Breath sampling device

Abstract

The present techniques relate to a breath sampling device, and in particular a breath sampling device for capturing volatile organic compounds in a user's breath. The breath sampling device comprising a housing which comprises an inlet, outlet, flow path, mechanical pressure regulator for regulating the pressure within the housing when breath is flowing through the flow path and at least one mechanical flow rate controller to control a flow rate of a breath along the flow path. In use, the breath sampling device may comprise a sorbent capsule. The breath sampling device may have two modes of operation, an activated state for sampling a user's breath and a deactivated state in which there is no breath flow into the sorbent capsule and optionally for removing the sorbent capsule for analysis. The pressure regulator and at least one flow rate controller are configured to provide a flow rate through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet whereby a controlled amount of breath is sampled from each of a plurality of breaths received from a user through the inlet.

Description

[0001] BREATH SAMPLING DEVICE

[0002] FIELD

[0003]

[0001] The present techniques relate to a breath sampling device, and in particular a breath sampling device for capturing volatile organic compounds in a user’s breath.

[0004] BACKGROUND

[0005]

[0002] Breath sampling devices are known in the art, such as the ReCIVA® Breath Sampler which is described for example in patent publications W02017 / 187120 or WO2017 / 187141. This breath sampler can collect volatile organic compounds and respiratory droplet samples from exhaled breath. The breath sampling device provides non-invasive sampling during normal tidal breathing with options for breath fraction targeting while ensuring patient safety and comfort. The device typically comprises a plurality of sorbent tubes which are used to sample the breath. Only a small amount of the exhaled breath (circa 2%) is typically sampled by each sorbent tube in the device. Given that only a small amount of the exhaled breath is captured in each breathing cycle, it is typically necessary to capture several breaths to ensure that a sufficient volume of exhaled breath has been sampled. The sorbent tubes are typically expensive, particularly when a relatively large amount (e.g. over 200mg) of sorbent material is used.

[0006]

[0003] The applicant has recognized the need for an alternative breath sampling device.

[0007] SUMMARY

[0008]

[0004] According to the present techniques, there is provided a device as set forth in the appended claims. Other features of the invention will be apparent from the dependent claims, and the description which follows.

[0009]

[0005] There is provided a passive breath sampling device comprising: a housing comprising an inlet section comprising an inlet for receiving at least one breath in the housing; an outlet for a first portion of each received breath to exhaust from the inlet section of the housing; and an inlet section flow path between the inlet and the outlet of the inlet section; and a sorbent section housing a sorbent capsule having a sorbent material for collecting a target compound from each received breath. The device further comprises a mechanical pressure regulator to regulate pressure within the inlet section of the housing when a breath is flowing along the inlet section flow path; at least one mechanical flow rate controller to control a flow rate of a second portion of each received breath from the inlet section to the sorbent section; and an activation mechanism which is usable to select an activated mode or a deactivated mode for the breath sampling device. In the deactivated mode, a flow path for the second portion of each received breath from the inlet section to the sorbent section is blocked; and in the activated mode, the flow path for the second portion of each received breath from the inlet section to the sorbent section is open and the second portion of each received breath flows along a sample flow path through the sorbent capsule. The pressure regulator and at least one flow rate controller are configured to provide a flow rate of the second portion of each received breath through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet, whereby, in the activated mode, a controlled amount of breath is sampled from each received breath. The first portion of each received breath may be termed an exhaust portion and the second portion of each received breath may be termed a sample portion.

[0010]

[0006] In other words, there is provided a breath sampling device comprising a housing. The housing comprises an inlet for receiving a breath into the housing; an outlet for breath to exit the housing; a fluid path between the inlet and the outlet; a mechanical pressure regulator to regulate pressure within the housing when a breath is flowing along the fluid path; and at least one mechanical flow rate controller to control a flow rate of a breath along the fluid path. The housing is for housing a sorbent capsule having a sorbent material for capturing (collecting) at least one target compound within a breath flowing along the fluid path. More specifically, the fluid path may comprise an inlet section flow path between the inlet and outlet of an inlet section and a sample flow path after the inlet section flow path and along which the sorbent capsule is located. The sample flow path may be connect to the outlet which may be a venting outlet. In use, the breath sampling device comprises the sorbent capsule housed in the housing. The breath sampling device is configurable to operate in two modes: an activated mode and a deactivated mode. The terms modes may be used interchangeable with states. The device further comprises an activation mechanism which is usable to select the activated mode or the deactivated mode for the breath sampling device. In the deactivated mode, the flow path from the inlet to the sorbent capsule is blocked and in the activated mode, the flow path from the inlet to the sorbent capsule is open to allow sampling.

[0007] The pressure regulator and at least one flow rate controller may be configured to optimise the flow rate of the or each breath through the sorbent material. In this way, the breath sampling device is designed to achieve a stable range of sampled flow rate which has low variance or is generally constant when in use. As an example, low or generally constant means that there is less than 20% variance in the sampled flow rate. The stable flow rate which may also be termed a nominal flow rate may be achieved even when receiving breaths having different flow rates, e.g. ranging from 10 - 80 L / min at the inlet. For example, the generally constant flow rate may be around 100ml / min. In other words, optimising the flow rate may comprise correcting an input flow rate of breath into the device which may be between 10 L / min to 80 L / min so that breath passes through the sorbent material at a generally constant flow rate, for example of 100ml / min. The fluid path may be termed a flow path and the terms may be used interchangeably. The sorbent material may be for collecting at least one target analyte (or target compound and the terms are used interchangeably) and may be for collecting multiple target compounds or families of compounds, e.g. short chain fatty acids and / or volatile compounds.

[0011]

[0008] The nominal flow rate which is achieved through the sorbent capsule is controlled by the pressure within the device and the flow resistance of the components within the inlet section and sample flow paths (including the components of the sorbent tube and other components which are downstream from the sorbent tube). The pressure regulator and at least one flow rate controller are thus configured to balance the flow rate by compensating for the pressure and flow resistance from the other components. The pressure regulator and the at least one flow controller are mechanical. In other words, they are not electronic and thus the nominal flow rate is adjustable mechanically to achieve the desired low variance across a range of input breath flows. The pressure regulator and the at least one flow controller may also be passive. In other words, a user’s breath flowing through the device operates the pressure regulator and the at least one flow controller. The pressure regulator and the at least one flow controller are not controlled electrically or electronically. For example, the pressure regulator may comprise at least one mechanical valve, e.g. an umbrella valve. Then at least one flow controller may be a venturi constriction, an orifice or other physical restriction. The at least one flow rate controller may control the flow rate linearly or non-linearly. Thus, in contrast to the ReCIVA® device which is described in the background section, the present device does not employ external air supplies or internal pumps and is thus a passive device.

[0009] The pressure regulator and the at least one flow controller may be collectively termed passive flow regulation components. In other words, there is provided a device which may be entirely passive and which, by virtue of the passive components, in use provides a low but highly controlled flow rate over the sorbent material. In this way, the target compound (also termed analyte) is taken from the highly controlled sample flow and thus may be collected using total absorption without any diffusion. The control of the sample flow rate may be achieved through a combination of different passive flow regulation components for example an orifice, a venturi and / or a low cost pressure regulator. The components may be optimised to operate even when there are small differences in pressure between two points in the system. In other words, the pressure regulator and at least one flow rate controller are configured to operate, in the activated mode, at extremely low-pressure differentials such as 0-5 mbar. As explained in more detail below, the low pressure differences within the device, and in particular the low pressure which is required to operate or open components means that after the device has been stored for a while, it may be difficult to use the device.

[0012]

[0010] The proposed level of control of the flow rate of the second portion of the breath through the sorbent capsule may thus create a reliable, i.e., low variability, breath sample. A total volume sample from an exhaled breath may be captured and this may be achieved via consistent and short collection times for user comfort and compliance. In this way, the proposed breath sampling device may be designed to provide test results that are at least as effective as the ReCIVA® breath sampler which is cheaper to produce, and easier and more comfortable to use.

[0013]

[0011] The pressure regulator may be configured to generate a positive pressure within the device when a breath is being received into the device, e.g. when a user of the device is exhaling. The pressure regulator may comprise at least one valve, e.g. an umbrella valve, duckbill valve, a positive end expiratory PEEP valve, which has a cracking pressure at the positive pressure. In other words, the valve is closed until the cracking pressure is reached and thereafter the valve remains open to maintain the pressure at or above the desired positive pressure. Such valves may be termed passive valves because they are opened by the breath flow rather than by an electronic or other mechanism. The desired positive pressure may be between Ombar to 20mbar, more preferably between 5mbar to 10mbar. In other words, the desired positive pressure may be described as the pressure needed to open the valve and this is ideally between 5mbar and 10mbar. A positive pressure of 5mbar is generally sufficient for a sample to be readily collected, i.e. is a positive pressure which is easily applied by a user’s breath. A positive pressure of 10mbar or higher typically reduces comfort for the user exhaling into the device and can interfere with normal breathing patterns. The pressure regulator may comprise a pair of valves, an exhalation valve (also termed an exhaust valve) which opens when a user exhales into the device and which is closed when a user inhales and an inhalation valve which opens when a user inhales from the device and which is closed when a user exhales into the device. The exhalation valve and the inhalation valve may each be different types of valves or they may be the same type of valve. For example, the exhalation valve and the inhalation valve may independently be an umbrella valve, duckbill valve and / or a positive end expiratory PEEP valve. The exhalation valve may be opened by a received breath that exceeds the cracking pressure to provide the outlet for the first portion of each received breath to exhaust from the inlet section of the housing. Similarly, the inhalation valve may be opened by an inhalation by the user that exceeds the cracking pressure.

[0014]

[0012] The at least one flow rate controller may provide a venturi effect to control the pressure within the system which as a result controls the flow rate through the sorbent (i.e. from the inlet section into the sorbent section and hence through the sorbent). The venturi effect may create local control of pressure within the system and may control the pressure in a non-linear manner. For example, the at least one flow rate controller may be a venturi restriction of any suitable form, e.g. venturi meter, a venturi nozzle or an orifice plate having a narrow section. The at least one flow rate controller may comprise a narrow section having a diameter which is selected, together with the other components within the device, to provide a flow rate through the sorbent capsule when the sorbet capsule is located in the device which is generally constant (e.g. 100ml / min) for a range of flow rates of breath (e.g. between 10 L / min to 80 L / min) into the inlet. The narrow section may have a diameter of between 5 mm to 7.5 mm, for example 6.5mm to 7.5mm. The at least one flow rate controller which provides a venturi effect may be located between the inlet and the sorbent capsule on the flow path. More specifically, the venturi restriction may directly connect the inlet section to the sorbent section. In this way, the sorbent section and hence the sorbent capsule may be connected to a narrowest part of the venturi.

[0013] The at least one flow rate controller may comprise an orifice which may be located after the sorbent capsule on the flow path, more specifically downstream from the sorbent capsule on the sample flow path. The orifice may have a fixed diameter, e.g. 5 or 6mm. The orifice may have a variable diameter whereby the flow rate through the device is adjustable. As described above, the flow rate through the sorbent capsule is generally constant in the activated mode but generally constant means that there may still be a variation of up to 20% for different flow rates of breath through the inlet. The orifice may be used in addition to the venturi to further tune the flow rate to further reduce variation in the flow rate.

[0015]

[0014] The at least one flow rate controller may comprise a restriction which may be located in the inlet section, for example near or adjacent the pressure regulator. The restriction may be in the form of a narrower diameter or orifice. Such a restriction may be used to increase the pressure within the device and hence make the device harder to breathe through at higher flow rates. Such a restriction may be useful when the device is used by users with a high rate of breath (i.e. those who breath very hard) to reduce the flow rate through the inlet section and hence reduce the flow of the second portion of the breath into the sorbent section and through the sorbent.

[0016]

[0015] A plurality of breaths may be received through the inlet. Each breath may have a volume of approximately 500ml with approximately 5 to 15 ml of each breath being sampled (i.e. collected) by the sorbent capsule. In other words, the second portion of each received breath may be between 5 to 15ml. The device may thus be used by a user, e.g. a patient, for a fixed period of time such as a few minutes such as 2 or 3 minutes or a fixed number of breaths such as 10 to 28 breaths so that a target fixed volume of breath, e.g. 100ml, is captured by the sorbent capsule.

[0017]

[0016] The device may comprise a metering device which provides an indication that indicates the target fixed volume has been sampled. The metering device may be external to the housing. The metering device may be connected to the sorbent section, downstream from the sorbent capsule so that the second portion of the breath passes through the sorbent capsule and then into the metering device. The housing may further comprise a venting outlet for venting breath which passes along the sorbent section flow path, e.g. to vent breath captured in the metering device. The metering device may be connected to the housing to complete the fluid path between the inlet and the venting outlet of the housing. The metering device may be located between the sorbent capsule and the venting outlet. Alternatively, there may be a first path through the housing between the inlet and the venting outlet, i.e. from the inlet section into the sorbent section and from the sorbent section into an outlet section. The metering device may be connected to the housing to form a second, different path between the inlet and the venting outlet.

[0018]

[0017] The target fixed volume may be defined by the breakthrough volume which is the retention volume of a specific compound or compounds by the sorbent material. In other words, the retention volume may be the volume of a specific compound or compounds in an exhaled breath which is actually sampled by the sorbent material as the exhaled breath passes through the device. The breakthrough volume can also be defined as the retention volume of the sorbent for specific compound(s) under defined conditions, such as humid and / or other conditions which are typically found in breath. The breakthrough volume may be proportional to the amount of breath which has passed through the device and the air speed through the sorbent and thus the target fixed volume of breath may be measured.

[0019]

[0018] The metering device may be in the form of an inflatable bag which in use inflates as breath(s) is received into the inlet. When the bag is fully inflated, the bag is taut which provides a visual indicator to the user that the target fixed volume has been reached. The metering device may comprise a colour changing indicator, specifically an indicator which is sensitive to a compound in the breath, e.g. carbon dioxide CO2. A rapid colour change may occur once a certain volume has passed through the indicator.

[0020]

[0019] The metering device may comprise a chemical depletion capsule which has a predetermined quantity of a pre-loaded chemical and during use, there is a depletion of the pre-loaded chemical, e.g. by the preloaded chemical being removed by air flowing through the device. The device may also comprise a sensor which detects depletion of the specific chemical as breath passes through the device. Alternatively, the chemical depletion capsule may be integrated with the removeable sorbent capsule or may be separately removably mountable within the device so that a sensor in a remote location, e.g. a laboratory, may be used to analyse the depletion of the chemical. The quantity of the chemical may be detected by the chemical depletion sensor and the quantity of breath may then be calculated by analysing the detected quantity. Merely, as an example, the sorbent capsule may comprise a molecular sieve which is uniformly loaded with 1 j g of the detectable chemical and which has a breakthrough volume of 150ml. After sampling a nominal volume of breath, say 100ml, the amount (which will be less than the original 1 .g) of the detectable chemical is detected (i.e. measured) by the sensor and a calibration curve between the sample volume and the remaining amount of chemical (or similar) may be used to estimate the sampled volume and determine whether the breakthrough volume has been achieved. It will be appreciated that more than one detectable chemical may be pre-loaded and each detectable chemical may be measured separately.

[0021]

[0020] The device may further comprise a one-way valve after the sorbent capsule. The one-way valve allows flow from the inlet through the sorbent capsule but prevents flow back through the sorbent capsule to the inlet, for example when a user is inhaling or when the metering device is full to capacity or when the device is not being used. When a metering device is used, the one-way valve may be between the metering device and the sorbent capsule. The one-way valve may be any suitable valve which has a cracking pressure at which the valve opens. The cracking pressure may be between Ombar to 20mbar, more preferably between 5mbar to 10mbar for the same reasons above. For example, the one-way valve may be a duckbill valve. Such valves may be termed passive valves because they are opened / closed by the breath flow rather than by an electronic or other mechanism.

[0022]

[0021] When the breath sampling device is not being used, e.g. when the device is stored ready for use, the one-way valve may develop excessive stiction between the two sealing surfaces. The skilled person will understand that stiction means that the surfaces of the valve have stuck together. Thus, when a user is exhaling into the device, stiction may prevent the one-way valve opening even though the pressure within the sorbent section exceeds the standard cracking pressure of the one-way valve (e.g. above 5mbar). Thus, the device does not operate as intended, with all the exhaled air passing through the outlet of the inlet section rather than allowing the second portion of the breath through the flow controlled path in the sorbent section.. The one-way valve may comprise two adjacent sealing surfaces and the device may further comprise a valve manipulation mechanism (also termed wiper mechanism) for separating the sealing surfaces within the one-way valve. It will be appreciated that the valve manipulation mechanism may be incorporated into any breath sampling device having a one-way valve which is subject to stiction.

[0023]

[0022] There is provided, according to a different aspect of the present techniques a breath sampling device comprising: a housing comprising an inlet section comprising an inlet for receiving at least one breath in the housing; an outlet for at least some of each received breath to exhaust from the inlet section of the housing; and an inlet section flow path between the inlet and the outlet of the inlet section; and a sorbent section housing a sorbent capsule having a sorbent material for collecting a target compound from a sampled portion of each received breath. The device further comprises an activation mechanism which is usable to select an activated mode or a deactivated mode for the breath sampling device. In the deactivated mode, a sample flow path for the sampled portion of each received breath from the inlet section to the sorbent section is blocked; and in the activated mode, a sample flow path for the sampled portion of each received breath from the inlet section to the sorbent section is open. The device further comprises a one-way valve after the sorbent capsule and a valve manipulation mechanism for separating the sealing surfaces of the one-way valve as the breath sampling device is changed from the deactivated state to the activated state.

[0024]

[0023] The valve manipulation mechanism may comprise an elongate body comprising at least one protrusion which is configured to engage with and temporarily open the oneway valve. The at least one protrusion may be located toward a first end of the elongate body, wherein the first end is adjacent the valve. The at least one protrusion may comprise multiple protrusions, e.g. at least two or three protrusions. When there are multiple protrusions, each protrusion may be spaced along the elongate body with a distance of between 1 to 3 mm between each protrusion. The protrusion closest to the first end may be termed the first protrusion and the protrusion adjacent the first protrusion may be termed the second protrusion and so on. Each protrusion may be triangular. Each protrusion may protrude from the elongate body by between 1 to 2 mm. When there is more than one protrusion, the protrusions may protrude by different amounts. For example, a first protrusion closest to the first end may be smaller than an adjacent, second protrusion which is smaller than a third protrusion and so on.

[0025]

[0024] The breath sampling device may comprise an activation mechanism, e.g. at least one button, switch, slider and so on, to select the activated mode or the deactivated mode. For example, the activation mechanism may comprise an activation button to select the activated mode and a deactivation button to select the deactivated mode. The activation mechanism may be mechanical and may trigger movement of components within the device. The activation mechanism may also be used to trigger movement of the valve manipulation mechanism when one is used. In this way, when passing from the deactivated state to the activated state the valve may be mechanically manipulated, i.e. opened, by the valve manipulation mechanism. When the valve manipulation mechanism comprises at least one protrusion, each protrusion on the valve manipulation mechanism protrudes between the sealing faces to separate them temporarily. When there are multiple protrusions, the sealing faces are separated multiple times as the device is activated. The valve manipulation mechanism may be integrated with the activation mechanism, or it may be mechanically connected to the activation mechanism.

[0026]

[0025] There may be flow path through the housing. The flow path may be considered to have an inlet section which is connected to the inlet, an outlet section which is connected to the venting outlet and a sorbent section which is between the inlet section and the outlet section. When a metering device such as the bag is used, the metering device may be used to connect the sorbent section to the outlet section. In other words, there may be an aperture on the housing through which breath can flow into the metering device from the sorbent section of the flow path and a second aperture on the housing through which breath can flow back into the device, specifically into the outlet section. Alternatively, the outlet section may be directly connected to the sorbent section. The metering device may be connected to both the sorbent section and the outlet section, for example at a location of the connection between the sorbent section and outlet section. When a valve manipulation mechanism is used, this may be located in the outlet section.

[0027]

[0026] In the activated mode, when the device comprises a venting outlet, the venting outlet may be closed. This may be useful when a metering mechanism such as the inflatable bag is used. Flow of the second portion of each received breath out of the device is prevented and thus the target volume may be determined by the metering device. When breath is stored in the device, e.g. in the bag, in the deactivated mode, the venting outlet may be open to allow stored breath to vent from the device. For example, breath may flow from the metering device, through the outlet section of the flow path to the venting outlet. When a valve manipulation mechanism is used, this may be used to close the venting outlet. The valve manipulation mechanism may comprise a seal at the opposed end of the elongate body to the first end. The seal may be used to prevent ambient ingress into the outlet section and subsequently into the sorbent capsule.

[0028]

[0027] The device may further comprise a moveable component housing the sorbent capsule wherein in the deactivated mode, the moveable component is in a first location which blocks or seals the flow path from the inlet to the sorbent capsule and in the activated mode, the moveable component is in a second location which opens the flow path from the inlet to the sorbent capsule, i.e. opens the flow path from the inlet section to the sorbent section. For example, when there is an inlet section and a sorbent section of the flow path, there may be a connector which fluidly connects the inlet section to the sorbent section, e.g. using the venturi restriction. The first location of the moveable component may block flow from the inlet section to the sorbent section by blocking the connector and the second location of the moveable component may be spaced away from the connector to allow the flow. In other words, the sorbent is sealed to prevent flow into or out from the sorbent. The moveable component may be a piston or similar device.

[0029]

[0028] In the deactivated state, the sorbent capsule may be removed from the housing, e.g. for subsequent analysis. In other words, the sorbent capsule may be removably insertable or removably housed in the device. This allows for the same device to be used for multiple users. The housing may comprise multiple parts which are detachable from one another to allow access to the sorbent capsule. The housing may be dismantled manually or using a dismantling mechanism.

[0030]

[0029] As explained above, in the deactivated mode, the flow path from the inlet to the sorbent capsule may be sealed or blocked. The sealing may be achieved by movement of a moveable component and may thus be a mechanical seal. It will be appreciated that other types of seals may be used. The seal may be adjacent or close to a first end of the sorbent capsule and may be termed a first seal. The device may further comprise a seal downstream from the sorbent capsule on the sorbent section flow path e.g. between the sorbent section and the venting outlet or between the sorbent capsule and the metering device when one is used. More specifically, the seal may be adjacent or close to a second end of the sorbent capsule and may be termed a second seal. The second seal may be a diffusive seal or may be a mechanical seal.

[0030] When a new sorbent capsule is inserted into the device, it is desirable to prevent ambient ingress (contamination) prior to activation and use of the device by a user. In the deactivated mode, the first and second seals protect the sorbent from such ambient ingress. Preventing ingress keeps the sorbent clean before sampling, which ensures the sorbent has adequate capacity. After a sample has been collected, the device is returned to the deactivated state and the first and second seals also ensure that sample which has been collected is not contaminated by contaminants from the ambient air. Additionally, the seals reduce the outgassing, i.e. loss of sample. Hence, once the breath sample is collected, the sorbent capsule may be stored in the breath sampling device for a pre-determined time before analysis, such as 2-4 weeks.

[0031]

[0031] Examples of mechanical seals are valves such as umbrella valves, duckbill valves and / or a positive end expiratory PEEP valves. When mechanical seals are used for both the first and second seals, the same or different valves may be used. When the second seal is a diffusive seal, the diffusive seal may be integrated with the removeable sorbent capsule or may be separately removably mountable within the device. The diffusive seal may be a sorbent material such as carbon foam or other sorbent known in the art such as tenax. The diffusive seal material may be up to 1 cm3in volume. The sorbent material may be provided in a seal capsule which is any suitable shape, for example cylindrical, disc-shaped, cuboid. The seal capsule may contain up to 1 cm3of sorbent material.

[0032]

[0032] The breath sampling device may be configured to fractionate a received breath, such that only VOCs in a part (earlier or later part) of an exhaled breath is captured within the sorbent capsule. Taking a small consistent sample from the main flow of exhaled breath ensures that the signal obtained is averaged over the duration of the collection, thus, removing variability introduced by uneven breathing patterns. This may be achieved using any suitable component. As an example, the device may further comprise a fixed volume bag which is located before the inlet of the inlet section, (for example on a mouthpiece which is connected to the inlet section). The fixed volume of the bag corresponds to an initial portion of the breath which is to be removed, e.g. 100ml. When a user initially exhales into the breath sampling device, breath passes into and fills the fixed volume bag until the initial portion has been received and the fixed volume bag cannot receive any more breath, so the rest of the breath (e.g. 400ml for a typical breath volume of 500ml) passes into the inlet section and a first portion of this received breath will be exhausted through the outlet of the inlet section as described above. A second portion of the breath, around 5 to 15mL, passes into the sorbent section and is sampled as described above. In other words, the initial portion of the breath may be received into the fixed volume bag without opening the at least one pressure regulator. When such a fixed volume bag is used, the user may rebreathe the air in the bag when inhaling, although it is noted that such air is typically low in carbon dioxide and the target compounds. Alternatively, the fractionating bag may deflate via another mechanism. This process may then be repeated for 10 to 28 breaths or a fixed amount of time as explained above.

[0033]

[0033] As described above, the breath sampling device may be used to sample a target compound (also termed analyte) from a user’s breath. According to another aspect of the present techniques, there is provided a method of using the breath sampling device described above, the method comprising: activating the activation mechanism to select the activated mode for the breath sampling device; receiving a plurality of breaths into the breath sampling device via the inlet; sampling, using the sorbent capsule, a controlled amount of each of the plurality of breaths to collect a target compound; and when the target fixed volume has been sampled, deactivating the activation mechanism to select the deactivated mode for the breath sampling device.

[0034]

[0034] The method may further comprise: removing the sorbent capsule from the breath sampling device after deactivating the device; and analysing the sorbent capsule to determine a concentration of the target compound in the target fixed volume breath sample.

[0035] BRIEF DESCRIPTION OF DRAWINGS

[0036]

[0035] Figure 1 is a side view of a breath sampling device according to the present techniques.

[0037]

[0036] Figures 2a and 2b are cross-sectional views of the breath sampling device of Figure 1 in a deactivated mode and an activated mode, respectively.

[0038]

[0037] Figures 3a and 3b are close-up views of part of the cross-sectional views of Figures 2a and 2b.

[0038] Figures 4a and 4b are perspective views of an alternative breath sampling device in a deactivated mode and an activated mode, respectively.

[0039]

[0039] Figure 4c is an exploded view of a sorbent capsule and its holder within the breath sampling device of Figure 4a.

[0040]

[0040] Figures 5a and 5b are cross-sectional views of the alternative breath sampling device of Figures 4a and 4b.

[0041]

[0041] Figure 5c is an exploded view of various components within the breath sampling device of Figure 4a.

[0042]

[0042] Figures 6a, 6b and 6c are detailed views of a component of the alternative breath sampling device of Figures 4a and 4b in three different arrangements.

[0043]

[0043] Figure 7a plots sorbent flow rate (slm) against exhaled flow rates for a user for various users of a breath sampling device shown in Figures 1, 2a and 2b.

[0044]

[0044] Figure 7b is a graph plotting flow through the sorbent against the flow of a user exhaling into the device for various designs of device.

[0045]

[0045] Figure 8a plots pressure at the venturi throat against flow for a variety of venturi throat diameters and a baseline with no venturi.

[0046]

[0046] Figure 8b plots pressure change as a percentage change of min to max pressure against venturi diameter for a fixed diameter of pipe (17mm) and different ranges of flow rates indicated in the brackets.

[0047]

[0047] Figures 9a and 9b are graphs plotting the concentration of various analytes on a sorbent capsule against time elapsed using the ReCIVA breath sampler and the presently disclosed breath sampler respectively.

[0048]

[0048] Figures 10a and 10b are whisker plots plotting the variation in concentration of analyte on breath for two discrete times using the ReCIVA breath sampler and the presently disclosed breath sampler for several users respectively.

[0049] Figures 11a and 11b illustrate schematically a breath sampling device as shown in Figures 1 , 2a and 2b, 4a and 4b.

[0049]

[0050] Figure 12 is a flow chart of a method of using the device in Figure 1 , Figure 4 or Figure 5.

[0050]

[0051] Figure 13a is a flow chart of a method of dismantling the device to access and replace the sorbent capsule.

[0051]

[0052] Figures 13b and 13c are perspective views of the breath sampling device of Figures 4a and 4b before and after disassembly respectively.

[0052] DESCRIPTION OF EMBODIMENTS

[0053]

[0053] The present techniques relate to a breath sampling device, and in particular a breath sampling device for capturing volatile organic compounds in a user’s breath. The breath sampling device comprising a housing which comprises an inlet, outlet, flow path, mechanical pressure regulator for regulating the pressure within the housing when breath is flowing through the flow path and at least one mechanical flow rate controller to control a flow rate of a breath along the flow path. In use, the breath sampling device may comprise a sorbent capsule. The breath sampling device may have two modes of operation, an activated state for sampling a user’s breath and a deactivated state in which there is no breath flow into the sorbent capsule and optionally for removing the sorbent capsule for analysis. The pressure regulator and at least one flow rate controller are configured to provide a flow rate through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet whereby a controlled amount of breath is sampled from each of a plurality of breaths received from a user through the inlet.

[0054]

[0054] Figure 1 shows an overview of a possible implementation of the breath sampling device according to the present techniques. The breath sampling device 10 comprises a housing 12 (which may also be termed a body), wherein the housing has an inlet 14 through which a breath flows into the device and an outlet 16 from which at least a portion of the breath that has been sampled can optionally be expelled from the device 10. The optional outlet 16 may be termed a venting outlet as explained in more detail below. There is a flow path through the device from the inlet to the outlet and components may be termed upstream when they are closer to the inlet and downstream when they are closer to the outlet. A mouthpiece 18 is connected to the inlet 14 of the housing 12. The mouthpiece may be detachably connected to the housing so that the mouthpiece can be discarded after use to improve the hygienic use of the sampling device.

[0055]

[0055] When breath is being sampled, a sorbent capsule (not shown) is located in the device, specifically housed within the housing 12. The housing may comprise multiple parts which are detachable from one another to allow access to the sorbent capsule. The housing may be dismantled manually or using a dismantling mechanism. Separate from the housing, there is a vial 36 of an oral solution which may be consumed by a user prior to giving a test sample.

[0056]

[0056] As explained in more detail with reference to Figures 2a and 2b, the breath sampling device may have two modes of operation: an activated state for sampling a user’s breath and a deactivated state for removing the sorbent capsule 20 from the housing. The device may be breathed into in the deactivated state, but the sorbent will not receive the sample. Hence, there is no breath sampling when the device is in the deactivated state. The device may comprise an activation mechanism for switching the device between the two modes of operation. In this example, the device has an activation mechanism comprising an activation button 24 on one side of the housing 12 and a deactivation button 22 on a top face of the housing 12. The device is “activated” (moved from the deactivated to activated mode) by pressing the activation button 24 which moves the deactivation button 22 upwards (in other words, the deactivation button 22 pops up together with the internal housing components around it). The device is then “deactivated” (moved from the activated to deactivated mode) by pressing the deactivation button 22. It will be appreciated that the buttons may be located on different parts of the housing. Furthermore, buttons are just one example of a suitable activation mechanism and other suitable arrangements such as sliders, switches, clips, threaded components and so on may be used. There may also be springs (not shown) to move the various components, including the switches.

[0057]

[0057] The device also comprises a pressure regulator 30 in the form of two one-way valves on each side of the housing. Once the device is in the activated state, breathing into the mouthpiece 18 opens and closes the valves as explained below. In this way, the pressure regulator 30 provides either a steady positive pressure during exhalation (5mbar - 10 mbar) or a low negative pressure during inhalation (-10 to 0 mbar). One of the one-way valves may thus provide an outlet through which most of a received breath is exhausted. Such an outlet may be termed an exhaust outlet to distinguish it from the venting outlet.

[0058]

[0058] The device also comprises a metering device 40 which in this example is in the form of an inflatable bag connected to one side of the housing. The bag is thus external to the housing and provides part of the fluid path between the inlet and the venting outlet. In other words, the bag connects the inlet to the venting outlet. In this example, an inlet for the bag is held open by a connector 44 so that the connector 44 ensures that the bag retains its shape. The connector 44 comprises a pair of protrusions 46 each of which form clips around the one-way valve 34. The connector 44 is also connected to the housing 12 using a pair of clips 42 which protrude from the housing. It will be appreciated that the flexible clips 42, 44 are just one way of removably detaching / attaching the connector and bag from the housing and any other suitable connection mechanism may be used.

[0059]

[0059] During exhalation, a portion of a received breath will flow through the sorbent capsule (which may also be termed a breath capture medium or a sorbent tube and the terms may be used interchangeably) inside the housing 12. As breath flows through the sorbent capsule the bag will inflate. The bag has a fixed volume and once the bag is full (indicated by the bag becoming visibly taut) the sample is complete and a user can stop breathing through the device. As well as providing a visual indicator, the bag being full may also mechanically prevent any more flow through the sorbent capsule and thus ends the sample collection. This is due to the bag being pressurised to a peak pressure value. The resulting change of pressure within the device will prevent other components within the device working as intended (as explained below). As an example, it may take approximately 10 to 28 normal breaths by a user to fully inflate the bag. The use of an inflatable bag may help to minimise moisture in the sorbent capsule because some moisture may be captured in the bag. Alternatively, the device may be designed in order to minimize the likelihood of a droplet blocking the system, for example by appropriate selection of the sorbent material or appropriate selection of other materials in the device.

[0060] It will be appreciated that the metering device 40 may be any mechanical system that indicated that a fixed volume has been sampled the desired flow. Alternative metering devices which may be used include a colour changing indicator, specifically an indicator which is sensitive to a compound in the breath, e.g. carbon dioxide CO2. Like the bag, the indicator may be mounted to one side of the housing and provides a visual indicator, in this case, a rapid colour change once a certain volume has passed through the indicator. Another metering device may be a chemical depletion sensor which detects depletion of a specific chemical as breath passes through the device. A known quantity of a chemical may be preloaded onto the sorbent or another section of material within or outside the housing. As the breath is sampled, the chemical is depleted via chemical breakthrough. The remaining quantity of the chemical may be detected by the chemical depletion sensor and the quantity of breath may then be calculated by analysing the detected quantity. Accuracy may be improved by using a combination of two or more known amounts of pre-loaded chemicals to address the dependence on chemical depletion to temperature. Each pre-loaded chemical may have a different breakthrough volume and / or temperature dependence on breakthrough.

[0060]

[0061] Figures 2a and 2b are cross-sectional views of the breath sampling device of Figure 1 in a deactivated mode and an activated mode, respectively. The description of the features which are shown in Figure 1 is not repeated for Figures 2a and 2b but the same reference numbers are retained for clarity. Figures 2a and 2b show the location of the sorbent capsule 20 within the housing 12. As shown, the sorbent capsule 20 is positioned in a device flow path which is the complete flow path through the device between the inlet and the venting outlet 16. The flow path may be considered to have a plurality of separate sections including a first or inlet section 80 which is connected to the inlet, an outlet section 60 which is connected to the venting outlet 16 and a sorbent section 70 in which the sorbent capsule 20 is located and which is between the inlet and outlet sections. Each section may have an inlet and an outlet with a flow path through each section. As shown the metering device 40 may be connected between the sorbent section and the outlet section. As explained in more detail below, the pressure regulator may be any device which has a cracking pressure of around 5 mbar so as to generate a useful pressure in the device and in this example a pair of umbrella valves 32 are used.

[0061]

[0062] The use of a pair of valves means that the pressure regulator 30 may be designed with a first valve for exhalation, wherein the first valve closes when the user inhales and opens when the user exhales to provide an outlet from the inlet section 80. The pressure regulator may comprise a second valve, or inhalation valve, wherein the second valve is closed when the user exhales and opens upon inhalation. This second valve should be low resistance and have a low opening pressure (i.e. have a low cracking pressure). It will be appreciated that the implementation of the valves for inhalation and exhalation can vary, including but not limited to the following: being two different umbrella valves, being identical umbrella valve parts but with alternate seating designs; being identical umbrella valve designs but in different materials; being a mixture of umbrella and duckbill valves; being a mixture of umbrella and PEEP valves; being a mixture of PEEP valves and duckbill valves; or being combined into a single valve such as an umbrella and duckbill combination, umbrella and PEEP valve combination, or duckbill and PEEP valve combination.

[0062]

[0063] The device comprises various features to control breath flow through the sorbent capsule within the device. More specifically, these features may be termed passive flow regulation components which in use provides a low but highly controlled flow rate over the sorbent material even for different input flow rates. These features include at least one of the pressure regulator 30 (e.g. umbrella valve 32), at least one flow rate controller such as a venturi 50, a restriction 54 (orifice) to regulate flow and / or a resistance 52, and a one-way valve 34 (e.g. a duckbill valve). The outlet section 60 of the flow path may optionally have a section with a larger cross-section. This larger section could be used to house additional material, e.g. carbon to capture moisture. In this example, the inlet section 80 comprises the pressure regulator 30, the venturi 50 and the resistance 52 with the resistance 52 being located between the pressure regulator 30 and the venturi 50. Noise dampening material, e.g. to reduce noise from the device, for example in the inlet section, more specifically between the resistance 52 and the umbrella valve 32. The sorbent section 70 comprises the restriction 54 and the one-way valve 34. It will be appreciated that other arrangements are possible provided the functionality described below to achieve the desired flow rate is maintained.

[0063]

[0064] Figure 2a shows the device 10 in a deactivated state. In this state, the device may be transported or stored, the sorbent capsule 20 may be removed for further analysis and / or any breath in the metering device 40 (bag) may be vented from the device. The venting outlet 16 is open in the deactivated state. In this example, this is achieved by the outlet cover 62 which surrounds the deactivation button being in a raised position relative to the housing 12. This creates a space (venting chamber) above an outlet end 64 of the outlet section 60 and allows any air within the bag to flow through an inlet end 66 of the outlet section 60, through the outlet section 60 and out of the device through the venting outlet 16.

[0064]

[0065] In the deactivated state of Figure 2a, the sorbent section 70 of the flow path is sealed to prevent breath flowing from the inlet section 80 into and through the sorbent capsule 20. Breath flow from the metering device 40 into the sorbent section 70 is prevented by using a one-way valve 34 to connect the sorbent section 70 of the flow path to the metering device 40. The one-way valve 34 may be located at an outlet end the sorbent section 70. The one-way valve 34 may be any suitable valve, such as a duckbill valve. This valve should have a low cracking pressure, namely the pressure which is required to open the valve to allow a breath to flow from the sorbent section to the metering device should be low and there should be no (or minimal) reverse flow through the valve. By low pressure it is meant that the cracking pressure of the one-way valve should be lower than the cracking pressure of the one or more valves used in the pressure regulator (e.g. the umbrella valve(s)). When the bag is full, this produces a back pressure that prevents further filling. The one-way valve thus prevents backflow through the sorbent capsule, particularly when the bag is full. The one-way valve may be termed a third valve and is valve for the sorbent flow which, like the second valve for inhalation described above, is closed when the user inhales.

[0065]

[0066] Figure 3a shows a close-up of part of Figure 2a showing an inlet end 72 of the sorbent section 70. The inlet end 72 of the sorbent section 70 is connected to the inlet section 80 of the flow path using a venturi 50. An O-ring 76 (or similar seal) is provided around the sorbent tube 26 to minimise ambient ingress into the sorbent section 70. A seal 78, e.g. a V-seal, is also used at an end of the sorbent tube 26 to make sure there is no or minimal leakage. In the deactivated state, an inlet end 26 (which may also be termed a downstream end) of the sorbent capsule 20 is in contact with the inlet end 72 of the sorbent section 70 and thus flow into the sorbent section is prevented. In this example, the sorbent material is housed in a sorbent tube 26 in the form of a thin metal tube. Meshes (not shown) at either end of the tube hold the sorbent material within the tube. These meshes may incorporate carbon foam or similar material to scrub any ambient ingress or contamination. Alternatively, carbon foam may be used outside the sorbent tube, for example between the sorbent capsule and the one-way valve. This may be particularly useful at the downstream end adjacent the one-way valve to reduce contamination if breath does leak back from the metering device.

[0066]

[0067] The device is moved from the deactivated state in Figure 2a to the activated state in Figure 2b by pressing on the activation button 24. Pressing on the activation button 24 effectively moves the outlet cover 62 towards the outlet section 60 by moving a moveable component within the housing towards the outlet cover. In the activated state, the outlet cover 62 seals or closes the venting outlet 16 so that flow out of the device after flowing through the sorbent capsule is prevented. The outlet cover 62 may be held in this sealed position by one or more retaining clips 68 (it will be appreciated that other similar sealing / connecting parts may be used). A seal 69, e.g. a V-seal is used around the outlet 16 to make sure there is no or minimal leakage.

[0067]

[0068] At the same time, and as shown in more detail in Figure 3b, the inlet end 26 of the sorbent capsule 20 is moved away from the inlet end 72 of the sorbent section 70 to create a chamber between the two ends. Flow from the inlet section 80 into the sorbent section through the venturi 50 is now possible. In other words, the sorbent capsule may be mounted in a moveable piston which is moveable between a position in which the piston seals the venturi (i.e. the deactivated state) to a position in which the piston is spaced away from the venturi (i.e. the activated state) to allow flow.

[0068]

[0069] The breath sampling device is designed to collect a small quantity of breath, for example approximately 100 mL, over a fixed time, e.g. approximately 2 minutes, by sipping a small, controlled amount of breath during exhalation of multiple breaths, e.g. 10 to 28 breaths. This small, controlled amount of breath may be termed a second portion of the received breath with the first, larger portion of received breath being exhausted through the exhaust valve. In other words, the device aims to sample a small amount from each exhaled breath. Sampling for a longer period of time results in a sample that contains a time averaged breath and hence generally more accurate readings when the sorbent capsule is later analysed. It will be appreciated that the same quantity of breath can be sampled by either using a higher sample flow rate and a shorter period of time or a lower sample flow rate and a longer period of time.

[0069]

[0070] The breath sampling device is designed to have an optimal flow rate through the sorbent capsule whereby the amount of sorbent material can be significantly reduced without compromising accuracy of the result. Thus, the amount of sorbent material may be reduced to approximately a quarter, e.g. from 200mg to 50mg. The flow rate through the sorbent capsule is controlled by the pressure within the device and the flow resistance of the components within the flow path (including the components of the sorbent tube such as the sorbent pellet and carbon foam and other components which are downstream from the sorbent tube such as the one-way valve and the metering mechanism). For example, the pressure regulator and at least one flow rate controller are configured to provide a flow rate of the second portion of each received breath through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet. The breath sampling device is designed to achieve a stable range of sampled flow (second portion), e.g. close to 100ml / min as the exhaled breath ranges from 10 - 80 L / min. The exhaled portion of breath typically lasts 3 to 9 seconds during exhale. Sampling at 100mL / min gives a small amount of approximately 5 to 15 mL of breath through the sorbent capsule.

[0070]

[0071] Figures 4a and 4b are perspective views of an alternative breath sampling device 110 in a deactivated mode and an activated mode, respectively. For simplicity, the mouthpiece and metering bag which are shown in Figure 1 are omitted from Figures 4a and 4b but it will be appreciated that they can be incorporated as explained above. Many features of the alternative breath sampling device are the same as those used in the first variation of the breath sampling device and thus a detailed explanation of these features is not repeated. The same or similar features are numbered to reflect the similarity, for example the housing of the alternative breath sampling device is labelled 112 to corresponding to the numbering of the similar feature in Figure 1 , namely the housing 12.

[0071]

[0072] The breath sampling device 110 comprises a housing 112 having an inlet 114 through which a breath flows into the device and a venting outlet 116 from which breath can optionally be expelled from the device 110. A clip 144 is attached to the housing 112 and in use, a metering bag (not shown) is held open by and connected to the housing using the clip 144. The device may comprise an activation mechanism for switching the device between the two modes of operation. Like the previous example, the device has an activation mechanism comprising an activation button 124 on one side of the housing 112 and a deactivation button 122 on a top face of the housing 112.

[0073] As in the previous arrangement, the device comprises various features to adapt the breath flow input into the device so that there is a generally constant flow rate of a sampled portion (second portion) of each received through the sorbent capsule within the device. The passive flow regulation components include at least one pressure regulator 130. The other components are described in more detail below.

[0072]

[0074] In this arrangement, the venting outlet 116 is on the opposed side of the housing 112 when compared to the first arrangement. In other words, in this arrangement, the venting outlet 116 is closer to the clip 144 than the deactivation button 122 whereas in the previous arrangement, the venting outlet was adjacent the deactivation button. As shown in Figure 4b, the venting outlet is closed / sealed in the activated state by an outlet cover 162 which also surrounds the deactivation button 122.

[0073]

[0075] Figure 4c shows the sorbent capsule 120 which is located within the housing. Figure 4c also shows the moveable component 136 which is within the housing and more specifically houses the sorbent capsule 120. In this arrangement, the moveable component 136 incorporates the deactivation button 122 and has an engagement section 139 which engages with the activation button to form the activation mechanism. An O-ring 176 (or similar seal) is provided around the moveable component 136 to minimise ambient ingress into the sorbent section. A seal 178, e.g. a V-seal, is also used at an end of the moveable component 136 to make sure there is no or minimal leakage. Meshes 128 at either end of the tube hold the sorbent material within the tube. It will be appreciated that a similar moveable component is incorporated within the first arrangement.

[0074]

[0076] The sorbent capsule 120 has an inlet end 126 and the moveable component 136 has an inlet end 172 which are aligned with each other in the activated and the deactivated state. In the activated state, the inlet end 126 of the sorbent capsule 120 and the inlet end 172 of the moveable component 136 are in a location which allows flow into the sorbent capsule 120. In the deactivated state, the inlet end 126 of the sorbent capsule 120 and the inlet end 172 of the moveable component 136 are adjacent and sealed against the inlet section to prevent flow into the sorbent capsule 120. This is better shown in Figures 5a and 5b which are cross-sectional views of the whole device in the deactivated and activated states respectively.

[0077] Figures 5a and 5b show the location of the sorbent capsule 120 within the housing 112. As shown, the sorbent capsule 120 is positioned in a venting flow path which is a flow path through the device between the inlet 114 and venting outlet 116. The device may be considered to have a plurality of separate sections including a first or inlet section 180 which is connected to the inlet 114, an outlet section 160 which is connected to the venting outlet 116 and a sorbent section 170 in which the sorbent capsule 120 is located and which is between the inlet and outlet sections. In this arrangement, in contrast to the previous arrangement of Figure 1 , the outlet section 160 is connected to the sorbent section 180 via a one-way valve 134.

[0075]

[0078] Figure 5a shows that in the deactivated state, there is no flow through the sorbent section 170 (indicated in red) even if a user breathes into the inlet 114. There may be flow (indicated in green) from the metering device which is clipped to the housing using the clip 144 through the outlet section 160 and out of the outlet 116. Breath flow from the metering device into the sorbent section 170 is prevented (or at least reduced) by using the one-way valve 134. The one-way valve 134 may be the same as the valve used in the previous arrangement of Figure 1. The device is moved from the deactivated state in Figure 5a to the activated state in Figure 5b by pressing on the activation button 122.

[0076]

[0079] Figure 5b shows that in the activated state, there is flow through the inlet section 180 and the sorbent section 170 (indicated in green) when a user breathes into the inlet 114. More specifically, there is a flow of a first portion of each received breath from the inlet 114 and out through the pressure regulator 132 (e.g. through an exhaust or exhalation valve within the pressure regulator as described in the previous example). There is also flow of a second portion of each received breath from the inlet section 180 into the sorbent section 180 and more specially through the sorbent capsule 120. The second portion may be significantly smaller than the first portion and may be termed a sampled flow. This sampled flow is along a sample flow path which may comprise a flow path through the sorbent section (e.g. sorbent section flow path) and continues into the metering device which is clipped to the housing using the clip 144. In this arrangement, there is a single pathway from the one-way valve 134 to the metering device and as indicated in red, there is no flow from the metering device through the outlet section 160 and out of the venting outlet 116. In the activated state, the venting outlet 116 is blocked by the outlet cover 162. Breath flow from the metering device into the sorbent section 170 is prevented by using the one-way valve 134. The one-way valve 134 may be the same as the valve used in the previous arrangement.

[0077]

[0080] As with the previous arrangement, the passive flow regulation components include at least one pressure regulator (e.g. umbrella valve 132), at least one flow rate controller such as a venturi 150, a restriction 154 (orifice) to regulate flow and / or a resistance 152, and the one-way valve 134. As explained in more detail elsewhere, the at least one pressure regulator and at least one flow rate controller are configured to provide a flow rate of the second portion of each received breath through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet, whereby, in the activated mode, a controlled amount of breath is sampled from each received breath.

[0078]

[0081] The arrangement of Figures 5a and 5b also comprises a diffusive seal 153 after the sorbent capsule and before the restriction 154. In this embodiment, the diffusive seal 153 is removably mounted within the device separately to the sorbent capsule 120. The diffusive seal 153 may be a carbon foam. Particularly, when the device is in the deactivated state and the venting outlet 116 is open, the diffusive seal 153 prevents ingress from contaminants in the ambient atmosphere from contaminating the sorbent capsule. Such a diffusive seal is not shown in the previous arrangement but it will be appreciated that it can be incorporated in a similar location.

[0079]

[0082] The arrangement of Figures 5a and 5b also comprises a valve manipulation mechanism 155. The valve manipulation mechanism 155 is located within the outlet section 160. In other words, the valve manipulation mechanism 155 (which may be termed a wiper) is located after the one-way valve (such as a duckbill valve) 134 and before the bag connector 144 in the flow path. The valve manipulation mechanism 155 is attached to the outlet cover 162 via a screw. The valve manipulation mechanism 155 thus moves with the outlet cover 162 relative to the rest of the device.

[0080]

[0083] Figure 5c shows more detail of the valve manipulation mechanism 155 which comprises an elongate body 156 having a first end 157 (which may be termed a distal end because it is distanced from the outlet cover 162) and a second end 159 (which may be termed a proximal end). The second end 159 is fixed to the outlet cover 162 via a screw (not shown). A seal 168 (e.g. a V-seal) is used, close to the second end 159, to seal the elongate body 156 to the outlet cover as shown in Figure 5a. As shown in Figure 5b, the seal 168 also seals the outlet from the device when the device is in the activated state.

[0081]

[0084] Figure 5c also shows that part of the sorbent section is formed from a one-way valve housing 182 which is connected to the moveable component housing the sorbent capsule and thus is also a moveable component. The restriction 154 (orifice) to regulate flow is incorporated into the one-way valve housing 182. As shown in Figure 5a, the valve manipulation mechanism 155 extends partially through the one-way valve housing 182 in the deactivated state. As shown in Figure 5b, the valve manipulation mechanism 155 extends fully through the one-way valve housing 182 in the activated state whereby the valve manipulation mechanism 155 does not impact the flow of breath into the metering device.

[0082]

[0085] Returning to Figure 5c, the outlet cover 162 comprises an aperture 186 through which the deactivation button extends. The outlet cover 162 also comprises a release button 184 which when depressed by a user allows the removal of the outlet cover 162 and extraction of the sorbent capsule as explained in more detail below.

[0083]

[0086] Returning to the valve manipulation mechanism 155, in this arrangement, the valve manipulation mechanism 155 has three protrusions 158a, 158b, 158c. It will be appreciated that three is an illustrative number and more or fewer protrusions may be used. The elongate body 156 may have an upper generally cylindrical section and a lower section on which the protrusions are located. The lower section has a smaller cross-section or diameter than the upper section so as not to impede air flow through the device. A first protrusion 158a is located at the first end 157 and the other two protrusions 158b, 158c spaced apart from the first protrusion 158a with all three protrusions close to the first end rather than the second end. The protrusions 158a, 158b, 158c are triangular or pyramidal in shape and a point of each protrusion extends towards the one-way valve 134. In this arrangement, the protrusions are configured to engage with the valve to different extents, for example, the second protrusion 158b is smaller than the first protrusion 158a and the third protrusion 158c is smaller than the second protrusion 158b. In other words, the first protrusion 158a which is closest to the first end is the largest and the other protrusions decrease in size. It will be appreciated that a larger protrusion will extend further into the one-way valve 134. The first protrusion 158a may have the same diameter as the upper cylindrical section of the elongate body 156.

[0084]

[0087] As explained with reference to Figures 6a to 6c, when the device passes from the deactivated state to the activated state the one-way valve 134 may be mechanically manipulated by the valve manipulation mechanism 155 to temporarily separate the sealing faces of the one-way valve 134 three times as the device is activated. This removes the stiction effects so that the device is easier to breath into and so that the sampled flow (second portion) does pass from the inlet section 180 into the sorbent section as intended. When the stiction is not released, it is possible that there is no sampled flow because the pressure from the closed one-way valve is too high and all the breath exhausts from the outlet of the inlet section.

[0085]

[0088] Figure 6a is a close up of the valve manipulation mechanism 155 and the one-way valve 134 when the device is in the deactivated state as shown in Figure 5a. In this state, the valve manipulation mechanism 155 sits above the one-way valve 134 and there is no engagement with the one-way valve 134 and its upper and lower valve surfaces 135a, 135b.

[0086]

[0089] Figure 6b is a close up of the valve manipulation mechanism 155 and the one-way valve 134 as the device changes between the deactivated state and the activated state. As shown, the valve manipulation mechanism 155 has moved downwards so that the first protrusion 158a is below the one-way valve 134 and the second protrusion 158b extends into the one-way valve 134. More specifically, the second protrusion 158b is between the upper and lower valve surfaces 135a, 135b and is thus releasing stiction between these surfaces. It will be appreciated that before the second protrusion 158b has engaged with the one-way valve 134, the first protrusion 158a will have first engaged with the one-way valve 134. Similarly, after the second protrusion 158b has engaged with the one-way valve 134, the continued downward movement of the valve manipulation mechanism 155 means that the third protrusion 158c will next engage with the one-way valve 134.

[0087]

[0090] Figure 6c is a close up of the valve manipulation mechanism 155 and the one-way valve 134 when the device is in the activated state as shown in Figure 5b. In this state, each of the protrusions on the valve manipulation mechanism 155 sits below the one- way valve 134 and there is no engagement with the one-way valve 134. Furthermore, the thinner lower section of the elongate body 156 is adjacent the outlet from the oneway valve 134 to minimise restriction of breath flowing through the device into the metering device in the activated state.

[0088]

[0091] Figure 7a plots sorbent flow rate (slm) against a constant speed air source. It will be appreciated that for exhaled flow rates for a user for various users of the proposed breath sampling devices similar results will be achieved but the results would be presented as a scatter plot rather than as the smoothed lines shown. A global mean is shown together with the standard deviation window. Here ranges from 0-100L / min are tested, but the actual flow rate from individuals is more like 10L / min-60L / min. The aim is to have a flow as close to 100ml / min as possible through the sorbent pellet (Y-axis). The average results show that flow stability over a wide range of exhalation flows can be achieved.

[0089]

[0092] Figure 7b illustrates the contribution of each of the features such as the pressure regulator, the venturi, the one-way valve, the restriction to regulate flow and / or the resistance which are shown in Figures 1 to 2b. Figure 7b is a graph plotting flow through the sorbent (i.e. sample flow) against the flow of a user exhaling into the device (i.e. exhaled flow). Figure 7b shows how the individual components of the device can provide the overall results shown in Figure 7a.

[0090]

[0093] Line 1 shows the results for a split flow in which some of the breath is discarded. Typically, the initial portion, e.g. first 100ml, of an exhaled breath is discarded because it is typically not useful for analysis. Indeed, the initial portion of breath is known to be mainly absent of volatile organic compounds (VOCs) from the deep lungs. This is because the initial portion is resident in the upper airways and mouth for a relatively short time and there is insufficient time for diffusion of the VOCs from the deep lungs to enrich this portion of the breath. It is sometimes beneficial to remove this fraction of the exhaled breath as it dilutes the breath sample. Removing this fraction may also allow for a shorter sample time due to the enriched breath sample. The remaining portion of each exhaled breath, e.g. 400ml or so, may be sampled and may be termed the target portion (second portion) of each exhaled breadth. The sorbent material will typically adsorb around 5 to 15ml per breath.

[0094] Line 2 of Figure 7b shows the impact of using a restriction which may also be termed a resistance, for example the resistance in the inlet flow path between the pressure regulator and the venturi. The resistance may be generated by using a 6mm diameter flow path wherein the length of the flow path is long relative to the diameter. For example, the length may be 3cm. As shown in Figure 7b, when including such a restriction, there is still a straight-line relationship between the sample and exhaled flow but the gradient is shallower. Thus, including the restriction increases the time required to reach the 100ml / min target flow.

[0091]

[0095] Line 3 of Figure 7b shows the importance of generating a positive pressure within the device when a user is exhaling. In the device described above, there is a pressure regulator to provide this function. The pressure regulator may be any device which has a cracking pressure which generates a useful pressure in the device, typically 5 mbar. For example, the pressure regulator may comprise one or more suitable valves, such as umbrella valves, duckbill valves or positive end expiratory PEEP valve. Once cracked (i.e. once open), the device should be operating at 5 mbar of pressure across a large range of expected respiratory flows. In other words, the device does not operate in constant flow, it operates at “constant” pressure. In practice the pressure may increase from 5 mbar to 10 mbar as the breath goes from 0 L / min to 100 L / min. The pressure regulation which is provided is non-linear, so that, for example, doubling the pressure does not double the flow. Once cracked (i.e. once open), there is an outlet through which most of the exhaled breath exhausts. Line 3 of Figure 7b shows that the inclusion of the pressure regulator means that there is a flattening of the sample flow rate towards the target flow rate, but the sample flow rate is still higher than desired.

[0092]

[0096] The sample flow rate may be reduced in a similar manner to the reduction between lines 1 and 2 by including a further restriction, this time in the form of an orifice. The restriction may be included in the sorbent section of the flow path, for example, adjacent the one-way valve. As shown in line 4, there is a similar flattened curve such as shown in line 3 but the sample flow rate is now reduced to be closer to the target flow rate for most exhaled flow rates.

[0093]

[0097] In the example of Figure 7b, the orifice has a fixed diameter of 6mm because this achieves the desired flow rate 100m L / min at the pressure of 5mbar which is achieved by the pressure regulator. However, it will be appreciated that the diameter of the orifice may be adjustable so that the diameter can be adjusted to achieve a desired flow rate (e.g. 10 mL / min or 500 mL / min). Adjustments to the diameter may be made via discrete steps or continuously until the desired flow rate is achieved. The device may be deployed to users with a particular diameter, e.g. 5 or 6mm as indicated, but the orifice can then be adjusted by the user (e.g. patient, subject or healthcare professional).

[0094]

[0098] Pressure regulators, such as umbrella valves and (PEEP) valves, are not perfect. The static pressure curves show a quadratic increase in pressure drop as flow rate is increased. Line 5 of Figure 7b shows the effect of including a flow rate controller (termed a venturi and the terms may be used interchangeably) which provides a venturi effect in the device to control the target flow. The venturi is close to an inlet end of the sorbent capsule. The venturi may be a venturi meter, a venturi nozzle or an orifice plate and in each arrangement comprises a short piece of narrow tube between wider sections (e.g. between the inlet section and the sorbent sections). A venturi enables generation of a stable positive pressure through the flow path during exhalation. The venturi may be designed for a specific pressure regulator (i.e. umbrella valve) such that across a range of flow rates, for example 10 to 80 L / min, the combination of the said pressure regulator and venturi obtained a maximally flat response of approximately 100ml / min as shown in Figure 7b by achieving usefully stable pressures within the device. In other words, the venturi together with the umbrella valves may generally provide the desired constant flow rate through the sorbent capsule. An orifice in the sorbent section may be used to fine tune or further improve this maximally flat response for the range of input breath rates. This maximally flat response may be obtained through mathematical minimization for example using the equations below. A skilled person will appreciate that when breath is input at a more narrowly defined range of flow rates, the generally constant flow rate through the sorbent may be more accurately or more stably achieved.

[0095]

[0099] The Venturi equation is: where pxis an input pressure (i.e. pressure before the Venturi narrowing), p2is an output pressure (at the Venturi narrowing), is an input velocity, v2is an output velocity (i.e. fluid velocity at the narrowing) and p is the density of the fluid. If the venturi is sufficiently lossless the pi term can be substituted to give: where pvaive(vi) is the pressure drop of an exhale valve as a function of input fluid speed. The output velocity v2can be altered by geometric changes to the venturi. The venturi is optimised by finding a geometry that minimises, across a suitable domain of fluid speeds (e.g. air speeds that correspond to 10 L / min to 80 L / min at the input), the following expression:

[0096] |(max(p2(v1)) - min (p2(vi))) / min (p2Oi)))|

[0097] That is to say the relative range of pressures is minimised across a specified range of flows. Optimization can be performed on discrete data using any suitable method such as least-squared.

[0098]

[0100] Figure 8a plots pressure at the venturi throat against flow for a variety of venturi throat diameters (from 6.0 to 9.4mm) when an umbrella valve is used, and a baseline with only an umbrella valve and no venturi. The throat is the narrow part of the Venturi and the width of the pipe before the narrowing is set at 17mm. In other words, the width of the inlet section of the flow path and the sorbent section of the flow path adjacent the Venturi is fixed at 17mm. In this case, the baseline is line 1 and is the device of Figure 1 with umbrella valves within the pressure regulator. In other words, the static pressure curve (without venturi) is the static-pressure curve from an umbrella valve. Line 1 shows the static-pressure data that is generated from an umbrella valve for various different flow rates. Without a venturi the relative range of pressure drops over a flow range of 10 to 80 L / min represents a +194 % increase. The relative range of pressure drops for each line is shown in the table below:

[0099] The graph can be used to optimise the venturi geometry to minimize the pressure range across a chosen input flow range (10 L / min) to (80 L / min). For this particular umbrella valve and configuration of breath sampling device the optimal venturi diameter is 6.8 mm. It will be appreciated that any change to the valve or other components within the breath sampling device will have an impact on the pressure and flow rate within the device. Accordingly, the venturi needs to be optimised for each configuration of breath sampling device.

[0100]

[0101] The skilled person will appreciate that outside the specified optimization range of flow rates or for an undersized venturi, the relative range of pressure drops increases again. In other words, the venturi effect causes excessive pressure reduction at the higher flow rates, and in extreme cases can actually cause a flow reversal (due to a net negative pressure relative to ambient). It is therefore important that the flow range over which the venturi is optimized is carefully considered. For example, the flow range should ideally specify a range of flow rates that 95 % of an entire population would output at all times. The skilled person will appreciate that the smaller the flow range, the smaller the relative range of pressure drops will be.

[0101]

[0102] Figure 8b plots pressure change as a percentage against venturi diameter for a fixed diameter of pipe (17mm). In other words, Figure 8b shows the relative range of pressure drops increase vs venturi for a 17 mm pipe. As shown in the table below, each curve represents a different range of input flow rates for which the relative range of pressure drops increase is calculated.

[0102] In each case, the minimum pressure range is achieved for a throat diameter between approximately 6.5 to 7.5mm. This Figure also shows that the absolute gradient is far steeper for an undersized venturi restriction than for an oversized one. In other words, making the venturi slightly oversized is better than having too small a restriction.

[0103]

[0103] Figure 9a shows the concentration of five different target analytes (2-pentanone, 2-butanone, limonene, 2-butanol and 2-pentanol - with the 2-butanol line under the 2- pentanol line) on the sorbent capsule when a breath sample is captured at five different times using the known ReCIVA breath sampler. Figure 9b shows the concentration for the same target analytes on the sorbent capsule when a breath sample is captured at five different times using the proposed breath sampler as described in Figure 4a.

[0104]

[0104] The results in Figures 9a and 9b are obtained by a subject drinking a small vial of water containing Limonene, 2-butanol, 2-pentanone (which may be termed an emulsion). This is time 0 on each graph. The 3 compounds then circulate the body where various biological processes happen. In general limonene is reduced via the liver. 2-butanol is converted to 2-butanone, and 2-pentanone is converted to 2-pentanol. Since these compounds are in the blood they will also appear on breath. The time at which the sample is taken is the time after the emulsion was consumed by the user. By sampling the user’s breath at fixed points after the emulsion, a concentration in the user’s breath (and by proxy blood) is obtained as it changes over time. Such an approach is used in trials and tests where certain diseases (such as liver cirrhosis) result in different ratios of the 5 compounds due to inadequate liver function. The data shows that the proposed breath sampler demonstrates at least comparable performance as compared with the ReCIVA. In other words, for each target analyte, the highest concentration is typically obtained around 22 minutes after consumption.

[0105]

[0105] Figures 10a and 10b give additional results from a clinical trial for one of the target analytes shown in Figures 9a and 9b, namely limonene. Figures 10a and 10b show the ranges of concentrations which were measured for subjects with liver cirrhosis (cases) and subjects without liver cirrhosis (control). The results in Figure 10a were captured with the known ReCIVA breath sampler and the results in Figure 10b were captured using the proposed breath sampler as described in Figure 4a. As shown in Figure 10a, a first set of results for both cirrhotic and control patients is captured 15 minutes after the patients have consumed the appropriate beverage to perform the test. There is a clear differentiation between the almost negligible amount of limonene (1 ng / ml) measured for the control patients and the range of concentrations of between approximately 1.8 to 4.4 ng / ml for the cirrhotic patients. A similar clear differentiation is obtained in the first set of results in Figure 10b which are captured after 22 minutes. It is noted that the concentrations measured in Figure 10b are higher than those measured in Figure 10a.

[0106]

[0106] Each of Figures 10a and 10b also shows the range of concentrations measured at a second, longer time after consuming the test beverage. In Figure 10a, the measurements are taken after 30 minutes and in Figure 10b, the measurements are taken after 37 minutes. In both sets of results, there is overlap between the ranges for cirrhotic patients and control patients. For example, as shown in Figure 10b, the range is from 2 to 8.4ng / ml for the cirrhotic patients and between 1 to 3 ng / ml for the control patients. The data shown in Figure 10a and 10b demonstrates that the presently disclosed breath sampler performs at least comparably with the ReCIVA breath sampler.

[0107]

[0107] Figures 11a and 11b illustrate schematically a breath sampling device 600 as described above. Some of the components illustrated in Figures 11a and 11 b are optional but together the components and their design contribute to achieving a desired nominal flow rate through the sorbent capsule. As shown in Figure 11a, the breath sampling device 600 comprises a housing 612 having an inlet 614 through which air from the atmosphere may enter the device when a user inhales but when a user exhales, breath from a user flows into the device using the mouthpiece 618. Both these input flows may be received at a junction 613. In this example, the mouthpiece is shown within the housing but it will be appreciated that the mouthpiece may be a separate component which is connected to the housing as described above. The housing 612 may be made from any suitable material, e.g. plastics and may have any suitable size, e.g. to house all the components but still be handheld. Similarly, the mass of the device may be controlled to ensure that it is handheld. The device may be re-useable and the material may be selected to be sterilisable for different uses. The inlet section of the breath sampling device 600 may optionally include an inhalation filter 602 which may have any suitable format, sorbent type / material, volume and mass as well as aspect ratio.

[0108]

[0108] There may also be an optional fractionating reservoir 608 which may have any size, material, compliance or sealing efficiency. The optional fractionating reservoir 608 is also connected to the flow junction 613. For example, the fractionating reservoir may be in the form of a fixed volume bag, wherein the fixed volume corresponds to the initial portion of the breath which is to be removed, e.g. 100ml. When a user initially exhales into the breath sampling device, breath passes into and fills the fixed volume bag until the initial portion has been received and the fixed volume bag cannot receive any more breath, so the rest of the breath passes into the inlet section and a sampled portion of the breath can then pass into the sorbent capsule as described above. The breath preferably flows into the bag with a high selectivity ratio (over 20:1). In other words, the initial portion of the breath may be received into the fixed volume bag rather than passing to the next portion of the flow path, namely the exhalation restriction 652.

[0109] Between the inlet 614 and the flow junction 613, there may be an inhale valve 632a. For example, the inhale valve 632a may be an umbrella valve which forms parts of the pressure regulator. The inhale valve 632a has a cracking pressure, a low reverse leak rate, a pressure flow curve and other parameters (e.g. material) which are optimised to suit the overall design of the device and achieve the nominal flow rate through the sorbent capsule. The inhale valve opens when a user inhales and closes when a user exhales. Similarly, there is also an exhale valve 632b which may be an umbrella valve which forms parts of the pressure regulator. When the exhale valve is open, at least some of the breath exhausts to atmosphere via the exhaust outlet 615. The exhale valve 632b has a cracking pressure, a resealing pressure, a pressure flow curve, ratio to sample restrictor and other parameters (e.g. material) which are optimised to suit the overall design of the device and achieve the nominal flow rate of the sample flow (second portion of the breath) through the sorbent capsule. The exhale valve opens when a user exhales and closes when a user inhales.

[0109]

[0110] The at least one pressure regulator may also comprise an exhalation restrictor 652 which has a ratio to sample restriction and pressure-flow curve which are optimised to suit the overall design of the device and achieve the nominal flow rate through the sorbent capsule. The device may comprise a venturi 650 which have a diameter of the restriction, a geometry and pressure-flow curve which are optimised to suit the overall design of the device and achieve the nominal flow rate through the sorbent capsule. The venturi may be termed a flow rate controller as described above. As illustrated, in this example the exhalation restrictor 652 and the venturi 650 are incorporated in a single component as indicated by the dotted line. The venturi 650 may be considered to be a junction with a first portion of the received breath flowing along an exhaust flow path out to the atmosphere through and a second portion of the received breath being sampled along a sample flow path 655 most of which is shown in Figure 11 b.

[0110]

[0111] When sampling a user’s breath, the flow (shown by the arrows) flows from the venturi 650 into the sorbent capsule 620. Referring now to Figure 11b, the sorbent capsule may a removeable / replaceable cartridge or may be built-in. The sorbent capsule 620 may comprise a sorbent bed 624. The sorbent bed may comprise any suitable type of sorbent having any suitable grain size and distribution. The sorbent may be retained in any suitable structure, e.g. a mesh. There may be a plurality of sorbent beds. For example, the sorbent capsule 620 may comprise a sorbent bed between two meshes or may comprise two sorbent beds and three meshes, i.e. mesh-sorbent-mesh-sorbent- mesh. The sorbent volume, mass, aspect ratio, thermal mass and conductivity may be designed to meet the intended use and achieve the desired nominal flow rate through the sorbent capsule.

[0111]

[0112] There may be a diffusion filter 626 downstream from the sorbent bed 624. The diffusion filter 626 may be of any suitable type or material and have a volume, mass, aspect ratio which is designed to meet the intended use and achieve the desired nominal flow rate through the sorbent capsule.

[0112]

[0113] As schematically illustrated, the sorbent bed may be conditioned, e.g. using an external sorbent conditioner 628. The sorbent bed may also be pre-loaded with a specific compound which can be used to measure the volume of breath which has passed through the sorbent capsule. The pre-loading may be done using an external depletion chemical conditioner 642.

[0113]

[0114] Downstream from the sorbent capsule, more specifically after the diffusion filter 626, there is a restriction 654 followed by a one-way valve 634. These help to control flow of the sampled portion through the sorbent capsule. The restriction 654 may be any suitable type of restrictor, e.g. a valve. The ratio to exhale restriction and the pressureflow curve of the restrictor 654 may be selected to achieve the desired nominal flow rate through the sorbent capsule. The one-way valve 634 may have a cracking pressure, a resealing pressure, a pressure flow curve and other parameters (e.g. material) which are optimised to suit the overall design of the device and achieve the nominal flow rate through the sorbent capsule.

[0114]

[0115] Downstream from the one-way valve 634 is a metering device 640 in the form of an inflatable bag. As explained above, breath within the inflatable bag may be expelled from the breath sampling device through the venting outlet 616. Flow out of the device via the sample flow path 655 may be controlled by use of the deactivation / activation button(s) 622. For simplicity a single button is shown in the schematic of Figure 11 b. The deactivation / activation button(s) 622 may be used to seal / unseal the sorbent capsule and thus are designed to provide appropriate sealing but also be simple to use. The inflatable bag may have a size which is selected to correspond to the target volume which a user needs to provide for a good sample to be taken. The bag may be made of any suitable material, may be suitable compliant and have a suitable sealing efficiency.

[0115]

[0116] For example, one use case is breath analysis in the field of medical diagnostics. The human breath carries a wealth of information, including gasses and volatile organic compounds (VOCs), which are generated from various physiological processes within the body. These molecules are influenced by disease states that alter their abundance in the breath. This phenomenon has led to the identification of specific compounds that can serve as biomarkers for various diseases. One intriguing facet of breath analysis lies in its non-invasive nature. Unlike traditional diagnostic methods that often require invasive procedures and complex sample collections, breath analysis offers an attractive alternative. By harnessing the unique metabolic information contained within exhaled breath, clinicians can potentially detect diseases swiftly and accurately, enhancing the overall diagnostic process. Merely as example, the rising prevalence of both acute and chronic liver disease highlights the need for diagnostics that distinguish between early- and late-stage liver disease.

[0116]

[0117] The sorbent material in the sorbent capsule may be selected to adsorb or capture one or more target volatile organic compounds (VOCs). The term VOC refers to any compound of carbon but typically excludes carbon monoxide, carbon dioxide, carbonic acid, metallic carbides or carbonates and ammonium carbonate, which participates in atmospheric photochemical reactions. Generally, VOCs are defined as organic chemical compounds whose composition makes it possible for them to evaporate under normal indoor atmospheric conditions of temperature and pressure. Since the volatility of a compound is generally higher the lower its boiling point temperature, the volatility of organic compounds is sometimes defined and classified by their boiling points. In one embodiment, a VOC is any organic compound having an initial boiling point less than or equal to about 250° C measured at a standard atmospheric pressure of about 101.3 kPa.

[0117]

[0118] The target VOC that is measured may not be endogenous to the subject. This ensures that any readings are not contaminated by endogenous VOC that are naturally produced. The VOC may thus have been administered to the subject, for example to measure drug metabolism or for detecting, diagnosing, staging, monitoring or prognosing a liver disease in a subject. For liver disease, the target VOCs may be at least one of limonene, 2-pentanone and / or 2-butanol and / or metabolites such as alpha-pinene, alpha-phellandrene, 2-pentanol, 2-methyl furan and / or 2-butanone. For measuring drug metabolism, the VOCs may be o-pinene, p-pinene, limonene, eucalyptol and menthol.

[0118]

[0119] Figure 12 is a flow chart of a method of using the device in Figure 1 or Figure 4a. In a first step S1200, a breath sampling device which includes an unused sorbent capsule is obtained and is in the deactivated state. At step S1202, a user activates the device, e.g. by pressing on the activation button. At step S1204, there is an optional step of engaging the valve manipulation mechanism with the one-way valve to reduce stiction in the one-way valve as the device moves from the deactivated to the activated state. The device is then in the activated state and ready to use. At step S1206, a breath is received into the breath sampler via the inlet, for example by having a user breath normally into the inlet via a mouthpiece. The user may breathe into the breath sampling device for 2 to 10 minutes, preferably 2 minutes, or the user may breathe into the breath sampling device for 20 to 28 breaths.

[0119]

[0120] A first portion of each received breath flows through a mechanical pressure controller, which may be a valve, such as an umbrella valve, duckbill valve, a positive end expiratory PEEP valve and is exhausted from the device. The mechanical pressure controller controls the pressure within into the breath sampling device so that a sample from each breath passes through a first mechanical flow rate controller such as a venturi, orifice or restriction into the sample flow through the sorbent capsule. Together with the mechanical pressure controller and other components within the device, the flow rate controller controls the flowrate of the breath sample entering the sorbent capsule and maintains the flow rate at a desired predetermined flow rate. Continuing the path of the sampled portion of the breath, the breath sample passes through the sorbent capsule where a target analyte (the term compound may be used interchangeably) is absorbed or adsorbed onto the sorbent at step S1208. The breath sample then passes through a second mechanical flow controller, such as a venturi, orifice or restriction and through a one-way valve into a metering device. When a metering device is used, none of the sampled portion of the breath typically vents through the venting outlet of the device in the activated state. In this way, an accurate sampled volume can be measured.

[0120]

[0121] Once the required amount of breath has been collected, at step S1210, the breath sampler is deactivated. In the deactivated state, the venting outlet is open to optionally allow breath in the metering device to be vented. The inlet to the sorbent tube is sealed and a diffusive seal (or other seal) together with the one-way valve are used to prevent / reduce contamination into the sorbent capsule. In other words, the flow path through the sorbent capsule is closed to the outside atmosphere to prevent contamination of the sorbent capsule while the sorbent capsule is still in the device during transport and / or storage prior to sample analysis. At step S1212, the outlet cover is released to allow access to the sorbent capsule. It will be appreciated that removing the outlet cover is one way to gain access to the sorbent capsule and other arrangements can be used. At step S1214, the sorbent capsule is removed from the breath sampling device for analysis. At step S1216, the sorbent capsule is analysed to determine the concentration of analyte in the breath sample.

[0121]

[0122] Figure 13a is a flow chart of a method of extracting the sorbent capsule from the breath sampling device. In a first step S1300, the user presses on the release button while holding the breath sampling device. The release button will move in allowing at step S1302, the outlet cover to be lifted off the device and placed to one side. This action leaves behind the rest of the device, namely the housing 112 with the deactivation button 122 and activation button 124, as shown in Figure 13c.

[0122]

[0123] Returning to Figure 13a, at step S1304, the user keeps some pressure on the deactivation button while pressing the activation button. The inner part of the breath sampling device (also termed the moveable component) will slide up under spring force. At step S1306, the movement of the moveable component is controlled by the user keeping a grip on the activation button. The activation button may forcefully eject if the activation button is not gripped. At step S1308, the sorbent capsule holder (and attached one-way valve holder) is removed from the device. At step S1310 the housing and other components of the device are placed to one side. The extracted moveable components are shown in Figure 13c. These include the one-way valve housing 182 which is connected to the moveable component 136 housing the sorbent capsule 120 and the clipl 44 for holding open the metering device.

[0123]

[0124] Returning to Figure 13a, at step S1312, the seal at the base on the moveable component housing the sorbent capsule is removed so that the sorbent capsule can be extracted. The seal may be a rubber V-seal, for example, and forceps can be used to grip the rubber V-seal to pull it away from the sorbent capsule. If the seal is a V-seal, the V-seal may tear while it is being removed. At step S1314, the sorbent capsule is extracted. Once the sorbent capsule is extracted, it may be prepared for analysis, for example by mass spectrometry, such as TD-MS.

[0124]

[0125] Although the example embodiments have been described with reference to the components, modules and units discussed herein, such functional elements may be combined into fewer elements or separated into additional elements. Various combinations of optional features have been described herein, and it will be appreciated that described features may be combined in any suitable combination. In particular, the features of any one example embodiment may be combined with features of any other embodiment, as appropriate, except where such combinations are mutually exclusive. Throughout this specification, the term “comprising” or “comprises” means including the component(s) specified but not to the exclusion of the presence of others.

[0125]

[0126] Attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0126]

[0127] All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0127]

[0128] The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Claims

CLAIMS1. A passive breath sampling device comprising: a housing comprising: an inlet section comprising: an inlet for receiving at least one breath in the housing; an outlet for a first portion of each received breath to exhaust from the inlet section of the housing; and an inlet section flow path between the inlet and the outlet of the inlet section; and a sorbent section housing a sorbent capsule having a sorbent material for collecting a target compound from each received breath; a mechanical pressure regulator to regulate pressure within the inlet section of the housing when a breath is flowing along the inlet section flow path; at least one mechanical flow rate controller to control a flow rate of a second portion of each received breath from the inlet section to the sorbent section; and an activation mechanism which is usable to select an activated mode or a deactivated mode for the breath sampling device; wherein in the deactivated mode, a flow path for the second portion of each received breath from the inlet section to the sorbent section is blocked; and wherein in the activated mode, the flow path for the second portion of each received breath from the inlet section to the sorbent section is open and the second portion of each received breath flows along a sample flow path through the sorbent capsule; and wherein the pressure regulator and at least one flow rate controller are configured to provide a flow rate of the second portion of each received breath through the sorbent capsule in the activated mode which is generally constant for a range of flow rates of breath into the inlet, whereby a controlled amount of breath is sampled from each received breath.

2. The breath sampling device of claim 1 , wherein the pressure regulator and at least one flow rate controller are configured to provide a flow rate through the sorbent capsule which is generally around 100 ml / min for inlet flow rates of breath of between 10 L / min to 80 L / min.

3. The breath sampling device of claim 1 or claim 2, wherein the pressure regulator and at least one flow rate controller are configured to operate, in the activated mode, at pressure differences within the breath sampling device of between 0 to 5mbar.

4. The breath sampling device of any one of the preceding claims, wherein the pressure regulator is configured to generate a desired positive pressure within the device when a breath is being received into the device.

5. The breath sampling device of any one of the preceding claims, wherein the pressure regulator comprises at least one valve having a cracking pressure between 5 to 10 mbar.

6. The breath sampling device of claim 5, wherein the at least one valve comprises an exhaust valve which is openable by a received breath that exceeds the cracking pressure to provide the outlet for the first portion of each received breath to exhaust from the inlet section of the housing.

7. The breath sampling device of any one of the preceding claims, wherein the at least one flow rate controller comprises a venturi restriction which provides a venturi effect to control the flow rate.

8. The breath sampling device of claim 7, wherein the venturi restriction comprises a narrow section having a diameter of between 5 mm to 7.5 mm, for example 6.5mm to 7.5mm.

9. The breath sampling device of claim 7 or claim 8, wherein the venturi restriction connects the inlet section to the sorbent section.

10. The breath sampling device of any one of the preceding claims, wherein the at least one flow rate controller comprises an orifice which is located downstream from the sorbent capsule on the sample flow path.

11. The breath sampling device of claim 10, wherein the orifice has an adjustable diameter.

12. The breath sampling device of any one of the preceding claims, wherein the at least one flow rate controller comprises a restriction in the inlet section.

13. The breath sampling device of any one of the preceding claims, further comprising a metering device connected to the sorbent section which provides an indication that a target fixed volume has been received through the sorbent section.

14. The breath sampling device of claim 13, wherein the metering device is one of an inflatable bag, a colour changing indicator which changes colour when the target fixed volume has passed through the indicator or a chemical depletion sensor which detects depletion of a specific chemical to determine whether the target fixed volume has been received through the inlet.

15. The breath sampling device of any one of the preceding claims, further comprising a one-way valve downstream of the sorbent capsule on the sample flow path to prevent flow back through the sorbent capsule towards the inlet section.

16. The breath sampling device of claim 14, further comprising: a valve manipulation mechanism for separating the sealing surfaces of the oneway valve as the breath sampling device is changed from the deactivated state to the activated state.

17. The breath sampling device of claim 16, wherein the valve manipulation mechanism comprises an elongate body comprising at least one protrusion which protrudes from the elongate body to separate the sealing surfaces.

18. The breath sampling device of claim 17, wherein the valve manipulation mechanism comprises a plurality of protrusions including a first protrusion at a first end of the elongate body.

19. The breath sampling device of claim 18, wherein the plurality of protrusions having different sizes with the first protrusion being the largest.

20. The breath sampling device of any one of the preceding claims, further comprising: a moveable component housing the sorbent capsulewherein in the deactivated mode, the moveable component is in a first location in which the flow path from the inlet section to the sorbent section is sealed and wherein in the activated mode, the moveable component is in a second location in which the flow path from the inlet section to the sorbent section is open.

21. The breath sampling device of any one of the preceding claims, wherein the sorbent capsule is removably housed in the housing and wherein in the deactivated mode, the sorbent capsule is removed and / or inserted into the breath sampling device.

22. The breath sampling device of claim 21 , further comprising: a detachable cover which is removably attached to the housing; wherein, in the deactivated state, the detachable cover is removable to access the sorbent capsule.

23. The breath sampling device of any one of the preceding claims, further comprising: a diffusive seal downstream from the sorbent capsule on the sorbent section flow path.

24. The breath sampling device of any one of the preceding claims, further comprising a seal adjacent the sorbent capsule wherein in the deactivated mode, the seal prevents flow from the inlet section to the sorbent section.

25. A method of using the breath sampling device of any one of the preceding claims, the method comprising: activating the activation mechanism to select the activated mode for the breath sampling device; receiving a plurality of breaths into the breath sampling device via the inlet; sampling, using the sorbent capsule, a controlled amount of each of the plurality of breaths to collect a target compound; and when a target fixed volume has been sampled, deactivating the activation mechanism to select the deactivated mode for the breath sampling device.

26. The method of claim 25, further comprising:removing, when the breath sampling device is in the deactivated mode, the sorbent capsule from the breath sampling device; and analysing the sorbent capsule to determine a concentration of the target compound in the target fixed volume breath sample.

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