide using this technique has the following disadvantages: when used for gas analysis in the gas phase, the liquid electrolyte must be bounded by a semi-permeable membrane. The membrane is impermeable to water but permeable to various gases including carbon dioxide. The membrane must reduce evaporation of the internal electrolyte without seriously hindering carbon dioxide gas permeation. The result of this configuration is an electrode that works well for a short period of time, but has a long response time and in which the electrolyte needs to be refreshed often.

WO 04/001407 discloses a sensor comprising a liquid electrolyte held by a permeable membrane which overcomes some of these disadvantages. However, it would be highly desirable to provide a sensor that does not rely on the presence and retention of a liquid electrolyte.

US 4,772,863 discloses a sensor for oxygen and carbon dioxide gas having a plurality of layers including an alumina substrate, a source of an anionic reference electrode, a lower electrical reference electrode of platinum connected to the anionic reference electrode, a solid electrolyte containing tungsten and connected to the lower reference electrode, a buffer layer for preventing the flow of platinum ions into the solid electrolyte, and an upper electrode for catalysing platinum.

GB2,287,543 a discloses a solid electrolyte carbon monoxide sensor having a first chamber formed in a substrate, the first chamber communicating with a second chamber in which a carbon monoxide adsorbent is located. The electrode detects the oxygen partial pressure in the carbon monoxide adsorbent. The sensor of GB2,287,543 is very sensitive to prevailing temperatures and can only measure low concentrations of carbon monoxide at low temperatures with any sensitivity. High temperatures are necessary to measure higher carbon monoxide concentrations, as long as complete saturation of the sensor is avoided. This renders the sensor unsuitable for measuring gas compositions over a wide concentration range.

GB2,316,178A discloses a solid electrolyte gas sensor in which a reference electrode is mounted in a chamber in the electrolyte. The gas-sensitive electrode is provided on the outside of the solid electrolyte. The sensor is said to be useful for the detection of carbon dioxide and sulfur dioxide. However, operation of the sensor requires heating to a temperature of at least 200 ℃, more preferably 300 to 400 ℃. This shows a major drawback in the practical application of the sensor.

Sensors for monitoring the composition of gases during thermal processing are disclosed in GB2,184,549 a. However, as with the sensor of GB2,316,178, operation at high temperatures (not exceeding 600 ℃) is disclosed and appears to be desirable.

Therefore, there is a need for a sensor that does not rely on the presence of liquid phase electrolytes or high temperature catalytic methods, which has a simple construction and can be easily applied to monitoring gas composition under ambient conditions.

EP 0293230 discloses a sensor for detecting acid gases such as carbon dioxide. The sensor comprises a sensing electrode and a counter electrode in an electrolyte body. The electrolyte is a solid complex with ligands that can be replaced with acid gases. A similar sensor arrangement is disclosed in US6,454,923.

Particularly effective sensors are disclosed in pending international application PCT/GB 2005/003196. The sensor includes a sensing element configured to be exposed to the gas flow, the sensing element including a working electrode; a counter electrode; and a solid electrolyte precursor extending between and in contact with the working electrode and the counter electrode; the gas stream can thereby be caused to impinge on the solid electrolyte precursor such that water vapour in the gas stream at least partially hydrates the precursor to form an electrolyte in electrical contact with the working and counter electrodes.

It would be advantageous if the response speed of known sensors could be increased while maintaining the accuracy of the sensors. In this respect, it is noted that carbon dioxide, a particularly preferred target molecule in particular in exhaled breath analysis of patients and subjects, is a relatively large molecule with a correspondingly low mass transfer rate for the sensing component of the sensing device.

The gas stream exhaled by a human or animal contains a range of components including carbon dioxide and water vapour. It has been found that there is a strong correlation between the water vapour content of the exhaled gas stream and the carbon dioxide content of the gas stream.

Accordingly, in a first aspect, the present invention provides a method for determining the carbon dioxide content of an exhaled gas stream, the method comprising:

measuring the water vapor content of the exhaled gas stream; and

the carbon dioxide concentration in the exhaled gas stream is determined from the measured water vapour content.

As mentioned above, it has been found that at a given temperature, the concentration of carbon dioxide present in the exhaled air stream is closely related to the concentration of water as a result of breathing in the respiratory tract of a human or animal. Typically, a human exhaled air stream contains about 79% by volume nitrogen, 15% by volume oxygen, 5% by volume carbon dioxide, and 2% by volume water vapor. Thus, the ratio of carbon dioxide to water vapour in exhaled breath is typically 2.5: 1.

The ability to determine the carbon dioxide concentration of the exhaled gas stream from the detection and measurement of water vapor content provides several advantages. First, among the various components that make up the exhaled gas stream, water is the only subcritical gas component present and can therefore easily condense in the sensor. Furthermore, because water molecules are significantly smaller than carbon dioxide molecules, the rate of diffusion and mass transfer is correspondingly faster, leading to the potential for providing sensors with fast response times. This is of importance when designing sensors for use on a regular basis by subjects such as patients who wish to detect respiratory disorders, for example asthmatics who wish to determine the onset of an asthma attack.

The sensor for measuring the water vapour concentration in the exhaled air stream may be sensitive to water vapour only. Alternatively, the sensor may be a sensor that is sensitive to both water vapor and carbon dioxide, which is taken into account when processing the output of the sensor to determine the carbon dioxide concentration.

In the human and animal respiratory system, gases may be inhaled and exhaled through the nasal passages (nasal passages) or through the mouth. The nasal passages provide a mechanism for heat and moisture exchange with the passing air stream, which function is not performed to the same extent by the structure of the mouth. Due to the different structures and their different functions, the composition of the gas exhaled through the mouth will be different from the composition of the gas stream exhaled through the nose. In the present invention, it is preferred that the method of measuring carbon dioxide concentration is carried out in a gas stream exhaled through the mouth to provide a result for assessing the respiratory function of a subject.

The method may employ any suitable technique for determining the water content of the exhaled gas stream. Suitable methods are known to those skilled in the art. One technique for measuring the absolute humidity of an exhaled gas stream is selected ion flow Mass Spectrometry (SIFT-MS), as disclosed by "On-line measurement of the absolute humidity of air, breath and liquid headspace samples by selected ion flow Mass Spectrometry" of p.span and d.smith, Mass Spectrometry Rapid communication in Mass Spectrometry, 2001, 15, 563 to 569.

In another aspect, the present invention provides a sensor for determining the concentration of carbon dioxide in an exhaled air stream, the sensor comprising:

means for determining the concentration of water vapour in the exhaled air stream;

means for calculating the concentration of carbon dioxide in the exhaled gas stream from the measured concentration of water vapour.

As noted above, the sensor may employ any suitable technique for determining the concentration of water vapor in the exhaled gas stream. In a preferred embodiment, the present invention employs an electrochemical sensor. Suitable electrochemical sensors are known in the art and include the sensors disclosed in the prior art documents discussed above. In one embodiment, an electrochemical sensor comprises:

a sensing element configured to be exposed to an airflow, the sensing element comprising:

a working electrode; and

a counter electrode.

The electrodes may be uncoated and directly exposed to the gas stream. Alternatively, the electrodes may be coated with a suitable material to provide an electrochemically conductive pathway between the electrodes when water vapor is present in the gas stream.

In a preferred sensor, the electrodes are coated with a layer of ion exchange material extending between the working electrode and the counter electrode; whereby contact between the ion exchange layer and the gas stream forms an electrical contact between the working and counter electrodes.

In this specification, by ion exchange material is meant a material having ion exchange properties such that contact with a gas stream component results in a change in the conductivity of the layer between the electrodes. The ion exchange material acts as a carrier medium for creating electrical conductivity as it allows the formation of a hydrated ionic layer between the electrodes. The layer of ion exchange material provides a highly controllable and uniformly hydrated medium to provide a suitable medium for creating conductivity.

Suitable ion exchange materials for use in the sensor of the present invention are those having high proton conductivity, good chemical stability, and the ability to maintain sufficient mechanical integrity. The ion exchange material should have a high affinity for the species present in the gas stream being analyzed, in particular for the various components present in the exhaled breath of the subject or patient.

Suitable ion exchange materials are known in the art and are commercially available products.

Particularly preferred ion exchange materials are ionomers, a class of synthetic polymers having ionic properties. One particularly preferred group of ionomers are sulfonated tetrafluoroethylene copolymers. Particularly preferred ionomers from this class are those commercially available from Du PontThe sulfonated tetrafluoroethylene copolymers have excellent conductivity due to their proton conductivity. Sulfonated tetrafluoroethylene copolymers having various cation conductivities can be prepared. They also exhibit excellent thermal and mechanical stability and are biocompatible, making them suitable materials for control electrode coatings.

Other suitable ion exchange materials include Polyetheretherketone (PEEK), polyarylene ether sulfone (PSU), PVDF-grafted styrene, acid-doped Polybenzimidazoles (PBI), and polyphosphazenes.

The ion exchange material may be present in the sensor in a dry state, in which case the material would require the addition of water, for example as water vapour present in the gas stream. This is the case when the sensor is used to analyse exhaled breath of a human or animal in which varying amounts of water vapour are present. Alternatively, the ion exchange material may be present in a saturated or partially saturated state with water, in which case the dried gas stream may be analyzed. In such a case, the output of the sensor will change in response to a change in the conductance of the ion exchange material due to the dissolution of ions in the water present.

The thickness of the ion exchange material will determine the response of the sensor to changes in the composition of the gas stream in contact with the ion exchange layer. To minimize internal resistance within the sensor, it is preferable to use an ultra-thin ion exchange layer.

The ion exchange layer may comprise a single ion exchange material or a mixture of two or more such materials, depending on the particular application of the sensor.

Where the ion exchange material exhibits the desired level of chemical and mechanical stability and integrity for the sensor service life, the ion exchange layer may be comprised of an ion exchange material. Alternatively, the ion exchange layer may comprise an inert support for the ion exchange material. Suitable supports include oxides, particularly metal oxides, including alumina, titania, zirconium oxide, and mixtures thereof. Other suitable supports include oxides of silicon and various natural and synthetic clays.

In a second preferred embodiment, the electrodes of the sensor are coated with a layer of mesoporous material extending between the working electrode and the counter electrode; whereby contact of the mesoporous layer with the gas stream forms an electrical contact between the working and counter electrodes.

In the present specification, by mesoporous material is meant a material having pores in the range of 1 to 75nm, more particularly in the range of 2 to 50 nm. The mesoporous material acts as a support medium for creating electrical conductivity as it allows the formation of a temporary layer of hydrated ions across the electrode. The layer of mesoporous material provides a highly controllable and uniformly hydrated medium to provide a suitable medium for creating conductivity.

Suitable mesoporous materials for use in the sensors of the invention include metal oxides, in particular oxides of metals from group IV of the periodic table of the elements, in particular oxides of titanium or zirconium. Particularly preferred metal oxides are titanium dioxide, including titanates. An alternative useful mesoporous material is synthetic clay, which is particularly preferred due to the inherent layered nature of clay. Laponite (Laponite) is a synthetic layered silicate with a structure similar to that of the natural clay mineral Laponite (hectonite). When added to water with stirring, it will rapidly disperse into nanoparticles. It is cost effective, thermally stable, thixotropic and capable of maintaining hydration levels. Laponite is of particular interest because of its single ion conducting properties that minimize concentration polarization. Hydrotalcite-like compounds are also known as layered double hydroxides or anionic clays. These compounds have a layered crystal structure consisting of a positively charged hydroxide layer and an intermediate layer containing anions and water molecules. These compounds exhibit anion exchange properties and are capable of recovering a layered crystal structure during rehydration.

The mesoporous material may be present in the sensor in a dry state, in which case the material would require the addition of water, for example as water vapour present in the gas stream. Alternatively, the mesoporous material may be present in a saturated or partially saturated state with water.

The thickness of the mesoporous material will determine the response of the sensor to changes in the composition of the gas stream in contact with the mesoporous layer. To minimize internal resistance within the sensor, it is preferable to use an ultra-thin mesoporous layer.

The mesoporous material may contain a binder, in particular a conductive (ion-exchanger type) binder. Suitable conductive binders include ionomers, a class of synthetic polymers having ionic properties. One particularly preferred group of ionomers are sulfonated tetrafluoroethylene copolymers. Particularly preferred ionomers from this class are those commercially available from Du PontThe sulfonated tetrafluoroethylene copolymers have excellent conductivity due to their proton conductivity. The pores in the mesoporous material allow the movement of cations without the membrane conducting anions or electrons. Sulfonated tetrafluoroethylene copolymers having various cation conductivities can be prepared. They also exhibit excellent thermal and mechanical stability and are biocompatible, making them suitable materials for control electrode coatings.

In a particularly preferred embodiment, the layer extending between the electrodes comprises an ion exchange material, optionally an inert filler, and a mesoporous material. In this respect, as mentioned above, by mesoporous material is meant a material having pores in the range of 1 to 75nm, more particularly in the range of 2 to 50 nm. Mesoporous materials provide a highly controllable and uniformly hydrated medium to provide a suitable medium for creating conductivity.

As noted above, suitable mesoporous materials for use in particularly preferred sensors of the present invention are known and commercially available in the art and include zeolites. Zeolites are particularly preferred components for inclusion in the ion exchange layer in the sensor of the present invention. One preferred Zeolite is Zeolite 13X (Zeolite 13X). Alternatively used mesoporous materials are Zeolite 4A (Zeolite 4A) or Zeolite p (Zeolite p). The ion exchange layer may contain one or a combination of zeolite materials.

The particle size and thickness of the mesoporous material will determine the response of the sensor to changes in the composition of the gas stream in contact with the ion exchange layer. To minimize internal resistance within the sensor, it is preferable to use an ultra-thin layer containing the mesoporous material.

The mesoporous material is preferably dispersed in the ion exchange layer, most preferably as a fine dispersion. The mesoporous material is preferably dispersed as particles having a particle size in the range of 0.5 to 20 μm, more preferably 1 to 10 μm. The particles of the mesoporous material are preferably finely dispersed in the ion exchange layer such that adjacent particles are generally separated by at least one particle size, more preferably by at least 3 to 5 particle sizes. More highly dispersed arrangements with particle spacing up to 10 diameters can also be used if desired.

Sensors comprising a layer of ion exchange material having a rare amount of mesoporous material therein can be prepared using any suitable technique. In a preferred process, the ion exchange/mesoporous material layer is applied in a two-step process. In said method, the particles of mesoporous material are first coated, for example by contacting the sensor to be coated with a suspension of mesoporous material suitably dispersed in a suitable solvent, such as an alcohol. The solvent is removed, for example by evaporation, leaving a layer of dispersed mesoporous particles. Other techniques for depositing particulate mesoporous material onto the sensor surface may also be used. Examples of other techniques include: dry aerosol deposition, spray pyrolysis (spray pyrolysis), and screen printing. More sophisticated techniques may also be employed, such as: in-situ crystal growth, hydrothermal growth, sputtering, autoclave treatment, and the like.

Thereafter, a layer of ion exchange material may be applied to a desired thickness. This can be accomplished by dispensing the desired volume of ion exchange material in a suitable solvent onto the dispersed layer of mesoporous material. The solvent is then evaporated, leaving a layer of the desired ion exchange material containing mesoporous particles retained therein in a highly dispersed arrangement.

In summary, in one embodiment, the mesoporous material is applied to the electrode as a suspension of particles in a suitable solvent, wherein the solvent is evaporated to leave a fine dispersion of particles on the electrode. The ion exchange material is subsequently coated onto the mesoporous dispersion. The mesoporous material is preferably coated at a concentration of 0.01 to 1.0g as a homogeneous suspension in 10ml of solvent, in which the electrode assembly is immersed more than once. More preferably, the mesoporous material is coated at a concentration of 0.05 to 0.5g/0ml of solvent, in particular about 0.1g/10ml of solvent. Suitable solvents for use in coating of mesoporous materials are known in the art and include alcohols, particularly methanol, ethanol and higher aliphatic alcohols. The dispersion of the mesoporous particles on the sensor element can be controlled by varying the concentration of the particle suspension and by the number and nature of the contacts between the suspension and the sensor element.

It has been found that the rare number of mesoporous particles within the (continuous) ion exchange membrane provides the highest discrimination for detecting target species, particularly water vapor, in a gas stream. In particular, it has been found that a sensor as described above having a layer of ion exchange material comprising zeolite particles dispersed therein is particularly sensitive to changes in the concentration of water vapour in the gas stream. In this way, the sensor can be used with very high specificity for the detection of water vapor and the measurement of water vapor concentration. One preferred arrangement under a Scanning Electron Microscope (SEM) shows that the density of the mesoporous particles is such that: each particle is at an average distance of several body diameters (body diameter) from the nearest particle, in particular 1 to 5 body diameters, more preferably 1 to 3 body diameters.

It has also been found that a thick film of ion exchange material degrades the performance of the sensor, as does a thick continuous coating of mesoporous material. In other words, the combination of a thin ion exchange layer and a rare number of mesoporous particles performs best.

Yet another sensor embodiment comprises a solid electrolyte precursor extending between and in contact with the working electrode and the counter electrode; the gas stream can thereby be caused to impinge on the solid electrolyte precursor such that water vapour in the gas stream at least partially hydrates the precursor to form an electrolyte in electrical contact with the working and counter electrodes.

In the context of the present invention, the term "solid electrolyte precursor" is for the following materials: which is in the solid phase at the prevailing conditions during use of the sensor and can react with (or be hydrated by) water vapour in the gas stream to reconstitute the aqueous electrolyte, thereby allowing current to flow between the working and counter electrodes.

The solid electrolyte precursor contains a ligand, preferably an organic ligand (hereinafter, denoted as "L") capable of forming a complex with a metal ion (hereinafter, denoted as "M") to form an organometallic complex. Within the electrolyte, the organic ligand is capable of dissociating according to the following equation:

a variety of ligands and metal ions may be employed in the organometallic complex of the solid electrolyte precursor. Preferred organic compounds for use as ligands are amines, especially diamines, such as diaminopropane; and carboxylic acids, especially dicarboxylic acids. The metal ion is preferably an ion of group VIII of the periodic Table of the elements, as provided in Handbook of chemistry and Physics, 62 nd edition, 1981 to 1982, published by Chemical Rubber Company (Chemical Rubber Company). Suitable metals include copper, lead and cadmium.

The solid electrolyte precursor preferably further comprises a salt. Metal halide salts are preferred, especially sodium and potassium halides, especially chlorides.

The specific selection and combination of metal ions and organic ligands can be theoretically calculated using the principles of equilibrium (speciation) chemistry. The principle behind the test substance is that the ligand should have a low pK_b. As noted above, a preferred class of ligands are diamines such as propylene diamine, ethylene diamine, and various substituted diamines. The performance of the sensor depends on the choice and concentration of the metal/ligand pair, and the optimal precursor composition can be obtained by routine experimentation.

For solid electrolyte precursors, one particularly preferred composition comprises copper, propylene diamine, and potassium chloride. One preferred composition has those components present in the following amounts: 4mM copper, 10mM propylenediamine, and 0.1M potassium chloride as a base electrolyte.

Those skilled in the art will appreciate that there are a considerable range and considerable combinations of other metals, ligands and base electrolytes.

The solid electrolyte precursor may be prepared from a solution of the constituent components in a suitable solvent. Water is the most convenient solvent. The solvent is removed by drying and evaporation to leave a solid electrolyte precursor. Evaporation of the solvent may be assisted by blowing a gas stream, such as air or nitrogen, across the surface of the precursor being dried.

The invention provides a sensor which is particularly compact and has a very simple construction. Furthermore, the sensor can be used under ambient temperature conditions without any heating or cooling, while the concentration of the target substance in the gas to be analyzed is accurately measured.

The sensor preferably comprises a housing or other protective body to enclose and protect the electrodes. The sensor may contain a passageway or conduit to direct the gas flow directly onto the electrodes. In a very simple arrangement, the sensor comprises a conduit or tube into which the two electrodes extend so as to be in direct contact with the gas flow through the conduit or tube. When the sensor is intended for use in the analysis of patient breathing, the conduit may contain a mouthpiece (mouthpiece) into which the patient can exhale. Alternatively, the sensor may be formed with electrodes at exposed locations on or in the housing to directly measure large amounts of gas flow. The precise form of the housing, passageway or conduit is not critical to the operation or performance of the sensor and may take any suitable form. Preferably the body or housing of the sensor is made of a non-conductive material such as a suitable plastic.

The electrodes may have any suitable shape and configuration. Suitable electrode forms include dots, lines, rings, and flat planar surfaces. The efficiency of the sensor may depend on the particular arrangement of electrodes, and may be improved in certain embodiments by having very small path lengths between adjacent electrodes. This can be achieved, for example, by: each of the working and counter electrodes is made to comprise a plurality of electrode portions arranged in an alternating, interlocking pattern, i.e. in the form of an array of interdigitated electrode portions, in particular in a concentric pattern.

Within the resolution of the manufacturing technique, the electrodes are preferably oriented as close to each other as possible. The width of the working and counter electrodes may be between 10 and 1000 microns, preferably between 50 and 500 microns. The gap between the working and counter electrodes is preferably between 20 and 1000 microns, more preferably between 50 and 500 microns. The optimum rail-gap distance is obtained by routine experimentation for the particular electrode material, geometry, configuration and substrate under consideration. In a preferred embodiment, the optimal working electrode track width is 50 to 250 microns, preferably about 100 microns, and the counter electrode track width is 50 to 750 microns, preferably about 500 microns. The gap between the working and counter electrodes is preferably about 100 microns.

The counter electrode and the working electrode may have the same size. However, in a preferred embodiment, the surface area of the counter electrode is larger than the surface area of the working electrode to avoid limitations in current delivery. Preferably, the counter electrode has a surface area at least twice the surface area of the working electrode. Higher surface area ratios of counter electrode and working electrode, such as at least 3: 1, preferably at least 5: 1 and up to 10: 1, may also be employed. The thickness of the electrode is determined by the preparation technique, but has no direct influence on the electrochemistry. The magnitude of the resulting electrochemical signal is determined primarily by the exposed surface area, i.e., the surface area of the electrode that is directly exposed to and in contact with the gas stream. Generally, an increase in electrode surface area will result in a higher signal, but may also result in an increased sensitivity to noise and electrical interference. However, the signal from the smaller electrode may be more difficult to detect.

The electrodes may be supported on a substrate. Suitable materials for the support substrate are any inert, non-conductive material, such as ceramic, plastic or glass. The substrate provides support to the electrodes and acts to hold them in their proper orientation. Thus, the substrate can be any suitable support medium. It is important that the substrate is non-conductive, i.e. electrically insulating or has a sufficiently high dielectric constant.

The electrode may be disposed on a surface of the substrate, with a layer of ion exchange material extending over the electrode and the substrate surface. Alternatively, the ion exchange material may be coated directly onto the substrate, with the electrodes being disposed on the surface of the ion exchange layer. This will have the following advantages: providing mechanical strength and a thin layer of substrate with greater control over the path length.

The ion exchange material is conveniently coated onto the surface of the substrate by evaporation from a suspension or solution in a suitable solvent. For example, in the case of sulfonated tetrafluoroethylene copolymers, a suitable solvent is methanol. The suspension or solution of ion exchange material may also comprise an inert support or precursor thereof, provided that one of them is to be present in the ion exchange layer.

In order to improve the electrical insulation of the electrode, a portion of the electrode that is disposed not in contact with the gas flow (i.e., a non-operating portion of the electrode) may be coated with a dielectric material, patterned in such a manner as to keep the active portion of the electrode exposed.

While sensors having two electrodes, as described above, work well, arrangements having more than two electrodes, including for example a third or reference electrode, are well known in the art. The use of a reference electrode provides better potentiostatic control of the applied voltage, or galvanostatic control of the current, when the "resistance drop" (iR drop) between the counter electrode and the working electrode is appreciable. Dual (dual) 2-electrode and 3-electrode cells may also be employed.

It is also possible to use another electrode arranged between the counter electrode and the working electrode. The temperature of the gas flow can be calculated by measuring the end-to-end resistance of the electrodes. Such techniques are known in the art.

The electrodes may comprise any suitable metal or alloy of metals, provided that the electrodes do not react with any species present in the electrolyte or gas stream. Metals of group VIII of the periodic Table of the elements, as provided in Handbook of chemistry and Physics, 62 nd edition, 1981 to 1982, published by Chemical Rubber Company (Chemical Rubber Company). Preferred group VIII metals are rhenium, palladium and platinum. Other suitable metals include silver and gold. Preferably, each electrode is made of gold or platinum. Carbon or carbonaceous materials may also be used to form the electrodes.

The electrodes of the sensor of the invention may be formed by printing the electrode material onto the substrate in the form of a thick film screen printing ink. The ink is composed of four components, namely a functional component, a binder, a vehicle, and one or more modifiers. In the case of the present invention, the functional component forms the conductive part of the electrode and comprises one or more powders of the metals described above for forming the electrode.

The binder holds the ink to the substrate and fuses with the substrate during high temperature firing. The vehicle acts as a carrier for the powder and contains both volatile components, such as solvents, and non-volatile components, such as polymers. These materials evaporate at the early stages of drying and firing, respectively. The modifier contains small amounts of additives that are active in controlling the properties of the ink before and after processing.

Screen printing requires control of the ink viscosity within limits determined by rheological properties such as the amount of vehicle components and powder in the ink, and also in the ambient, such as ambient temperature.

Printing screens can be prepared by drawing a stainless steel wire mesh cloth through a screen frame while maintaining high tension. The emulsion is then spread over the entire web, filling all of the effective mesh area of the web. It is common practice to add an excess of emulsion to the web. The areas to be screen printed are then patterned on the screen using a suitable electrode design stencil.

A squeegee is used to spread the ink over the screen. The shearing action of the squeegee causes the ink to decrease in viscosity, allowing the ink to pass through the patterned areas to the substrate. The screen is peeled off as the squeegee passes. The ink viscosity returns to its original state and a clear print is obtained. The mesh is critical when determining the appropriate thick film print thickness and hence the thickness of the finished electrode.

The mechanical limit (down stop) for the downward movement of the squeegee should be set to allow the limit of the print stroke to be 75-125um below the substrate surface. This will allow to achieve a uniform print thickness through the substrate while protecting the mesh from distortion and possible plastic deformation due to overpressure.

The following equation may be used to determine the print thickness:

Tw＝(Tm×Ao)+Te

wherein Tw ═ wet caliper (um);

tm ═ mesh weave thickness (um);

ao is% effective screen aperture area;

te ═ emulsion thickness (um).

After the printing process, the sensor element needs to be leveled before firing. Leveling causes the screen marks (meskmark) to fill and some of the more volatile solvent slowly evaporates at room temperature. If not all of the solvent is removed during this drying process, the remaining amount will cause problems during firing by contaminating the atmosphere surrounding the sensor element. Most of the solvents used in thick film technology can be completely removed when kept in an oven at 150 ℃ for 10 minutes.

Firing is typically accomplished in a belt furnace. The firing temperature varies according to the ink chemistry. Most commercially available systems fire 10 minutes at 850 c peak. The total oven time is 30 to 45 minutes, including the time it takes to heat the oven and cool to room temperature. The purity of the firing atmosphere is critical to successful processing. The air should be free of particulates, hydrocarbons, halogen-containing vapors and water vapor.

Alternative techniques for preparing the electrodes and, if present, coating them onto the substrate include spin/sputter coating and visible/ultraviolet/laser lithography. In order to prevent impurities in the electrodes that may alter the electrochemical performance of the sensor, the electrodes may be prepared by electrochemical plating. In particular, each electrode may comprise multiple layers applied by different techniques, wherein the bottom layer is prepared using one of the above-mentioned techniques, such as printing, and the uppermost or outer layer or layers are applied by electrochemical plating using a pure electrode material, such as a pure metal.

In use, the sensor is capable of operating over a wide temperature range.

In a further aspect, the present invention provides a method of determining the carbon dioxide content in an exhaled gas stream comprising water vapour, the method comprising:

impinging a gas stream against a sensing element comprising a working electrode and a counter electrode;

applying an electrical potential between the working electrode and the counter electrode (across);

measuring a current flowing between the working electrode and the counter electrode as a result of the applied potential;

determining from the measured current an indication of the concentration of water vapour in the gas stream; and

the concentration of carbon dioxide in the exhaled gas stream is determined from the measured concentration of water vapour.

During operation, the impedance between the counter electrode and the working electrode, which can be measured electronically by a variety of techniques, shows the relative humidity of the gas stream and the target substance content where the measurement is made.

The method of the invention may be carried out using a sensor as described above.

The method requires the application of an electrical potential between the electrodes. In a simple arrangement, a voltage is applied to the counter electrode while the working electrode is connected to ground (grounded). In its simplest form, the method applies a single, constant potential difference between the working electrode and the counter electrode. Alternatively, the potential difference may vary over time, for example, by pulsing or sweeping over a series of potentials. In one embodiment, the potential is pulsed between a so-called "rest" potential where no reaction occurs and the reaction potential.

In operation, a linear potential sweep, multiple voltage steps, or one discrete potential pulse is applied to the working electrode, and the resulting faradaic reduction current is monitored as a positive function of the dissolution of the target molecule in the water bridging the electrodes (direct function).

The measurement current in the sensor is usually small. The current is converted to a voltage using a resistor R. Due to the small currents, careful attention to electronic design and details may be necessary. In particular, special "protection" techniques may be employed. Ground loops need to be avoided in the system. This may be accomplished using techniques known in the art.

The current passing between the counter electrode and the working electrode is converted to a voltage and recorded as a function of the concentration of carbon dioxide in the gas stream. The sensor responds faster by pulsing the potential between two voltages, a technique known in the art as "square wave voltammetry". Several measurements of the response during the pulse can be used to estimate the impedance of the sensor.

For simple resistive and capacitive elements, the shape of the transient response may be related only to the electrical characteristics (impedance) of the sensor. By carefully analyzing the shape, the respective contributions of resistance and capacitance can be calculated. Such mathematical techniques are well known in the art. Capacitance is an unwanted noise component generated by electronic artifacts such as charging and the like. The capacitive signal can be reduced by selecting the design and arrangement of the electrodes in the sensor. Increasing the surface area of the electrodes and increasing the distance between the electrodes are two major factors affecting the resulting capacitance. The desired faradaic signal generated from the current path due to the reaction between the electrodes can be optimized experimentally. For example, measuring the response of the growth period within a pulse is one technique that can preferentially select between capacitive and faraday components. Such application techniques are well known in the art.

As mentioned above, the potential difference applied to the electrodes of the sensor element may be alternated or periodically pulsed between a rest potential and a reaction potential. Fig. 1 shows an example of a voltage waveform that may be applied. FIG. 1a is a diagram at rest potential V₀And reaction potential V_RA representation of the pulsed voltage signal alternating therebetween. The voltage may be pulsed at a range of frequencies, typically from sub-Hertz (sub-Hertz) frequencies, i.e. from 0.1Hz up to 10 kHz. Preferred pulse frequencies are in the range of 1 to 500 Hz. Alternatively, the potential waveform applied to the counter electrode may consist of a "swept" series of frequencies as shown in FIG. 1 b. Yet another alternative waveform shown in fig. 1c is a frequency of the so-called "white noise" series. The complex frequency response resulting from such a waveform would have to be deconvoluted (deconvoluted) after signal acquisition using techniques such as fourier transform analysis.

One preferred voltage regime is 0V ("rest" potential), 250mV ("reaction" potential) and a 20Hz pulse frequency.

An electrochemical reaction potential of about +0.2 volts is an advantage of the present invention, which avoids most if not all of the possible competing reactions that would interfere with the measurement, such as reduction of metal ions and dissolution of oxygen.

The method of the invention is particularly suitable for the analysis of exhaled breath in humans or animals. From the results of this analysis, an indication of the respiratory condition of the patient can be derived.

The sensors and methods of the present invention can be used to monitor and determine lung function in a patient or subject. The methods and sensors are particularly useful for analyzing tidal concentrations (tidal concentrations) of carbon dioxide in human or animal exhaled breath to diagnose and monitor various respiratory conditions. The sensor is particularly useful in applications requiring fast response times, such as personal breath detection of tidal breathing (capnography). Capnography measurements can generally be applied in the following fields: respiratory medicine, restrictive and obstructive airway diseases, airway disease management, and airway inflammation. The invention finds particular application in the fields of capnography, and asthma diagnosis, monitoring and management, where the shape of the capnogram varies as a function of the extent of the disease. In particular, due to the high response rate obtainable by using the sensor and method of the present invention, the results may be used to provide an early warning of the onset of an asthma attack in an asthma patient.

As mentioned above, it has been found that the concentrations of carbon dioxide and water vapour in the airflow exhaled by a subject are closely related, such that changes in carbon dioxide concentration can be monitored by measuring changes in the concentration of water vapour. As discussed above, knowledge of the concentration of carbon dioxide in exhaled breath of a subject can provide very valuable information about the health of the subject, in particular the condition and performance of the lungs and respiratory system in general. However, it has also been found that the condition and performance of the respiratory system of a subject in general, and the lungs of a subject in particular, can be readily determined directly from the measurement and monitoring of the water vapour content of the exhaled air flow of a subject.

Accordingly, in a further aspect, the present invention provides a method of determining respiratory function of a subject, the method comprising:

measuring the concentration of water vapor in the airflow exhaled by the subject; and

determining the respiratory function of the subject from the measured water vapor concentration.

The method may be used to provide a determination of the overall respiratory function of a subject, but is particularly suitable for determining the pulmonary function of a subject.

The measurement of the water vapour content of the exhaled gas stream may be applied to gases exhaled through the nose and/or mouth of the subject. In a preferred embodiment, the water vapor content of the gas stream exhaled through the mouth of the subject is measured.

Furthermore, the water vapour present in the air stream exhaled by the subject is generated by metabolic processes occurring within the subject. Thus, measurement of the water vapour content of the exhaled gas stream may be used to provide a direct indication of the nature and performance of a number of metabolic processes in the subject, and/or to provide an overall indication of the metabolism of the subject. This can in turn be used to derive important information about the general condition of the subject, as well as information about the specific condition of the disease from which the subject is suffering.

As with the concentration of carbon dioxide in the exhaled airflow of a subject, the concentration of water vapor in exhaled breath varies throughout the duration of the breath. In particular, a tracing of water vapour concentration (a graphical trace) may be obtained which is similar in overall form to a capnogram derived from measuring the concentration of carbon dioxide in the exhaled air stream. The resulting traces of water vapor concentration may be analyzed similarly to that known for capnography. Specific techniques for analyzing water vapor tracing and capnography are described below and form another aspect of the invention.

The measurement of the water vapour content of the exhaled breath may be performed for a portion of the exhaled breath duration or more preferably for the entire exhaled breath duration. More preferably, the change in water vapour concentration is measured over several cycles of inhalation and exhalation, resulting in a measurement of the water vapour concentration for tidal breathing.

The concentration of water vapor in the exhaled airflow of the subject may be measured using any suitable device. The device is preferably an electrochemical sensor which has been found to be particularly convenient for use in measuring water vapour concentration. One particularly preferred form of electrochemical sensor is outlined above and described in detail below.

As described, the concentration of gas species in the exhaled breath of a subject can be measured and their change with exhalation time can be determined. The measurements thus obtained may be illustrated in the form of a tracing, referred to as a capnogram in the case of carbon dioxide. The carbon dioxide and water vapor traces are similar and have a generally rectangular shape, with the concentration rising steeply in the early stages of the exhaled breath, reaching a generally flat or flat-topped (plateau) region, and then falling into the final stages of the exhaled breath. A typical plot is shown in fig. 10, in which the concentration of carbon dioxide in the exhaled gas stream is plotted against time for a single exhalation.

Monitoring of changes in the concentration of components in the exhaled airflow of a subject, particularly during normal tidal breathing, is non-invasive and is often easy to perform. In particular, the subject does not need to perform any additional effort as with other techniques when exhaling. The concentration profile with expired breath reflects changes in the volume and physiological changes of the lungs of the subject. Analysis of the traced shape can provide valuable information and indications about normal lung function as well as about various conditions and ailments of the lung. The present invention provides two specific methods for analyzing a plot of the concentration of a component of an exhaled airflow of a subject versus time.

Referring to fig. 10, a plot of the concentration of a gas component in the exhaled gas stream versus time is shown and discussed in detail in the specific examples below. However, in general, it can be seen that the profile includes a rise phase in which the concentration rapidly increases over time as the subject exhales. Then a plateau phase is followed, in which the concentration variation is significantly smaller than the rise phase. Finally, towards the end of the breath, the concentration falls rapidly into a decline phase. The ascending phase and the plateau phase are particularly affected by changes in ventilation (V) and perfusion (Q) of the subject. In a first specific method, the slope of the ascending phase and/or the plateau phase is used to determine lung function.

Accordingly, the present invention also provides a method of determining lung function in a subject, the method comprising:

measuring a change in concentration of a gas component in the exhaled airflow of the subject;

determining the change in concentration as a function of time for the exhaled gas stream to obtain a profile of the change in concentration over time;

measuring the slope of the rising phase in the profile; and is

The slope of the ascending phase is used to make a determination of the subject's lung function.

The angle of the ascending phase with respect to the x-axis or the slope of the ascending phase changes as the function and condition of the lung changes. This allows the angle or slope of the ascent phase to be measured and a determination of the subject's lung function to be made. For example, by comparing the angle of the ascending phase in a given trace with the angle of the corresponding phase in other traces obtained for the same subject, an indication of the subject's lung function can be obtained. In this way, changes in the subject's lung function over time may be monitored, for example to provide an early indication of the onset of a particular condition, such as asthma, COPD or the like.

Furthermore, changes or trends in the profile obtained from measurements of the water vapour content of the exhaled airflow of a subject are particularly useful once a particular condition is identified or diagnosed. In particular, the methods and apparatus of the present invention allow for monitoring changes in the condition of a subject by identifying changes and trends in the profile over a period of time. In this way, for example, a subject's response to a particular treatment can be gauged and appropriate action can be taken if the condition worsens or does not improve as expected.

The method may measure only the slope of the rise phase and use this for the determination of lung function. However, the method may also employ the slope of the plateau phase in the concentration versus time plot. In this phase, although the concentration of the gas component does not generally vary as significantly as in the rise phase, the concentration will vary over time between the end of the rise phase and the beginning of the fall phase. As noted above, the angle or slope of the plateau phase may also be affected by changes in the subject's lung function. Thus, the determination of lung function may also utilize the angle or slope of the plateau phase in the profile. In particular, the ratio of the slopes of the rise phase and the plateau phase may be calculated. It has been found that this ratio can also be used to provide an indication of lung function, in particular that a change in the ratio indicates a possible onset of certain conditions in the lungs such as asthma, COPD etc.

This method may be performed by measuring one or more gaseous components of the exhaled gas stream, most preferably using carbon dioxide or water vapour.

In addition, or as an alternative, to the use of the slope of the trace, it has been found that the region of the trace near the transition from the ascending phase to the plateau phase can provide a very valuable indication of the subject's pulmonary function.

Accordingly, in a further aspect, the present invention provides a method of determining lung function in a subject, the method comprising:

measuring a change in concentration of a gas component in the exhaled airflow of the subject;

determining the change in concentration as a function of time for the exhaled gas stream to obtain a profile of the change in concentration over time;

analyzing a portion of the profile in a region of transition from the ramp-up phase to the plateau phase; and

the results of the analysis are used to determine the lung function of the subject.

The method takes the analysis of the region of the concentration-time profile near the transition between the ascending phase and the plateau phase. A suitable analysis technique is a mathematical transformation (including a regression technique) to calculate a best fit line (line of best fit) from the transformed data. The best fit coefficient provides an indication of lung function, in particular the degree of apnea (breathlessness) the subject is experiencing. The best fit may be calculated using any suitable mathematical technique, such as least squares, median fit (mean fit), and the like. Other techniques for transforming data may also be employed and include polynomials, splines, and the like.

Any range of data points from the trace may be used, provided they span the transition from the ramp-up phase to the plateau phase. Preferably, data from at least the midpoint of the rise phase and the end of the plateau phase is used.

Furthermore, the method may employ measuring one or more gaseous components, most preferably carbon dioxide or water vapour, in the exhaled gas stream.

One specific example of an analytical method is provided in the following examples.

As mentioned above, one technique for detecting a condition of the respiratory system, in particular lung function, of a subject consists in measuring the change in concentration of a gas component of a gas stream exhaled by the subject and determining a plot or curve of the concentration against time. The shape of the trace will change as the subject's lung function changes, e.g., a given condition begins, worsens or improves. This in turn provides a technique for monitoring the lung function of a subject.

Accordingly, the present invention also provides a method for monitoring lung function in a subject, the method comprising the steps of:

measuring a change in concentration of a gas component of the exhaled gas stream of the subject;

determining the change in concentration as a function of time for the exhaled gas stream to obtain a profile of the change in concentration over time;

comparing the profile thus obtained with a pre-existing profile; and

the comparison is used to determine the lung function of the subject.

There is also provided a device for monitoring lung function in a subject, the method comprising the steps of:

means for measuring a change in concentration of a gas component in an exhaled airflow of the subject;

means for determining the change in concentration as a function of time for the exhaled gas stream to obtain a profile of the change in concentration over time;

means for storing a plurality of profiles; and

means for comparing the profile thus obtained with a pre-existing profile extracted from the storage means.

A profile obtained from analyzing the concentration of the gas component of the exhaled gas stream is compared to a pre-existing profile. The pre-existing profile may be a profile of a healthy subject or a representative profile. In this way, an indication of the subject's lung function can be obtained by direct comparison to a normal or healthy profile. Alternatively, as described, the pre-existing profile may be a profile obtained from the same subject at an earlier stage. In this way, the progression or development of a subject can be monitored, for example to provide an indication of the onset, worsening or improvement of a particular condition, such as asthma or COPD.

The method may use a pre-existing profile or trace. Alternatively, a plurality of pre-existing profiles may be used, for example to provide a pattern of lung function over an extended period of time. In such a case, the means for storing the profile may store a library of pre-existing profiles.

Comparison of profiles may again be as simple as providing a display in which more than two profiles are displayed. Alternatively, the comparison may employ one or more techniques for analyzing the trace data, such as the specific techniques described above.

Furthermore, the method and apparatus may be used with respect to one or more gaseous components of the exhaled gas stream, most preferably carbon dioxide or water vapour.

The methods of the invention, in various aspects thereof, may be used as described above to provide a range of indications regarding the condition and function of the lungs of a subject, particularly a human subject, and to provide an indication of the health of the lungs of the subject. In particular, the method may be used to provide information relating to lung diseases such as asthma, COPD, Tuberculosis (TB) and lung cancer. In addition, the method may be used to provide information relating to diseases and conditions directly associated with the lung of a subject, for example cancer, such as ovarian cancer in a female subject, which may metastasize to other parts of the subject's body, such as the lung. Other conditions that originate outside the lungs but produce phenomena in the pulmonary system include rheumatoid arthritis (rhematoid arthritis) and heart failure (heart failure).

In yet another embodiment, the method may be used to provide comparisons with data obtained using other lung function tests, for example, subjecting a subject to a forced expiratory volume test (FEV1), wherein the volume forced expired within 1 second is measured; and forced vital capacity test (FVC). The data generated by the methods of the invention may be used to verify or confirm data generated by other lung function tests, or to provide a further data set to aid in the diagnosis of a subject.

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

FIGS. 1a, 1b and 1c are representations of voltage versus time of possible voltage waveforms that may be applied to an electrode in a method of the invention as described hereinabove;

FIG. 2 is a cross-sectional representation of one embodiment of a sensor of the present invention;

FIG. 3 is an isometric (isometric) schematic view of a surface of one embodiment of a sensor element according to the invention;

FIG. 4 is an isometric schematic view of an alternative embodiment of a sensor element according to the present invention;

FIG. 5 is a schematic diagram of a potentiostat electronic circuit that may be used to excite electrodes of a sensor element;

FIG. 6 is a schematic diagram of galvanostat electronics that may be used to excite an electrode;

FIG. 7 is an illustration of a breathing tube adapter for use in the sensor of the present invention;

FIG. 8 provides a flow chart of an overview of the interconnection of sensor elements and their connection to a suitable measurement instrument according to one embodiment of the present invention;

FIG. 9 is a graphical representation of the output from an experiment measuring the water and carbon dioxide content in exhaled breath;

FIG. 10 is a graphical representation of an exemplary plot of the concentration of carbon dioxide or water vapor in the exhaled gas stream plotted against time;

FIG. 11 is an illustration of three different traces of the general type of FIG. 10;

FIG. 12 is a plot of a best fit analysis of the plot of plot 10 to determine the coefficient 'a';

FIG. 13 is a schematic cross-sectional view through a portion of a sensor element according to a preferred embodiment of the present invention;

FIG. 14 is a graphical representation of the distribution of mesoporous particles in the ion exchange material layer of the sensor of FIG. 13;

FIG. 15 is a diagram of an abstract circuit representing the electrical impedance present in the sensor shown in FIGS. 13 and 14;

FIG. 16 is a Scanning Electron Microscope (SEM) image of the surface of an electrode of a sensor according to a preferred embodiment of the present invention after deposition of mesoporous material particles on the sensor element but before application of a layer of ion exchange material;

FIG. 17 is a plot of water vapor concentration in the airflow exhaled by the subject plotted against time as measured using the sensor shown in FIG. 16;

referring to fig. 2, a sensor according to the present invention is shown. The sensor is used for analyzing the carbon dioxide content and humidity of the exhaled breath. The sensor, generally designated 2, comprises a conduit 4 through which the exhaled air flow can pass. The catheter 4 comprises a mouthpiece 6 into which the patient can breathe 6.

A sensing element, generally designated 8, is located within the conduit 4 such that airflow through the conduit from the mouthpiece 6 impinges on the sensing element 8. The sensing element 8 comprises a support substrate 10 of inert material onto which support substrate 10 a working electrode 12 and a reference electrode 14 are mounted. Working electrode 12 and reference electrode 14 each comprise a plurality of electrode portions, 12a and 14a, arranged in concentric circles so as to provide an interwoven pattern that minimizes the distance between adjacent portions of working electrode 12 and reference electrode 14. In this way, the current path between the two electrodes is kept to a minimum.

A layer 16 of insulating or dielectric material extends over portions of both the working and counter electrodes 12 and 14, leaving portions 12a and 14a of each electrode exposed for contact with the gas stream being passed through the conduit 4. The arrangement of the support, electrodes 12 and 14 and the coating applied to the electrodes is shown in more detail in figures 3 and 4.

Referring to fig. 3, an exploded view of a sensor element, generally designated 40, including a substrate layer 42 is shown. The working electrode 44 is mounted on the base layer 42 with a series of elongated electrode portions 44a extending from the base layer 42. Similarly, a reference electrode 46 is mounted on base layer 42, with a series of electrode portions 46a extending from base layer 42. As can be seen in fig. 3, working electrode portion 44a and reference electrode portion 46a extend in a close, interdigitated finger-type array with respect to each other, thereby providing a large surface area of exposed electrodes with minimal spacing between adjacent portions of the working and reference electrodes. A layer 48 of a coating material such as an ion exchange material, electrolyte precursor, zeolite, or mesoporous clay overlies the working and reference electrodes 44, 46.

The coating material 48 is applied by repeated dipping in a suspension or slurry of the coating material in a suitable solvent. After each impregnation and before the subsequent impregnation, the sensor element is dried to evaporate the solvent. Other materials may be incorporated into the coating by subsequent dipping in additional solutions or suspensions. The number of dips is determined by the desired thickness of the coating and the chemical composition is determined by the number and type of additional solutions into which the sensor is immersed.

There are obviously a number of other means by which coating thickness and composition can be similarly achieved, such as: padding (pad), jetting, silk screening, and other mechanical printing methods. Such techniques are well known in the art.

An alternative electrode arrangement is shown in fig. 4, in which parts common to the sensor element of fig. 3 are designated with the same reference numerals. It will be noted that the working electrode portions 44a and the reference electrode portions 46a are arranged in a close circular array. The electrodes and substrate were coated as described above with respect to fig. 3.

An enlarged schematic cross-sectional view through a portion of a sensor element of one particularly preferred embodiment is shown in fig. 13. The sensor element, generally designated 60, includes an inert substrate 62, on which substrate 62 working and counter electrodes 64 and 66 are deposited, for example using the screen printing technique described hereinabove. A layer 68 of ion exchange material is spread over the surfaces of the inert substrate 62 and the electrodes 64, 66. In fig. 13, the relative dimensions of the electrodes, their spacing and the thickness of the ion exchange layer are indicated. Specifically, electrodes having a track width (T)70 are separated by a gap (G) 72. The thickness (W) of the layer 74 of ion exchange material has the same general dimensions as the gap 72 between the electrodes.

Referring to fig. 14, the general distribution of mesoporous material particles within the ion exchange layer 68 of the sensor element of fig. 13 is shown in plan view. Thus, the working and counter electrodes 64, 66 are separated by a gap 72. The mesoporous material particles 76 are shown as being sparsely dispersed in the layer of ion exchange material. Fig. 14 is a diagram of a preferred sensor element of the general type, a practical example of which is shown in fig. 16, fig. 16 being an image obtained using a Scanning Electron Microscope (SEM) for mesoporous material particles dispersed on the electrode surface before coating with a layer of ion exchange material. The image of fig. 16 is discussed in more detail in example 3 below.

If the coating is considered to be a dielectric layer, the limiting factor for the sensor shown in FIGS. 13 and 14 would be the relative dielectric constant, which for zeolite is about 23 (compared to 3 for polyimide and 80 for water). The adsorption of water simultaneously increases the relative dielectric constant, which will improve the response speed. In other words, the response speed increases as the thickness of the ion exchange material layer decreases, and is fastest with the thinnest coating. In many cases of thin ion exchange material coatings, the layer will adsorb enough water to facilitate the measurement signal in the first few milliseconds. After the initial chemisorption, further (and continued) adsorption of water will not increase the signal significantly.

Whether the sensor impedance is resistive or capacitive, the sensor response time is always limited by the rate of adsorption/desorption of water from the ion exchange material layer and varies over a range of seconds to minutes. Therefore, substrate geometry and composition are important to optimize sensor performance. The use of thinner ion exchange material coatings dramatically reduces adsorption time; the characteristic diffusion time varies with the square of the film thickness. Many prior art devices have attempted to minimize desorption times by using polymer substrates that adsorb less moisture. Although this speeds up the response, it also reduces sensitivity. By incorporating the ion exchange material into a very thin layer with finely dispersed (particulate) mesoporous material, in particular zeolite, which also increases the surface area, response times of orders of magnitude less than those of prior art devices have been obtained.

The track-gap distance of the electrodes and the coating thickness of the ion exchange material define the overall performance of the sensor, in particular the response speed. In most cases, an electrochemical sensor can be represented as a (electrically equivalent) conventional resistor-capacitor combination. However, the sensors of the preferred embodiments of the present invention using ion exchange layers with finely dispersed mesoporous materials are more complex. The sensor may be interpreted as a two-electrode battery, represented as a set of resistors and capacitors. A typical representation is shown in fig. 15. In fig. 15, the implicit connector impedances (Rc and Cc) are shown and the components are assumed to be symmetrical (equal) at each electrode. Rs is the solution resistance to the adsorbed water layer. The term inter-electrode capacitance Ci is included to describe the dielectric properties of the solute (outside the diffusion layer). Finally, a frequency-dependent faraday impedance (Zf) is included for each electrode, the frequency-dependent faraday impedance (Zf) including both a charge transfer resistance and a Warburg (Warburg) impedance.

Analysis of experimental impedance data from sensors as shown in fig. 13 and 14 shows that the sensors can be modeled in terms of resistors and capacitors. Both the impedance and the capacitance of the coating change as a function of humidity. The impedance only limits the magnitude of the current through the sensor. Changing the capacitance changes the phase of the output signal (relative to the applied waveform). The high capacitance reduces the response speed by filtering the current flowing between the electrodes. The values of the resistors and capacitors are a function of the track width and gap distance, and of the ratio between the track and gap. The capacitance is primarily a function of the coating thickness.

In summary, as previously mentioned, the reaction speed of the sensor to changes in the concentration of water vapour in the monitored gas stream and the specificity of the sensor to water vapour are significantly improved by using a sensor element in which the electrodes are coated with a layer of ion exchange material, in particularThe layer of ion exchange material having a fine dispersion of mesoporous material particles, in particular zeolites, and wherein the layer of ion exchange material having finely distributed mesoporous particles is particularly thin.

Referring to fig. 5, there is shown a potentiostat electronic circuit that may be used to provide a voltage applied between a working electrode and a reference electrode of a sensor of the invention. The circuit, generally designated 100, includes an amplifier 102, identified as "OpAmp 1," which amplifier 102 acts as a control amplifier to receive an externally applied voltage signal V_IntoThe function of (1). Will come fromThe output of the OpAmp1 is applied to the control (counter) electrode 104. The second amplifier 106, identified as "OpAmp 2," converts the passage of current from the counter electrode 104 to the working electrode 108 into a measurable voltage (V)_{Go out}). Resistors R1, R2 and R3 are selected according to the input voltage and the measured current.

An alternative galvanostat circuit for exciting the sensor electrodes is shown in fig. 6. The control and working electrodes 104 and 108 are connected between the input and output of a single amplifier 112, denoted "OpAmp 1". Further, resistor R1 is selected according to the desired current.

Turning to fig. 7, an adapter for monitoring patient breathing is shown. In a manner similar to that shown in fig. 2 and described above, the sensor element is mounted within the adapter and directed directly into the airflow flowing through the adapter. The preferred embodiment illustrated in fig. 7 includes an adaptor, generally designated 200, having a cylindrical housing 202 with a male (push-fit) taper coupling 204 at one end and a female (push-fit) taper coupling 206 at the other end. A side inlet 208 is provided in the form of an aperture in the cylindrical housing 202 to allow the adapter to be used to monitor tidal breathing of a patient, as described in more detail in example 2 below. During inhalation by the patient through the device, the side inlet 208 directs gas onto the sensor element. Monitoring of tidal breathing may be improved by providing a one-way valve on the outlet of the housing 202.

Referring to fig. 8, a general design of a sensor system according to the invention is shown in schematic form. The system, generally designated 400, includes a sensor element having a counter electrode 402 and a working electrode 404. The voltage is applied to the counter electrode 402 by a control potentiostat 406 of the form shown in fig. 5 and described hereinabove. The input signal for controlling the voltage regulator 406 is provided by a digital-to-analog converter (D/a)408, to which digital input signal the microcontroller 410 provides itself. The output signal produced by the sensing element is in the form of a current at the working electrode 404, which is sent to a current-to-voltage converter 412, the output of which is in turn sent to an analog-to-digital converter (A/D) 414. Microcontroller 410 receives the output of a/D converter 414 and uses the output to generate a display indicative of the concentration of the target substance in the monitored gas stream. The display (not shown in fig. 8 for clarity) may be any suitable form of display, such as an audio display or a visual display. In a preferred embodiment, microcontroller 410 generates a continuous display of the concentration of the target substance, an arrangement that is particularly useful in monitoring tidal breathing in patients.

The invention will be further illustrated by the following examples.

Examples

Example 1

Analysis of the water and carbon dioxide content of the exhaled breath of the subject was obtained as follows:

the carbon dioxide content of the exhaled breath of the subject was analyzed by infrared mass spectrometry using known techniques and an Oxicap Model 4700 mass spectrometer (commercially available instrument, Datex-Ohmeda, louisivale, colorado). The results of the analysis are illustrated in fig. 9.

The water content of the same breath of the same subject was analyzed using a sensor as described above and shown in the figures. As described above, the sensor includes two electrodes having a coating comprising zeolite and highly fluorinated ion exchange resin (nafion). Breath analysis was performed by breathing the subject into a mouthpiece as shown in fig. 7, in which the electrochemical sensor of the above-described configuration was mounted. The output of the sensor is illustrated in fig. 9.

Referring to fig. 9, the results of the analysis of a single exhalation for a subject are shown in the figure. Data points related to carbon dioxide content are shown as light circles while those related to water content are shown as dark circles. The ratio of the data points is adjusted to achieve the best overlap of the two traces. The figure shows that there is a very strict correlation between the water content of the breath and the carbon dioxide concentration throughout the exhaled breath. The profile of the tracing has the shape of a typical capnogram as would be expected when measuring changes in carbon dioxide content throughout the exhaled breath. It can be seen that the tracing profile for water concentration follows the tracing profile for carbon dioxide over almost the entire breath.

It will be noted that the two tracing profiles differ in width, with the tracing for water being slightly wider than the tracing for carbon dioxide. This difference is explained by the arrangement of the conduits for guiding the exhaled breath to the relevant sensor device. As noted, the subject exhales through the mouthpiece and the conduit as described in fig. 7. Thus, the electrochemical sensor is placed in the mainstream of exhaled breath. To provide a flow to the mass spectrometer for analysis, a sample of exhaled breath is withdrawn as a sidestream and pumped to the mass spectrometer inlet.

It will thus be appreciated that detailed knowledge of the concentration of one of carbon dioxide or water in exhaled breath of a subject and the correlation between the two, as shown in figure 9, allows the concentration of the other components to be readily determined. This shows a significant discovery and provides a significant improvement over techniques that can be used to measure and analyze the composition of exhaled breath in a subject. This in turn will greatly assist the medical practitioner (medicalpractioner) in diagnosing a range of respiratory disorders.

Example 2

Referring to fig. 10, a graph is shown of carbon dioxide concentration plotted against time obtained from measuring the carbon dioxide concentration in the exhaled air stream throughout the exhalation process. This form of map is known in the art as a "capnogram". Similar profiles are obtained from other gas components in the exhaled gas stream, most particularly water vapor. The following analytical techniques may be equally applied to similar profiles obtained from components other than carbon dioxide.

The trace in fig. 10 may be characterized as having inflection points, denoted as A, B, C, D and E, that generally divide the trace into four stages. Stage I is the volume of gas without carbon dioxide, soThe gas is generated at the beginning of the subject's exhalation. Phase II is an ascending phase characterized by a rapid increase in carbon dioxide concentration and exhibiting a transition from non-carbon dioxide containing gas to the early emptying portion of the lungs. Phase III is the (alveolar) plateau phase and corresponds to the late emptying part of the lungs, where the carbon dioxide concentration continues to increase slowly over time. Point D generally represents the tidal concentration Limit of carbon dioxide (PetCO)₂). Stage IV of the plot is the final stage where the carbon dioxide concentration rapidly drops to that of the ambient gas composition.

Two midpoints can be identified, namely BC50 between points B and C and DE50 between points D and E. These midpoints are used to define data points within the shape analysis.

The slope 1 shown in fig. 10 is the slope of the trace in the rising phase, phase II. The slope may be calculated in any suitable manner, for example as a tangent to the curve at the midpoint BC 50.

Slope 2 shown in fig. 10 is the slope of the plateau phase, i.e., phase III.

Finally, the slope 3 is the slope of the falling phase, i.e. phase IV. Again, this may be calculated using any suitable technique and may be, for example, a tangent to the point DE 50.

The area depicted near point C typically contains a "shoulder" and can be mathematically represented using general equation 1.

Wherein Y is the concentration of carbon dioxide and X is time.

The coefficient "a" in equation 1 determines the shape of the curve and may be used to represent the degree of curvature of the plot. The curvature of the shoulder varies according to the subject's lung function. Specifically, a plot for normal lung function provides a value of a ═ 1. an increase in the value of a indicates a decrease in lung function, particularly in the absence of breathing in the subject. Thus, the coefficient a may be used to provide a numerical scale of the subject's degree of non-respiration. An example of a plot with varying values of the coefficient a (a-1, a-20, a-100) is shown in fig. 11.

The inverse operation of equation 1 is represented by equation 2 below:

aX²＝Y’＝(1/(Y-1))^1/2 (2)

equation 2 can be used to linearly transform the trace data so that standard regression techniques can be applied to the data generated by the measurement of gas concentration to provide a best fit line and find the coefficients of the best fit line. In particular, the plot of Y' against time (X) is represented by a straight line, where the slope of the line is a coefficient a, and a best-fit analysis may be used to find the best-fit straight line, and hence the best value of the coefficient a, for the resulting measurement data. An exemplary plot of Y' versus time (X) is shown in fig. 12.

The deviation of the actual data points from the lines of fig. 12 can be used to estimate the fitting confidence (fitting confidence) of the coefficients with respect to the resulting data and/or to represent the noise level in the data.

Other techniques may also be used to analyze the resulting data, with the alternative of expressing equation 1 as follows:

and

example 3

A sensor having the general configuration shown in fig. 2 and 3 was prepared. The electrodes were coated with an ion exchange layer comprising a commercially available sulfonated tetrafluoroethylene copolymer (A)DuPont (DuPont) ex d.) and zeolite 4A. The coating was prepared as follows:

the suspension of the zeolitic material was suspended in 10ml of methanol. The zeolite has a uniform particle size range of about 1 micron particle size.

The suspension was sonicated for 10 minutes to ensure uniform dispersion of the zeolite in the solution. Ultrasonic baths or probes may also be used. The electrode to be coated was then immersed in the solution and held for 2 seconds before removal. The electrode was laid flat and the solvent was allowed to evaporate naturally. If necessary, forced air convection (forced air convection) may also be used to accelerate the evaporation of the solvent.

The electrode was examined using Scanning Electron Microscopy (SEM) to determine the distribution of zeolite particles on the electrode. The results are shown in fig. 16. As can be seen, in the case where the interval between particles is generally at least 1 particle diameter, zeolite particles are finely dispersed on the surface of the electrode.

With the sensor still in a horizontal position, a tiny volume of highly fluorinated ion exchange resin (Nafion) polymer is then dispensed onto the surface of the sensor using a syringe, and the edge of the syringe needle used to dispense the fluid is spread over the entire surface of the sensor. The solvent is again allowed to evaporate naturally.The volume is such that: ensuring complete coverage of the surface area of the sensor and ensuring that the resulting film thickness is as small as possible. Typical volumes are in the range of 1 to 10ul to cover 1cm²Preferably 2 ul. The resulting thickness of the remaining layer (after evaporation of the solvent) should be reasonably thin to fit the intended application. In practice, layer thicknesses of 10 to 1000nm, preferably 100nm, can be achieved using this method.

The sensor is used to analyze the composition of the exhaled breath of the patient, in particular the water vapor content of the exhaled breath, by having the patient inhale and exhale through the combination of figure 2. The resulting trace of water vapour concentration versus time, from which it can be seen that the sensor produced a very accurate trace of the concentration of water in exhaled breath as a function of time, is shown in figure 17.

It has been found that the sensor of this embodiment provides a very fast response to changes in water vapour concentration in the gas stream being in contact with the sensor element, while providing an output signal that allows a very accurate determination of the changes in water vapour concentration. This in turn allows the sensor to be very accurate in detecting water vapour, providing a means for accurately tracking changes in the water vapour content of the exhaled airflow of the subject over short, medium and long periods.

Claims (62)

1. A method for determining respiratory function of a subject, the method comprising:

measuring the concentration of water vapor in the airflow exhaled by the subject; and

determining respiratory function of the subject from the measured water vapor concentration.

2. The method of claim 1, wherein the water vapor concentration is measured for at least one complete exhalation duration.

3. The method of claim 2, wherein the water vapor concentration is measured during tidal breathing of the subject.

4. The method of claim 1, wherein the exhaled gas stream is exhaled from the mouth of the subject.

5. The method of claim 1, wherein the water vapor content is measured using an electrochemical sensor.

6. The method of claim 5, the method comprising:

impinging the gas stream on a sensing element comprising a working electrode and a counter electrode;

applying an electrical potential between the working electrode and a counter electrode;

measuring a current flowing between the working electrode and a counter electrode as a result of the applied potential; and

determining an indication of the water vapour concentration in the gas stream from the measured current.

7. The method of claim 6, wherein a constant voltage is applied between the working electrode and the counter electrode.

8. The method of claim 6, wherein a variable voltage is applied between the working electrode and the counter electrode.

9. The method of claim 8, wherein the variable voltage alternates between a rest potential and a potential above a reaction threshold potential.

10. The method of claim 9, wherein the voltage is pulsed at a frequency of 0.1Hz to 20 kHz.

11. The method of claim 5, wherein the electrochemical sensor comprises a plurality of electrodes and a layer of ion exchange material extending between the electrodes, the layer of ion exchange material comprising mesoporous material particles dispersed therein.

12. The method of claim 11, wherein the dispersion of mesoporous material is a fine dispersion.

13. A method for determining lung function in a subject, the method comprising:

measuring a change in concentration of a gas component of the exhaled gas flow of the subject;

determining the concentration change as a function of time for the exhaled gas stream to obtain a concentration over time profile;

measuring the slope of the rising phase of the profile; and

using the slope of the ascending phase to make a determination of the subject's lung function.

14. The method of claim 13, wherein the gas component is selected from the group consisting of carbon dioxide and water vapor.

15. The method of claim 13, further comprising measuring a slope of a plateau phase of the profile.

16. The method of claim 15, wherein a ratio of slopes of the rise phase and the plateau phase is determined.

17. A method for determining lung function in a subject, the method comprising:

measuring a change in concentration of a gas component of the exhaled gas flow of the subject;

determining the concentration change as a function of time for the exhaled gas stream to obtain a concentration over time profile;

analyzing a portion of the profile in a region of transition from a rise phase to a plateau phase; and

using the results of the analysis to make a determination of lung function in the subject.

18. The method of claim 17, wherein the analyzing comprises applying a regression technique to the data of the distribution curve.

19. The method of claim 17, wherein the analyzing comprises applying a best fit technique to the data of the distribution curve.

20. The method of claim 17, wherein the analyzing comprises representing a portion of the profile in a region of the transition from the ascending phase to the flat-top phase with equation 1:

wherein Y is the concentration of carbon dioxide and X is time.

21. The method of claim 20, wherein a best fit analysis is applied to the curve of Y 'versus time, wherein Y' is defined by equation 2:

Y’＝(1/(Y-1))^1/2 (2)

and the slope of the line thus obtained is determined to provide the value for the coefficient a in equation 1.

22. The method of claim 21, wherein the value of the coefficient a is used to provide an indication of lung function.

23. The method of claim 17, wherein the gas component is selected from the group consisting of carbon dioxide and water vapor.

24. A method for monitoring lung function in a subject, the method comprising the steps of:

measuring a change in concentration of a gas component of the exhaled gas flow of the subject;

determining the concentration change as a function of time for the exhaled gas stream to obtain a concentration over time profile;

comparing the profile thus obtained with a pre-existing profile; and

a comparison is used to make a determination of the subject's lung function.

25. A method according to claim 24, wherein the profile so obtained is compared with a plurality of pre-existing profiles to provide a pattern of lung function over time.

26. The method of claim 24, wherein the pre-existing profile is a profile obtained from the subject.

27. The method of claim 24, wherein the pre-existing profile is a profile that exhibits normal lung function.

28. The method of claim 24, wherein the gas component is selected from the group consisting of carbon dioxide and water.

29. A device for monitoring lung function of a subject, the device comprising:

means for measuring a change in concentration of a gas component of the exhaled gas flow of the subject;

means for determining said concentration change as a function of time for said exhaled gas stream to obtain a concentration over time profile;

means for storing a plurality of profiles; and

means for comparing the profile thus obtained with a pre-existing profile extracted from the storage means.

30. The apparatus of claim 29, wherein the means for storing a plurality of profiles is adapted to store a plurality of pre-existing profiles.

31. The apparatus of claim 29, wherein the means for comparing profiles comprises a display means for displaying a plurality of profiles for visual comparison by a user.

32. The apparatus of claim 29, wherein the means for comparing profiles comprises means for performing a mathematical analysis of profiles.

33. A method for determining the carbon dioxide content of an exhaled gas stream, the method comprising:

measuring the water vapor content of the exhaled gas stream; and

determining a carbon dioxide concentration in the exhaled gas stream from the measured water vapor content.

34. The method of claim 33, wherein the exhaled gas stream is exhaled from the mouth of the subject.

35. The method of claim 33, wherein the water vapor content is measured using an electrochemical sensor.

36. The method of claim 35, the method comprising:

impinging the gas stream on a sensing element comprising a working electrode and a counter electrode;

applying an electrical potential between the working electrode and a counter electrode;

measuring a current flowing between the working electrode and the counter electrode as a result of the applied potential; and

determining an indication of the water vapour concentration in the gas stream from the measured current.

37. The method of claim 36, wherein a constant voltage is applied between the working electrode and the counter electrode.

38. The method of claim 36, wherein a variable voltage is applied between the working electrode and the counter electrode.

39. The method of claim 38, wherein the variable voltage alternates between a rest potential and a potential above a reaction threshold potential.

40. The method of claim 39, wherein the voltage is pulsed at a frequency of 0.1Hz to 20 kHz.

41. A sensor for determining the concentration of carbon dioxide in an exhaled gas stream, the sensor comprising:

means for determining a concentration of water vapor in the exhaled gas stream;

means for calculating a carbon dioxide concentration in the exhaled gas stream from the measured water vapour concentration.

42. The sensor of claim 40, comprising:

a sensing element disposed to be exposed to the airflow, the sensing element comprising:

a working electrode; and

a counter electrode.

43. The sensor of claim 42, further comprising a conduit through which the airflow is directed to impinge on the sensing element.

44. The sensor of claim 43, wherein the conduit includes a mouthpiece into which a patient can exhale.

45. The sensor of claim 42, wherein the working and counter electrodes are in a form selected from the group consisting of a point, a line, a loop, and a flat plane.

46. The sensor of claim 42, wherein one or both of the working electrode and the counter electrode comprise a plurality of electrode portions.

47. The sensor of claim 46, wherein the working electrode and the counter electrode both comprise a plurality of electrode portions arranged in an interlocking pattern.

48. The sensor of claim 47, wherein the electrode portions are arranged in a concentric pattern.

49. The sensor of claim 42, wherein the surface area of the counter electrode is greater than the surface area of the working electrode.

50. A sensor according to claim 49, wherein the surface area ratio of the counter electrode to the working electrode is at least 2: 1, more preferably at least 5: 1.

51. The sensor of claim 42, wherein the electrodes are supported on an inert substrate.

52. The sensor according to claim 42, wherein each electrode comprises a metal selected from group VIII of the periodic Table of the elements, copper, silver and gold, preferably gold or platinum.

53. The sensor of claim 42, further comprising a layer of insulating material disposed over a portion of each electrode, the insulating layer shaped to expose a portion of each electrode for contact with a gas stream.

54. The sensor of claim 42, further comprising a reference electrode.

55. The sensor according to claim 42, wherein the electrodes are mounted on a substrate, the electrodes being applied to the substrate by thick film screen printing, spin/sputter coating or visible/ultraviolet/laser lithography.

56. The sensor of claim 42, wherein one or more electrodes comprise multiple layers, the outer layer being a pure metal layer applied by electrochemical plating.

57. A system for monitoring the composition of a gas stream, the system comprising:

the sensor of claim 41;

a microcontroller for receiving an output from the sensor; and

a display; wherein

Programming the microcontroller to generate a continuous image of the carbon dioxide concentration in the gas stream analyzed on the display.

58. Use of the method of any one of claims 1 to 28 or 33 to 40 in providing an indication of lung function in a subject.

59. The use of claim 58, wherein the indication relates to the presence of a lung disease comprising asthma, COPD, Tuberculosis (TB), or lung cancer.

60. The use of claim 58, wherein the indication relates to a disease or condition in which the subject is indirectly associated with the lung.

61. The use according to any one of claims 58 to 60, wherein the method is for comparison with one or more other pulmonary function tests.

62. The use of claim 61, wherein the other pulmonary function tests comprise FEV1 and FVC.