Analyte sensing device and method for respiratory therapy control and assessment

Abstract

Disclosed is a minimally-invasive sensing device for measuring or estimating respiratory biomarkers. The device contacts a target body fluid detects for at least one target analyte and outputs a signal representative of a concentration of the analyte, from which biomarker information is determined. The present disclosure also relates to methods and systems using measurements or estimations of respiratory biomarkers to assess patient respiratory state, and / or assist in providing respiratory therapy to a patient.

Description

[0001] ANALYTE SENSING DEVICE AND METHOD FOR RESPIRATORY THERAPY CONTROL AND

[0002] ASSESSMENT

[0003] FIELD

[0004] [1] The present disclosure relates to a sensing device for measuring or estimating respiratory biomarkers. The present disclosure also relates to methods and systems using measurements or estimations of respiratory biomarkers to assess patient respiratory state, and / or assist in providing respiratory therapy to a patient.

[0005] BACKGROUND

[0006] [2] Respiratory therapy devices are used in various environments to deliver breathable gases to users or patients. A breathing assistance or respiratory therapy device (collectively, "respiratory apparatus" or "respiratory devices" may be used to deliver supplementary oxygen or other gases with a flow of gases, and / or a humidification apparatus to deliver heated and humidified gases. A respiratory therapy device may allow adjustment and control over characteristics of the gases flow, including flow rate, temperature, gases concentration, humidity, pressure, for example.

[0007] [3] For patients with impaired respiratory function, detecting an impairment, identifying the type and cause of the impairment, determining if it is necessary to commence respiratory therapy, and / or assessing the effectiveness of respiratory therapy provided to the patient can be challenging. Assessing the effectiveness of respiratory therapy and / or selecting appropriate settings for the therapy may rely on clinical observations and a clinician's judgement, which can be subjective and dependent on their experience and preferences.

[0008] [4] In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally to provide a context for discussing features of the disclosure. Unless specifically stated otherwise, reference to such external documents or sources of information is not to be construed as an admission that such documents or such sources of information, in any jurisdiction, are prior art or form part of the common general knowledge in the art.

[0009] SUMMARY

[0010] [5] In a first aspect, the present disclosure provides a device for minimally-invasive sensing of a respiratory biomarker. The device comprises a patch having a sensor arranged to contact a target body fluid and arranged to form an electrochemical cell therewith, the sensor being selective for at least one target analyte. The device further comprises a power source and a circuit configured to output a signal representative of a concentration of the target analyte in the target fluid.

[0011] [6] In an embodiment, the sensor may be configured to measure two or more target analytes in the target fluid. The target analytes may be utilised in a calculation to estimate one or more respiratory biomarkers. Some examples of respiratory biomarkers include partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3), base excess (BE), glucose, and lactate.

[0012] [7] The device may comprise a plurality of microneedles. One or more of the plurality of microneedles may be configured to penetrate through a patient's stratum corneum. One or more of the plurality of microneedles may comprise a solid body.

[0013] [8] The sensor may comprise one or more working electrodes. One or more of the plurality of electrodes may be provided on one or more microneedles. In an embodiment, one or more of the microneedle comprises an electrode.

[0014] [9] The device may include one or more working electrodes, one or more counter electrodes, and one or more reference electrodes. In an embodiment, each working electrode may be functionalised to select for a respective target analyte. The target analyte may be a target ion.

[0015]

[0010] One or more of the plurality of microneedles may comprise a bevelled tip. One or more of the plurality of microneedles may comprise a leading point configured to pierce a patient's skin.

[0016]

[0011] The device may be configured to measure potentiometric pH. For example, the device may include one or more working electrodes configured to select for H+ions.

[0017]

[0012] In an example, one or more working electrodes are configured to select for CC2-ions.

[0018]

[0013] One or more of the electrodes may comprise an electrically conductive and biocompatible material.

[0019]

[0014] The circuit may comprise an integrated circuit on the device. The circuit may be remote from the device and electrically attached to the device via leads.

[0020]

[0015] The device may include a transmitter arranged to transmit a signal indicative of one or more outputs of the circuit. The transmitter may be configured to transmit a wireless signal.

[0021]

[0016] The device may include an electrochemical sensing module comprising the sensors, in communication with a signalling module, the signalling module comprising the power source, the transmitter, and being configured to process and transmit a signal from the sensing module.

[0022]

[0017] The power source may comprise one or more of a battery, a biofuel cell, or an enzymatic biofuel cell. The power source may be arranged to power the transmitter. The transmitter may be a low power transmitter such as a Bluetooth transmitter.

[0023]

[0018] The device may comprise a substrate for placing in contact with a patient's skin. The substrate may be flexible. The substrate may comprise one or more of silicone, hydrocolloid, polyurethane, and polyimide The substrate may comprise a biocompatible material. The device may be configured as a wearable patch.

[0024]

[0019] A plurality of microneedles may protrude from the substrate. For example, the microneedles may protrude in an orthogonal direction.

[0020] The substrate may comprise a conductive layer arranged to electrically connect the circuit with the respective electrodes.

[0025]

[0021] In a second aspect, the present disclosure provides a respiratory interface or headgear therefore, comprising the device described above in relation to the first aspect.

[0026]

[0022] In a third aspect, the present disclosure provides a system for minimally-invasive measurement of a respiratory biomarker comprising a minimally-invasive sensor configured to measure a signal indicative of or useful for the calculation of the respiratory biomarker, and a communication module configured to communicate a signal indicative of a concentration of the respiratory biomarker to a remote device; wherein the remote device is configured to display data based on the transmitted signal.

[0027]

[0023] The remote device may comprise a monitoring display, a hospital monitoring hub, or a respiratory therapy device, for example. The respiratory therapy device may comprise a ventilator, a flow-controlled device, a pressure-controlled device, a positive airway pressure device, a continuous positive airway pressure device, a bi-level positive airway pressure device, or a high-flow therapy device, for example.

[0028]

[0024] In one example, the respiratory biomarker is blood partial pressure of carbon dioxide for respiratory therapy (PaCOz). The device may be configured to obtain the signal indicative of a patient's PaCOz using capnography (etCO2), transcutaneous measurements (TCCO2), or using a wearable microneedle device.

[0029]

[0025] The data may be displayed is in a form to assist a clinician in decision regarding the provision of respiratory therapy to the patient.

[0030]

[0026] The remote device may be configured to process the transmitted signal and display a respiratory therapy recommendation to clinician based on the transmitted signal.

[0031]

[0027] The system may include a respiratory therapy module and a controller, wherein the controller is configured to alter at least one setting of the respiratory therapy module based on the transmitted signal.

[0032]

[0028] In a fourth aspect, the present disclosure provides a system for measurement of a respiratory biomarker, comprising a minimally-invasive sensor device configured to measure the respiratory biomarker; and a communication module to communicate an output signal indicative of the respiratory biomarker to a remote device.

[0033]

[0029] The remote device may be configured to modify one or more parameters of a respiratory therapy module or assist a clinician in a decision regarding the modification of one or more respiratory therapy parameters based on the blood analyte measurement.

[0034]

[0030] The remote device may comprise a monitoring display, a hospital monitoring hub, or a respiratory therapy device.

[0035]

[0031] The decision regarding the modification of respiratory therapy parameters may include one or more of: whether respiratory therapy should be started or stopped, selection of a type of respiratory therapy, whether the type of respiratory therapy should be changed, and changing one or more settings of the respiratory therapy.

[0032] The parameters of the respiratory therapy include: a gas flow rate, operating pressure, patient interface type, humidity level, humidity settings, pressure support, inspiratory positive airway pressure (IPAP), expiratory positive airway pressure (EPAP), positive end-expiratory pressure (PEEP), tidal volume, fraction of inspired oxygen (FiO2).

[0036]

[0033] The sensor device may be configured to monitor the respiratory biomarker continuously.

[0037]

[0034] The system may comprise a controller, wherein the controller is configured to alter at least one setting of the respiratory therapy based on the output signal. The controller may be configured to alter at least one setting of the respiratory therapy based on the output signal after confirmation or authorization by the clinician. A respiratory therapy setting may be altered manually by the clinician.

[0038]

[0035] The system may be configured to detect if a patient is hypercapnic. If a patient is detected to by hypercapnic the system may direct modifications to respiratory therapy to decrease deadspace, for example by increasing flow rate and / or, increasing pressure support.

[0039]

[0036] The respiratory biomarker may be selected from the list: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0040]

[0037] The decision regarding the modification of one or more respiratory therapy parameters may be made based on two or more respiratory biomarker measurements.

[0041]

[0038] The decision regarding the modification of one or more respiratory therapy parameters may be made by comparing a biomarker estimate or measurement with an acceptable range of a biomarker. The system may include one or more acceptable ranges for each biomarker. For example, a pH between about 7.35 and about 7.45, a PaCO2 between about 4.7kPa and about 6 kPa, a PaO2 between about llkPa and about 13 kPa, a HCO3- between about 22 and about 26 mEq / L, and / or a base excess (BE) between -2 and + 2 mmol / L.

[0042]

[0039] The sensor device may comprise a patch having a sensor arranged to contact a target body fluid and arranged to form an electrochemical cell therewith, the sensor being selective for at least one target analyte. The target analyte may be a target ion. The device further comprises a power source and a circuit configured to output a signal representative of a concentration of the target analyte in the target fluid.

[0043]

[0040] In an embodiment, the sensor may be configured to measure two or more target analytes in the target fluid. The target analytes may be utilised in a calculation to estimate one or more respiratory biomarkers. Some examples of respiratory biomarkers include partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0041] The sensor device may comprise a plurality of microneedles. At least one of the plurality of microneedles may be configured to penetrate through a patient's stratum corneum. At least one of the plurality of microneedles may comprise a solid body.

[0044]

[0042] The sensor may comprise one or more working electrodes. The electrodes may be provided on one or more microneedles. In an embodiment, at least one of the plurality of microneedles comprises an electrode.

[0045]

[0043] The sensor device may include one or more working electrodes, one or more counter electrodes, and one or more reference electrodes. In an embodiment, one or more working electrode may be functionalised to select for a respective target analyte. The functionalisation may be a coating. One or more of the working electrodes may be functionalised with a coating.

[0046]

[0044] The sensor device may be configured to measure potentiometric pH. For example, the device may include one or more working electrodes configured to select for H+ions.

[0047]

[0045] In an example, one or more working electrodes are configured to select for CC2-ions.

[0048]

[0046] The electrodes may each comprise an electrically conductive and biocompatible material.

[0049]

[0047] The circuit may comprise an integrated circuit on the device. The circuit may be remote from the device and electrically attached to the device via leads.

[0050]

[0048] The device may include a transmitter arranged to transmit a signal indicative of one or more outputs of the circuit. The transmitter may be configured to transmit a wireless signal.

[0051]

[0049] The sensor device may include an electrochemical sensing module comprising the sensors, in communication with a signalling module, the signalling module comprising the power source, the transmitter, and being configured to process and transmit a signal from the sensing module.

[0052]

[0050] The power source may comprise one or more of a battery, a biofuel cell, or an enzymatic biofuel cell. The power source may be arranged to power the transmitter. The transmitter may be a low power transmitter such as a Bluetooth transmitter.

[0053]

[0051] The wearable patch may comprise a substrate for placing in contact with a patient's skin. The substrate may be flexible. The substrate may comprise a biocompatible material.

[0054]

[0052] A plurality of microneedles may protrude from the substrate. For example, the microneedles may protrude in an orthogonal direction.

[0055]

[0053] The substrate may comprise a conductive layer arranged to electrically connect the circuit with the respective electrodes.

[0056]

[0054] The remote device may be configured to provide a respiratory therapy recommendation to modify one or more parameters of a respiratory therapy module. The respiratory therapy recommendation may be displayed on a clinician interface. The respiratory therapy recommendation may be automatically transmitted to the respiratory therapy module. The respiratory therapy recommendation may be initiated automatically by the respiratory therapy module. The recommendation to modify one or more parameters may include a recommendation to modify one or more of: whether respiratory therapy should be started or stopped; selection of a type of respiratory therapy; whether the type of respiratory therapy should be changed; and changing one or more settings of the respiratory therapy.

[0057]

[0055] In a fifth aspect, the present disclosure provides a method of assessing and treating patient for a respiratory condition, comprising measuring a respiratory biomarker and modifying of one or more parameters of respiratory therapy based on the respiratory biomarker measurement.

[0058]

[0056] The parameters of respiratory therapy parameters may include one or more of: whether respiratory therapy is provided to the patient; a type of respiratory therapy; one or more settings of the respiratory therapy.

[0059]

[0057] The parameters of the respiratory therapy may include one or more of: a gas flow rate; operating pressure; patient interface type; humidity level; humidity settings; pressure support; inspiratory positive airway pressure (IPAP); expiratory positive airway pressure (EPAP); positive end-expiratory pressure (PEEP); tidal volume; fraction of inspired oxygen (FiO2).

[0060]

[0058] The respiratory biomarker may be monitored continuously or intermittently.

[0061]

[0059] The system may include a controller configured to modify the one or more parameters of respiratory therapy based on the respiratory biomarker measurement. The controller may automatically modify parameters of the respiratory therapy or may do so upon confirmation or authorization by a clinician.

[0062]

[0060] The system may be configured to detect if a patient is hypercapnic. If a patient is detected to by hypercapnic the system may direct modifications to respiratory therapy to decrease deadspace, for example by increasing flow rate and / or, increasing pressure support.

[0063]

[0061] The respiratory biomarker may be selected from one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate

[0064]

[0062] The decision regarding the modification of one or more respiratory therapy parameters may be made based on two or more respiratory biomarker measurements.

[0065]

[0063] The decision regarding the modification of one or more respiratory therapy parameters may be made by comparing a biomarker estimate or measurement with an acceptable range of a biomarker. The system may include one or more acceptable ranges for each biomarker. For example, a pH between about 7.35 and about 7.45, a PaCO2 between about 4.7kPa and about 6 kPa, a PaO2 between about llkPa and about 13 kPa, a HCO3- between about 22 and about 26 mEq / L, and / or a base excess (BE) between -2 and + 2 mmol / L.

[0064] The method may comprise displaying a value or an indication of the biomarker on a screen.

[0066]

[0065] The method may comprise assessing a value of the biomarker against an acceptable threshold range of the biomarker for the patient. Modifying of one or more parameters of respiratory therapy occurs if the respiratory biomarker value is outside the threshold range or within the threshold range but trending towards a limit of the range.

[0067]

[0066] In a sixth aspect, the present disclosure provides a method of assessing a patient for a respiratory condition. The method comprises obtaining one or more signals representative of one or more target analyte concentrations from the device disclosed herein, and determining one or more respiratory biomarker measurements based on the one or more signals.

[0068]

[0067] The method may further comprise assessing a value of the biomarker against an acceptable threshold range of the biomarker for the patient.

[0069]

[0068] The method may further comprise determining if a patient is hypercapnic based on the respiratory biomarker measurement.

[0070]

[0069] The one or more signals may be obtained continuously.

[0071]

[0070] The one or more respiratory biomarker may be selected from one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0072]

[0071] The method may comprise determining two or more respiratory biomarker measurements.

[0073]

[0072] The method may comprise displaying a value or an indication of the one or more biomarkers on a display.

[0074]

[0073] In a seventh aspect, the present disclosure provides a method of treating a patient for a respiratory condition, comprising: applying the device disclosed herein to a patient; assessing the patient for a respiratory condition in accordance with the method described in the sixth aspect, and modifying of one or more parameters of respiratory therapy based on the one or more respiratory biomarker measurement.

[0075]

[0074] A controller may modify the one or more parameters of respiratory therapy based on the respiratory biomarker measurement. Modification of one or more parameters of respiratory therapy may occur if the respiratory biomarker value is outside the threshold range. Modification of one or more parameters of respiratory therapy may occur if the respiratory biomarker value is within the threshold range but trending towards a limit of the range.

[0076]

[0075] The parameters of respiratory therapy parameters includes one or more of: whether respiratory therapy is provided to the patient; a type of respiratory therapy; and one or more settings of the respiratory therapy.

[0077]

[0076] In an eighth aspect, the present disclosure provides a method for controlling a respiratory therapy device providing respiratory therapy to a patient, comprising: receiving a signal indicative of at least one respiratory biomarker concentration of the patient, from a wearable device comprising a plurality of microneedles in contact with the patient's skin; obtaining supplementary information; determining a recommended adjustment to a respiratory therapy setting using a therapy adjustment algorithm based on the received signal and the supplementary information; and causing a respiratory therapy device to implement the recommended adjustment to the respiratory therapy setting.

[0078]

[0077] The respiratory biomarker may comprise one or more of partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0079]

[0078] The supplementary information may comprise one or more data on the patient, selected from: current respiratory settings, gender, height, breathing pattern, body weight, BMI, age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders, other comorbidities, and other chronic disorders e.g. cardiac disorders.

[0080]

[0079] The wearable device may comprise a patch comprising a plurality of microneedles arranged in a microneedle region. The patch may comprise two or more microneedle regions. At least one microneedle region may comprise a plurality of microneedles extending from the substrate and functionalised to selectively detect a different target analyte in a body fluid.

[0081]

[0080] The therapy adjustment algorithm may compare the received respiratory biomarker concentration to a predetermined threshold range.

[0082]

[0081] The recommended adjustment may be a recommended adjustment of any one of: commencement of respiratory therapy, cessation of respiratory therapy, changing a respiratory therapy setting, changing a mode of respiratory therapy, or changing the type of respiratory therapy.

[0083]

[0082] The recommended adjustment may comprise an adjustment of at least one of: gas flow rate, pressure support, tidal volume, fraction of inspired oxygen, or therapy mode.

[0084]

[0083] The therapy mode may be selected from invasive or non-invasive respiratory therapy; flow-based therapy including high flow therapy (including nasal high-flow therapy), low flow therapy; oxygen therapy; pressure-based therapy (including positive airway pressure and continuous positive airway pressure); continuous mandatory ventilation; synchronised intermittent mandatory ventilation; pressure support ventilation; continuous positive airway pressure; airway pressure release ventilation; bilevel positive airway pressure; pressure- regulated volume control; mandatory minute ventilation; adaptive support ventilation; proportional assist ventilation; and neurally adjusted ventilatory assist.

[0085]

[0084] The respiratory therapy device may be selected from one or more of: a ventilator, a flow-controlled device, a pressure-controlled device, a positive airway pressure device, a continuous positive airway pressure device, a bi-level positive airway pressure device, or a high-flow therapy device.

[0085] The method may further comprise displaying the recommended adjustment and the respiratory biomarker concentration on a clinician-facing display.

[0086]

[0086] The recommended adjustment may be implemented automatically by the respiratory therapy device, or upon confirmation by a clinician.

[0087]

[0087] The respiratory biomarker concentration may be monitored continuously, or at predetermined intervals.

[0088]

[0088] In a ninth aspect, the present disclosure provides a system for respiratory therapy management, comprising a first device, wearable by a patient, configured to generate a signal indicative of at least one respiratory biomarker concentration from a patient; a communication module configured to transmit the signal to a device; and a second device, separate from the first device. The second device comprises a display and a processor. The second device is configured to: receive the signal; process, on the processor, the signal to determine a current value of the at least one respiratory biomarker; compare the current value to a predetermined threshold range; determine a therapy recommendation based on the comparison; and display, on the display, the current value of the at least one respiratory biomarker and the therapy recommendation.

[0089]

[0089] The first device may comprise a microneedle-based sensor patch configured to detect the respiratory biomarker in a target fluid. The target fluid may be interstitial fluid. The first device may comprise the device as described herein.

[0090]

[0090] The respiratory biomarker may be selected from one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0091]

[0091] The communication module may be configured to transmit the signal wirelessly.

[0092]

[0092] The second device may be further configured to receive supplementary information. The supplementary information may be selected from: current respiratory settings, gender, height, breathing pattern, body weight, BMI, age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders, other comorbidities, and other chronic disorders e.g. cardiac disorders.

[0093]

[0093] The therapy recommendation may indicate an adjustment to at least one of: gas flow rate, pressure support, tidal volume, fraction of inspired oxygen, or therapy mode.

[0094]

[0094] The display may be configured to present an alert if the current value of the respiratory biomarker is outside the predetermined threshold range.

[0095]

[0095] The remote device may be configured to store on a memory a plurality of current values corresponding to respiratory biomarker data.

[0096]

[0096] The therapy recommendation may be implemented automatically by a respiratory therapy device, or upon confirmation by a clinician.

[0097]

[0097] In a tenth aspect, the present disclosure provides a microneedle patch for multianalyte detection. The microneedle patch comprises a flexible substrate configured for placement on a patient's skin; two or more microneedle regions on the substrate, microneedle region comprising a plurality of microneedles extending from the substrate and functionalised to selectively detect a different target analyte in a body fluid; and a circuit configured to receive signals from the microneedles of each region and output data indicative of the concentration of each respective target analyte.

[0098]

[0098] The target analyte may be a target ion. The target ion may be selected from COs2', HCO3' ions or H+.

[0099]

[0099] The flexible substrate may comprise a biocompatible material. The flexible substrate may comprise one or more of silicone, hydrocolloid, polyurethane, and polyimide.

[0100]

[0100] The plurality of microneedles in one or more of the microneedle regions may comprise a plurality of microneedles as described herein. For example, the at least one microneedle in the plurality of microneedles in one or more of the microneedle regions may be configured to access interstitial fluid without penetrating blood vessels. The microneedles in each region may be functionalised to be selective for the target analyte.

[0101]

[0101] The circuit may comprise a signal conditioning module configured to filter and amplify the signal(s) received. The circuit may be configured to output data in real time or at predetermined intervals.

[0102]

[0102] The microneedle patch may further comprise a wireless transmitter configured to transmit the output data to a remote device.

[0103]

[0103] In a tenth aspect, the present disclosure provides a microneedle patch for customisable analyte sensing. The microneedle patch comprises a flexible substrate configured for placement on a patient's skin; and one or more microneedle arrays removably mounted on the substrate; wherein the one or more microneedle arrays are configured to detect a selected target analyte in a body fluid; and a circuit configured to receive signals from the one or more microneedle arrays and output data indicative of the concentration of each detected target analyte.

[0104]

[0104] The one or more microneedle arrays may be selected from a set of microneedle arrays. Each microneedle array may comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles to another microneedle array in the set. Each microneedle array in the set of microneedle arrays may be interchangeable with other microneedle arrays in the set. For example, the set of microneedle arrays may comprise a first microneedle array and a second microneedle array, wherein the first microneedle array is interchangeable with the second microneedle array. The first microneedle array and the second microneedle array may comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles. The number, shape, analyte selectivity, and / or arrangement of microneedles in each of the plurality of microneedle arrays may be selected based on patient specific clinical requirements.

[0105]

[0105] Each microneedle array may be functionalised to selectively detect a target analyte. For example, a first microneedle array may be functionalised to selectively detect a first target analyte, and a second microneedle array may be functionalised to selectively detect a second target analyte.

[0106] The target analyte may be a target ion. The target ion may be selected from COs2', HCO3' ions or H+.

[0106]

[0107] In an eleventh aspect, the present disclosure provides a microneedle patch for analyte detection. The microneedle patch comprises: a flexible substrate configured for placement on a patient's skin; one or more distinct microneedle regions on the substrate, each microneedle region comprising a plurality of microneedles extending from the substrate and comprising one or more working electrodes functionalised to selectively detect a target analyte in a body fluid; a reference electrode array comprising microneedles, the reference electrode array being electrically connected to the working electrodes in the at least two microneedle regions; and a circuit configured to receive signals from the working electrodes and the reference electrode array, and to output data indicative of the concentration of each respective target analyte.

[0107]

[0108] The microneedle patch may comprise two or more distinct microneedle regions on the substrate.

[0108]

[0109] The target analyte may be a target ion. The target ion may be selected from COs2-, HCOs" ions or H+.

[0109]

[0110] The flexible substrate may comprise a biocompatible material. The flexible substrate may comprise one or more of silicone, hydrocolloid, polyurethane, and polyimide.

[0110]

[0111] One or more of the plurality of microneedles may be solid and configured to access interstitial fluid without penetrating blood vessels.

[0111]

[0112] One or more of the plurality of microneedles may comprise a bevelled tip defined by an oblique truncation of the microneedle body.

[0112]

[0113] One or more of the plurality of microneedles may comprise a leading edge configured to pierce a patient's stratum corneum.

[0113]

[0114] One or more of the plurality of microneedles may be functionalised to be selective for the target analyte.

[0114]

[0115] The circuit may comprise a signal conditioning module configured to filter and amplify the signal(s) received. The circuit may be configured to output data in real time or at predetermined intervals.

[0115]

[0116] The microneedle patch may further comprise a wireless transmitter configured to transmit the output data to a remote device.

[0116]

[0117] At least one of the distinct microneedle regions may be removably mounted on the substrate. At least one of the microneedle regions may be interchangeable with another microneedle region in the same manner as described herein for an interchangeable microneedle array. For example, one or more of the microneedle regions in the plurality of microneedle regions may be selected from a set. Each microneedle region may comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles to another microneedle region in the set. Each microneedle region in the set of microneedle regions may be interchangeable with other microneedle regions in the set. The number, shape, analyte selectivity, and / or arrangement of microneedles in each of the plurality of microneedle regions may be selected, at least in part, based on patient specific clinical requirements.

[0117]

[0118] In a twelfth aspect, the present disclosure provides a method of assessing and treating a patient for a respiratory condition. The method comprises obtaining and processing a signal representative of a concentration of a target analyte from the device as described herein, the system as described herein, or the microneedle patch as described herein; determining a respiratory biomarker measurement based on the respiratory biomarker measurement; and modifying one or more parameters of respiratory therapy based on the respiratory biomarker measurement.

[0118]

[0119] This disclosure may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features. Where specific integers are mentioned herein which have known equivalents in the art to which this disclosure relates, such known equivalents are deemed to be incorporated herein as if individually described.

[0119]

[0120] The term 'comprising' as used in this specification and claims means 'consisting at least in part of'. When interpreting statements in this specification and claims that include the term 'comprising', other features besides those prefaced by this term can also be present. Related terms such as 'comprise' and 'comprised' are to be interpreted in a similar manner.

[0120]

[0121] As used herein the term '(s)' following a noun means the plural and / or singular form of that noun. As used herein the term 'and / or' means 'and' or 'or', or where the context allows, both. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0121] BRIEF DESCRIPTION OF THE DRAWINGS

[0122]

[0122] The present disclosure will now be described by way of example only and with reference to the accompanying drawings in which:

[0123]

[0123] Figure 1 is a schematic view showing an example of a three electrode circuit, including a single working electrode, for the measurement of a respiratory biomarker;

[0124]

[0124] Figure 2 is a schematic view corresponding to Figure 1 but showing a four electrode circuit having two working electrodes;

[0125]

[0125] Figure 3 is a perspective view of the underside of a second example device for the measurement of a respiratory biomarker, having electrodes provided by microneedles arranged into seven arrays;

[0126]

[0126] Figure 4 is a partial cut-away section view of the device of Figure 3, taken through one of the microneedle arrays;

[0127]

[0127] Figure 5 is a perspective view of the underside of a third example device for the measurement of a respiratory biomarker, having the microneedles arranged into four arrays;

[0128] Figure 6 is a perspective view of the underside of a fourth example device similar to the device of Figure 5, but with arrays of different sizes;

[0128]

[0129] Figure 7 is a partial cut-away section view, showing layers of an example device;

[0129]

[0130] Figure 8 is an exploded perspective view of the example device of Figure 7;

[0130]

[0131] Figure 9 is a schematic illustrating a system utilising respiratory biomarker measurements from a device, such as a device illustrated in one of Figures 1 to 8, to inform and / or control the provision of respiratory therapy;

[0131]

[0132] Figure 10 is a diagram illustrating an example respiratory support system;

[0132]

[0133] Figure 11 is an example of a screen display for communicating respiratory biomarker(s) information;

[0133]

[0134] Figure 12 is a flow chart illustrating a method of measuring a respiratory biomarker, and deciding whether to commence respiratory therapy;

[0134]

[0135] Figure 13 is a flow chart illustrating a method of using patient respiratory biomarker(s) to assess the effectiveness of respiratory therapy supplied to a patient, and to modify or maintain the therapy;

[0135]

[0136] Figure 14 is a flow chart illustrating an example method to adjust respiratory therapy based on patient respiratory bioma rker(s);

[0136]

[0137] Figures 15 to 17 are side perspective views of a microneedle tip; and

[0137]

[0138] Figure 18 is a flow chart illustrating a method for determining a therapy recommendation.

[0138] DETAILED DESCRIPTION

[0139]

[0139] Respiratory biomarkers are measurable indicators of the presence, severity or type of a disease. They can be used to assist in understanding the cause, progression or regression, prognosis, or outcome of treatment of a disease. Accurate and timely measurement or estimation of patient respiratory biomarkers can assist clinical decision making.

[0140]

[0140] Measurement of respiratory biomarkers, for example, blood gas parameters such as PaO2 and PaCOz can indicate how well the lungs are working and may be useful for assessing a patient's respiratory state. For example, these measurements can indicate whether gas exchange of O2 and CO2 occurring in the lungs is normal or impaired. For example, hypercapnia is the presence of too much CO2 in the blood and is indicative of a condition in which the body cannot adequately remove CO2 from the body. However, existing methods to obtain this data have shortcomings. For example, methods to measure PaCO2 can be invasive and / or time inefficient. Some methods may suffer from poor accuracy.

[0141]

[0141] The method generally regarded to be most accurate for assessing respiratory function is the arterial blood gas (ABG) test. An ABG test measures levels of oxygen and carbon dioxide in the blood and checks the balance of acids and bases (pH level) of blood, among others. This test requires collecting a blood sample from an artery such as the radial artery in the wrist, the brachial artery in the arm, or a femoral artery in the groin. The sample must then be taken away for lab testing, causing a time delay between the blood sample being taken and the clinician receiving information. This delay can be from tens of minutes, up to several hours. The invasive nature of the arterial blood gas test also limits the frequency at which measurements can be taken due to discomfort for the patient, and a risk of complications.

[0142]

[0142] Some less invasive methods to measure or estimate indicators of patient respiratory state exist but have a number of disadvantages. One method is transcutaneous CO2 (TcPCOz) monitoring utilising a skin mounted transcutaneous sensor. In this method, the skin underneath the sensor is heated to improve local perfusion for monitoring TCPCO2. This methodology may risk burns to the skin, particularly for fragile neonate and infant skin. Transcutaneous CO2 sensors may also require frequent recalibration and the stability of the sensor over time can diminish. Some clinicians have observed reduced sensor accuracy in some settings, such as in the ER or ICU.

[0143]

[0143] End-tidal CO2 (EtCC ) monitoring or capnography is a method that may be utilised to measure the level of CO2 that is released at the end of an exhaled breath. This measured CO2 may be indicative of the adequacy with which CO2 is carried in the blood back to the lungs and exhaled. Capnography measurements may correlate to PaCC in healthy subjects but can be unreliable. For example, PaCC may be underestimated for patients with compromised lung function.

[0144]

[0144] Figures 1 to 8 show example devices 1, 101, 201, 301 for minimally-invasive measurement or estimation of one or more respiratory biomarkers. In these embodiments, unless otherwise specified, like reference numerals with the addition of 100, 200, or 300 indicate like features. For the purpose of promoting an understanding of the principles of the device, reference will first be made to the schematics of Figures 1 and 2.

[0145]

[0145] The device 1 comprises a wearable patch 11 that is placed in contact with a patient's skin S. The wearable patch 11 has one or more sensors 3 to detect one or more electrochemical signals in a target body fluid such as blood or interstitial fluid.

[0146]

[0146] In the examples shown in Figures 1 8<. 2, the sensors 3 comprise electrodes in the form of or provided on microneedles 5, 7, 9, 10 or other components that may at least partly penetrate the epidermis. As shown in Figure 2, the microneedles 5, 7, 9, 10 may penetrate a patient's stratum corneum SC such that at least the tips 5a, 7a, 9a, 10a or another portion of the electrodes are in contact with a target body fluid. The body fluid may be an intracellular fluid (ICF) and / or extracellular fluid (ECF). For example, the body fluid may be intravascular fluid, including blood volume. The body fluid may be interstitial fluid.

[0147]

[0147] The concentration of target analytes in the target fluid may be representative of the levels in the blood. Measurement of target analyte(s) in the target fluid may enable estimation of respiratory biomarkers without the microneedles necessarily coming in contact with blood. The penetration depth PD of the microneedles may be sufficient to ensure adequate contact of functionalised portions of the microneedles with the target fluid. The PD may assist to minimise or avoid contact with blood vessels. The penetration depth PD may be substantially the entire length of the microneedles or only a portion of the length of the microneedles. In a given device 1, the penetration depth PD may vary between microneedles in the device 1.

[0148]

[0148] The microneedles 5, 7, 9, 10 are elongate members configured to penetrate the skin.

[0149]

[0149] The dimensions of the microneedles 5, 7, 9, 10 such as the length and width, may be selected to provide sufficient contact with the target fluid, for example. The dimensions and / or the shape of the microneedles 5, 7, 9, 10 may be selected to assist with minimising pain and discomfort for the patient. The microneedles 5, 7, 9, 10 may all be of the same length, or the lengths may vary. The dimensions of the microneedles 5, 7, 9, 10 may be selected based on, for example, the intended position of the device on the body, the body fluid containing target analyte(s) and / or the attributes of the patient.

[0150]

[0150] As an example, the microneedles may be between about 25 pm and about 5000 pm in length. Different microneedle lengths may be suitable for different intended locations of the patch on the body. The microneedles may taper towards the tip. The microneedle may taper along a full length, such as from a base to the tip, or may be tapered along part of the length of the microneedle. The taper may be a linear or non-linear taper. The taper angle may be any suitable angle between 0° and 90°. For example, the taper angle may be any suitable angle less than about 45°. The microneedles may have a width between about 20 pm and about 250 pm at or near a base of each microneedle. A tip width may be less than 50 pm, for example between about 1 and about 25 pm.

[0151]

[0151] The microneedles 5, 7, 9, 10 may be generally circular in cross section but may have other cross-sectional shapes such as triangular, oval, square, hexagonal, or semi-circular. The cross-sectional shape may have radial symmetry or radial asymmetry. The microneedles 5, 7, 9, 10 may have one or more acute or sharp longitudinal edges. For example, Figures 3 to 8 illustrate microneedles 105, 107, 109 having a shape resembling a cone with a portion of the cone cut away through a plane perpendicular to the patch 11, creating a curved surface, a substantially planar surface and two sharp edges.

[0152]

[0152] The cross-sectional shape may change along the length of the microneedle or may be constant.

[0153]

[0153] The cross-sectional dimensions of the microneedles may reduce along at least a portion of the microneedle, from a base of the needle to its tip. The change in dimensions may be linear or non-linear.

[0154]

[0154] The microneedles 5, 7, 9, 10 may be arranged to penetrate the skin at an angle that is substantially orthogonal to the surface S of the skin. For example, the microneedles may project at an angle of about 90° from a skin facing surface of the wearable patch 11.

[0155]

[0155] In the embodiment shown, at least a lower portion or a tip portion 5a, 7a, 9a of each microneedle forms an electrode to provide sensing capability. In some embodiments, the whole body of each microneedle may form an electrode, or a middle portion of the microneedle may form the electrode. In some embodiments, an upper part of each microneedle may form part of the electrode or be in electrical communication with the respective electrode.

[0156]

[0156] The microneedles 5, 7, 9, 10 may comprise any suitable material. The microneedles 5, 7, 9, 10 may each comprise an electrically conductive material or coating. In some embodiments, the microneedles may comprise one or more metals such as stainless steel, titanium, gold, silver, platinum, or silicon, or one or more polymers or ceramics. The microneedles material preferably has good biocompatibility to reduce the risk of adverse reactions to the microneedles. Alternatively, or additionally, the microneedles may be coated in a material with good biocompatibility.

[0157]

[0157] Figures 15-17 show examples of a tip portion of a microneedle 401, in which the tip portion is defined by an oblique truncation of the microneedle body. In these examples, the tip portion comprises an oblique face 403, a rim 405, a trailing edge 407, and a leading edge 409.

[0158]

[0158] The tip portion may have a height defined by the difference between the microneedle height hl at the trailing edge and the microneedle height h2 at the leading edge 409 (where hl may be zero or greater than zero). The taper angle 9 may be between 0° and 90°, for example between 10° and 80°, between 10° and 20°, between 20° and 30°, between 30° and 40°, between 40° and 50°, between 50° and 60°, between 60° and 70°, between 70° and 80°, or between 80° and 90°.

[0159]

[0159] A single plane of truncation of the microneedle body 401 defines a bevelled tip portion, in which the trailing edge 407 and leading edge 409 respectively culminate in a trailing point and a diametrically opposed leading point on the oblique face 403.

[0160]

[0160] Other tip geometries may be used, including conic, chiselled, and triangular shapes, which may be produced by two or more planes of truncation of the microneedle body. A bevelled tip may be more efficiently manufactured than tip geometries having two or more planes of truncation and may therefore preferred in some circumstances.

[0161]

[0161] Whilst cylindrical microneedle bodies comprising circular cross sections are shown, other three dimensional microneedle shapes may be used, provided the microneedle geometry is suitable for piercing the skin or stratum corneum. For example, the microneedle body may comprise conical, frustoconical, prismatic, pyramidal, or wedge geometries.

[0162]

[0162] The overall shape of the tip, including the face, rim, trailing edge and leading edge, may be dependent on the microneedle geometry, such as the geometry of the microneedle body. For a microneedle comprising a cylindrical body (and circular cross section) and a tip portion defined by an oblique truncation thereof (as shown in Figures 15 to 17), the tip comprises an elliptical face, an elliptical rim, and the leading edge and trailing edge each culminate at respective leading and trailing points. For microneedles having a non- cylindrical body shape and a tip defined by a truncation thereof, the face, rim, leading edge and trailing edge may be defined by the cross section of the microneedle body at its truncation. The device 1 may comprise one or more reference electrodes (RE) 9 and one or more working electrodes (WE) 5, 7. The reference electrode(s) 9 are configured to have a stable and known electrode potential, such that it provides a reference against which the electrical potential of the working electrode can be measured. The reference electrode 9 is arranged to have substantially no current flow therethrough, for example by way of a high impedance.

[0163]

[0163] The device 1 may include one or more counter electrodes (CE) 10 arranged to form a three-electrode cell with respective reference and working electrodes 5, 9, 7. The counter electrode may be arranged to have current flow therethrough.

[0164]

[0164] Each working electrode 5, 7 may be functionalised such that it is selective to a target analyte. For example, a working electrode may be analyte-selective to a target analyte of interest. The functionalisation may be, for example, a coating, surface treatment, or other treatment to the working electrode. A coating 6, 8 or membrane may be applied to or deposited on an outer surface of the electrode. The functionalisation is selected to enable target analytes present in the target fluid to generate an electrical signal or potential in the respective working electrode that is representative of the concentration of the target analyte in that fluid. As an example, the target analyte may be an ion. The working electrode may be functionalised to be ion-selective to the target ion. For example, the functionalisation on the working electrodes 5, 7 may be a coating that may select for target ions such as COs2', HCOs' ions or H+.

[0165]

[0165] Each working electrode 5, 7 may compromise a single layer or coating or a plurality of coatings and / or layers. For example, additional coatings or layers may be included to enhance selectivity, improve conductivity and / or improve the adherence of other layer(s). In some devices, the microneedles may include a structural component that may be electrically non-conductive, to support one or more layers or coatings of the electrode. For example, the microneedles may comprise a polymeric body or core with a suitable electrically conductive coating thereon. The electrically conductive coating may be metal or metal-based, such as copper, or polymer-based, for example poly (3,4- ethylenedioxythiophene) or PEDOT.

[0166]

[0166] Each working electrode 5, 7, is in electrical communication with one or more of the counter electrodes 10. Each counter electrode 10 may be in electrical communication with one working electrode, a group of like working electrodes, and / or common to working electrodes of different types.

[0167]

[0167] Each counter electrode 10 may comprise a single layer or coating or a plurality of coatings and / or layers of an inert material. That is, a material that is not selective for analytes present in body fluids. In some devices, the microneedles may include a structural component that may be electrically non-conductive, to support one or more layers or coatings of the counter electrode. For example, the microneedles may comprise a polymeric body or core with a suitable electrically conductive coating thereon.

[0168]

[0168] Each reference electrode 9 may compromise a single layer or coating or a plurality of coatings and / or layers. For example, additional coatings or layers may be included to increase the impedance of the electrode 9 and provide a constant electrochemical potential. In some devices, the microneedles may include a structural component that may be electrically non-conductive, to support one or more layers or coatings of the reference electrode. For example, the microneedles may comprise a polymeric body or core with a suitable electrically conductive coating thereon. The electrically conductive coating may comprise gold or rhodium or another metal or suitable material selected to modify impedance, for example, increase or decrease.

[0169]

[0169] Each reference electrode 9 may be in electrical communication with one working electrode, a group of like working electrodes, and / or common to working electrodes of different types. The term 'electrical communication' is intended to encompass the linking of electrodes in an electrical circuit, for example via components such as op amps. As one example, one or more reference electrodes 9 may be electrically connected to an inverting terminal of an op amp and one or more like working electrodes may be electrically connected to the non-inverting input. In the embodiment shown in Figure 2, the reference electrode 9a is common to working electrodes 5, 7, of different types, which select for different target analytes.

[0170]

[0170] In one example of the device 1, as shown in Figure 1, the electrodes 5, 9, 10 may be electrically connected via electrical terminals 13 to form an electrochemical cell using a suitable known integrated circuit 15. The integrated circuit 15 may be in the form of a potentiostat or galvanostat, for example. The integrated circuit 15 may include arrangements to amplify signals, and / or reduce noise. For example, integrated circuit 15 may include a signal conditioning module (not shown) configured to amplify and / or filter a signal.

[0171]

[0171] The electrodes 5, 7, 9, 10 may be electrically connected to the electrical terminals 13 via an electrically conductive layer 29.

[0172]

[0172] In another example of device 1, as shown in Figure 2, the electrodes 5, 7, 9, 10 may have electrical terminals 13 that form part of an electrochemical cell. The electrical terminals 13 may enable connection of the electrodes to a suitable remote circuit via electrical leads (not shown). The remote circuit may apply a potential to the electrodes 5, 7, 9, 10. The remote circuit may be in the form of a potentiostat or galvanostat, for example.

[0173]

[0173] In use, the interstitial fluid or other target body fluid containing the target analytes acts as an electrolyte. The counter electrode(s) may pass current through the target fluid to the working electrode(s) and / or reference electrode. The electrode(s) 5, 7, 9, 10 and circuit 15 together with the target fluid electrolyte forms an electrochemical cell.

[0174]

[0174] In embodiments where the electrochemical cell comprises a potentiostat, the working electrodes(s) 5, 7 may be configured to supply current to a known resistor, coupled to a ground. The circuit may be configured to measure a potential difference across the resistor to estimate the current and therefore measure a concentration of the target analyte. The resistor may be of fixed or variable resistance. A higher concentration of a target analyte in the target fluid corresponds to a higher potential differential between the reference electrode 9 and the respective sensing electrode(s). This enables estimation of the concentration of the target analyte in the target fluid, which can function as a proxy of the concentration in the patient blood.

[0175]

[0175] In some embodiments, the working electrodes(s) 5, 7 may be configured to supply current to a capacitor.

[0176]

[0176] In some embodiments, the working electrode(s) may be excited with an electrical pulse (excitation signal) from the integrated circuit 15 or remote circuit 13. Either circuit may be arranged to measure a phase difference between the potential of the excitation signal and the potential response of the body fluid. Either circuit may also measure a total impedance difference of the potential of the excitation signal and the potential response of the body fluid. The excitation signal may be a sine wave at a selected frequency, for example. Measurement of the phase difference and / or total impedance may be repeated at different frequencies.

[0177]

[0177] The device 1 may be configured to detect a single type of analyte, as shown in Figure 1. The device 1 may be configured to detect two or more target analytes, such as in the embodiment shown in Figure 2. Respiratory biomarkers may be estimated using measurements of a single target analyte or may require the measurement of two or more target analytes. In devices for sensing two or more target analytes, one or more working electrodes may be provided for each target analyte. A single, common reference electrode 9 may be provided, as illustrated in Figure 2, or multiple reference electrodes 9 may be provided.

[0178]

[0178] The device 1 may be configured for the estimation of PaCOz. In such an embodiment, the first working electrode 5 may comprise a coating 6 for the selection of analytes carbonate COs2' or bicarbonate HCOs' , for example. Measurement of the potential generated at the first working electrode 5 enables estimation of the concentration carbonate CO32’ ion or bicarbonate HCOs' ion in the interstitial fluid or other target body fluid.

[0179]

[0179] The second working electrode 7 may comprise a coating 8 for the selection of H+ions, for example. Measurement of the potential generated at the second working electrode 7 enables the estimation of pH. Blood pH is of itself a useful respiratory biomarker.

[0180]

[0180] Together, the measured pH and the measured carbonate CCh2' or bicarbonate HCOs' in the target fluid can be used to estimate the partial pressure of carbon dioxide (PaCO2) in the patient blood.

[0181]

[0181] Some examples of respiratory biomarkers that the device may be configured to measure or estimate include: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (CO32-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0182]

[0182] The microneedles 5, 7, 9 may be arranged on the device in one or more arrays. For devices that are configured to measure two or more target analytes, the device may comprise a plurality of arrays or sub-arrays. Each array may form a different functional region of the device.

[0183] For devices that are configured to measure concentrations of two or more different analytes in interstitial fluid, blood, or other target body fluid, the device may comprise a plurality of different functional regions. For example, one region of working electrodes for each type of target analyte. The reference and counter electrodes may be provided in dedicated regions. Alternatively, or additionally, the device may include one or more reference electrodes that are shared between multiple regions.

[0183]

[0184] Figures 2 to 6 show examples of devices having multiple distinct arrays 121, 221, 321 of microneedles. The arrays 121, 222, 321 may be spaced from each other, as shown, or may be continuous. In these examples, each array has a dedicated function, with each array having a plurality of microneedles in electrical contact such that each array acts as a single electrode. In other embodiments, the device may include a single device array with two or more regions or sub-arrays. The microneedles in each sub-array may all include electrodes of the same type. The microneedles within each sub-array may be in electrical contact with each other.

[0184]

[0185] The arrays 121, 222, 321 may be removable from an underlying array contacting portion such as secondary layer 327, contact pads 328 or conductive layer 329. The arrays may be configured to be interchangeable. For example, an array configured to be selective for a first analyte may be interchangeable with an array configured to be selective for a second analyte. An interchangeable set of arrays may improve the efficiency of manufacture of the device or parts thereof, as well as allowing for ease of repair or replacement of the arrays. For example, each microneedle array provided to the device 1 may be selected from a set of different, interchangeable microneedle arrays (e.g., the set comprising a first, second, third, fourth, or fifth microneedle array). Each different microneedle array in the set may comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles.

[0185]

[0186] Each region of microneedles may include any suitable number of microneedles. The number of microneedles may be selected to ensure there is sufficient electrical contact of the region with a target fluid, such as the interstitial fluid. In each region, a proportion of the microneedles may not reach or come into contact with the target fluid. Increasing the number of microneedles in a given region or array increases the likelihood that the functionalised region of a sufficient number of microneedles can contact the target fluid.

[0186]

[0187] Increasing the density, or number of microneedles in a given area or array, may increase the available functionalised region or functionalised surface area. In other words, increasing microneedle density increases the collective functionalised region surface area for a given array. Number and / or density of microneedles in a given region or array may be optimised for the particular application, taking into considering factors such as intended application site, patient population, type of target body fluid, and types / numbers of target analytes to be measured.

[0187]

[0188] In the examples shown, the device 101, 201, 301 may include one array of microneedles 109, 209, 309 that acts as the reference electrode, one array of microneedles 105, 205, 305 that acts as a first working electrode for measurement of a first target analyte, and an array of microneedles 110, 210, 310 that acts as a counter electrode. Optionally, where the device is for the measurement of two or more target analytes, the device 101, 201, 301 may include one or more further arrays of microneedles 107, 207, 307 to act as further working electrode(s) for measurement of additional target analytes.

[0188]

[0189] In some embodiments, such as the example shown in Figure 2 having seven arrays, the device may include two or more like arrays having the same function. For example, two or more arrays that act as working electrodes for the same target analyte, and / or two or more arrays that act as reference electrodes. Like arrays may be electrically linked such that the plurality of like arrays act as a single electrode.

[0189]

[0190] The like arrays may be electrically distinct. For example, one reference array may be connected to the first working electrode(s) and a second reference array may be connected to the second working electrodes(s).

[0190]

[0191] The device 1, 101, 201, 301 may have any suitable number of arrays. The arrays 121, 221, 321 may be all substantially the same size or may vary in size. The arrays may each include the same number of microneedles. The number of microneedles may vary between arrays.

[0191]

[0192] In the example device 301 shown in Figure 6, the array of microneedles 310 that act as the counter electrode is larger than the other arrays. This may be helpful to minimize polarization of the counter electrode and may reduce the surface currents compared to a smaller or more dense microneedle arrangement.

[0192]

[0193] The microneedles 105, 107, 109, 110, 205, 207, 209, 210, 305, 307, 309, 310 in each array may all be of the same length, width, and / or shape. The lengths, and / or widths, and / or shape of the microneedles may vary within each array or between arrays.

[0193]

[0194] The microneedles 5, 7, 9 may comprise a solid body and / or a solid tip such that fluid cannot flow into an interior of the microneedles. This distinguishes the physical form of the solid microneedles of the present examples from those in some blood glucose sensors or drug delivery patches, which require hollow needles and rely on fluid flow therethrough.

[0194]

[0195] The device 1 comprises a wearable patch for placing in contact with a patient's skin. The wearable patch comprises a substrate 11 that contacts or faces the skin. The substrate 11 may be flexible to accommodate movement and contours in the skin to enable at least part of an undersurface of the substrate to remain in contact with the patient's skin during use. The substrate may have little or no stretch to prevent the patch from being stretched over the skin and potentially bunching skin up after adhesion.

[0195]

[0196] The substrate 11 may comprise a material selected from a flexible material such as silicone, hydrocolloid, polyurethane or polyimide or other suitably flexible material. The substrate 11 may comprise an inert, biocompatible material such as silicone or hydrocolloid, for example, to minimise the likelihood of skin reactions such as contact dermatitis. The wearable patch may include a plurality of layers and / or components. The layers may comprise any suitable materials such as one or more of a polymer such as a thermoplastic, polymer resin, polymer plastic, polyurethane, or polyimide, or a cellulose or composite material, for example.

[0196]

[0197] One or more layers of the substrate 311 may comprise a material that is 'breathable', that is one that permits transmission of moisture vapor therethrough, for example with a Moisture vapor transmission rate (MVTR)>0g / m2 / 24h.

[0197]

[0198] The substrate 311 is generally a planar pad with a thickness that is significantly less than both its width and length. The substrate and patch may have any suitable shape. For example, it may be generally square, rectangular, oval, elliptical or round. Radiused corners may be provided to minimise inadvertent catching and lifting of the pad. Referring to Figure 7, the substrate 311 may include one or more openings 312 for the receipt of the microneedles.

[0198]

[0199] The substrate 311 has a patient side that faces the patient's skin for adhering or otherwise attaching or lying adjacent to a patient's skin. The patient side of the substrate may be attached to the skin S of a patient using a dermatologically sensitive adhesive such as a hydrocolloid or hydrogel, for example. The adhesive may be breathable or moisture permeable, and / or may be porous. The adhesive of the patient side of the substrate may be protected prior to use by a removable backing material that is peeled off the substrate immediately prior to placing the device on the patient.

[0199]

[0200] The microneedles 5, 7, 9, 105, 107, 109, 110, 205, 207, 209, 210, 305, 307, 309, 310, may project substantially orthogonally from the substrate 11, 111 ,211, 311. The bases of the microneedles may be positioned within the substrate, for example in an aperture as shown in Figure 7, or embedded within the substrate.

[0200]

[0201] A frame 323 may be provided to hold the arrays 321 in place relative to the substrate and relative to each other. The frame 323 may be disengageable from an underlying portion of the device, for example to permit access to, or removal of, an array 321. The frame 323 may comprise any suitable material such as silicone, a thermoplastic elastomer, or other suitable plastic, for example. The frame may have a stiffness that is similar to the stiffness of the substrate 311 or that is stiffer.

[0201]

[0202] The arrays 321 are electrically connected to each other and to an electrical component 325 that receives the signal from the arrays 321. Each array 321 may be removable from the conductive layer 329. The arrays may be configured to be interchangeable, for example, each array 321 may be interchangeable with one or more other arrays 321. In the embodiment shown in Figure 6 each array 321 is in contact with a conductive layer 329. A base of each array and the frame 323 that overlies the arrays 321 may be adhered to a patient facing surface of the conductive layer 329. The conductive layer may be sized such that the perimeter of the conductive layer and the perimeter of frame align.

[0202]

[0203] The conductive layer may be a unidirectionally conductive material. The conductive layer may comprise a conductive tape. The conductive layer may comprise a plurality of embedded wires or other conductive components that extend across the thickness of the layer 320. For example, substantially perpendicular to a surface of the conductive layer 329. The patient facing surface and or the non-patient facing surface of the conductive layer 329 may be adhesive.

[0203]

[0204] A non-patient facing side or outward side of the wearable patch may comprise a secondary layer 327. The secondary layer may be flexible. This layer may comprise a flexible PCB. One or more electrical contact pads 328 may be provided between the secondary layer and the microneedle arrays 32. Contact pad(s) 328 may be provided between the secondary layer 327 and the conductive layer 329. The electrical contact pad(s) 328 may correspond to the microneedle array(s) 321. For example, the number of electrical contact pads 328 may correspond to the number of arrays 321 and / or the electrical contact pads 328 may be aligned with respective microneedle arrays 321, and / or the size of each contact pad 328 may correspond to the size of a respective overlaid array 321.

[0204]

[0205] The electrical contact pad(s) 328 provide an electrical path between the microneedle arrays 321 / conductive layer 329 and the PCB to form the electrochemical circuit.

[0205]

[0206] Other components of the electrical circuit such as components of a potentiostat, galvanostat, instrumentation, or other meters may be provided. For example, by the PCB or in an electrical component housing 325 on a non-patient facing side of the device 301.

[0206]

[0207] A fixation element or other feature may be provided on the outwardly facing surface of the substrate to provide the ability to secure elements or components of the respiratory system, for example to secure a part of the respiratory interface. The fixation element may be a one part of a two-part connection system, attachable to a second part of the two-part connection system, which may be provided on the connecting element. For example the first and second parts can be complementary mechanical fasteners, e.g. hook / loop.

[0207]

[0208] The device 1 may comprise a power source (not shown) arranged to provide electrical power to the electrodes 5, 7, 9, 10 of the electrochemical cell.

[0208]

[0209] The device 1 may comprise a transmitter. The power source may be arranged to provide electrical power to the transmitter. The transmitter may be a low-energy transmitter such as a Bluetooth or wi-fi transmitter.

[0209]

[0210] The transmitter is configured to transmit a wireless signal that is representative of the output signal from each electrochemical cell, for example the detected potential or current from each working electrode. The output signal can provide a measurement or estimation of a target analyte, for example, analyte concentration. The output signal can be used for measurement or estimation of a respiratory biomarker. The transmitter may transmit a signal representative of each measured potential or current along with identifiers, the identifiers indicating what the signal represents, to enable a receiver to match the measured potential or current to the measured analyte.

[0210]

[0211] The transmitter is arranged in electrical communication with the electrochemical cell. The transmitter may be partially or fully embedded in the substrate or may sit on top of the substrate. In some embodiments, the transmitter and / or the power source may be separate from the wearable patch and electrically connected via wires.

[0211]

[0212] The device may not include a transmitter and may be configured for wired transmission of the detected signal to a receiver.

[0212]

[0213] The output signal from the device 1 may require processing to provide a useful readable signal or reading for a clinician. The device 1 may include a processing module for processing and digitising the signal from the electrochemical cell prior to transmission by the transmitter. Processing the signal may include, for example, filtering and / or amplification of the signal. The filtering and / or amplification of the signal may be performed by a signal conditioning module in device 1. Alternatively, or additionally, processing of the signal may be carried out remote to the device 1, as described further below.

[0213]

[0214] The power source may comprise any suitable power source. For example, the power source may comprise one or more of a battery, a biofuel cell, or an enzymatic biofuel cell. The power source may hold sufficient stored energy to power the device for a predetermined minimum time period. The power source may hold sufficient energy to enable the transmitter to transmit a signal for a predetermined minimum time period. The signal may be transmitted continuously or intermittently.

[0214]

[0215] The power source may be partially or fully embedded in the substrate or may sit on top of the substrate. The power source may be provided in an electrical housing 325 on a non patient facing side of the device. In some embodiments, the power source may be a separate from the wearable patch and electrically connected via wires. The power source may be arranged alongside the transmitter.

[0215]

[0216] The wearable device advantageously can provide continuous or semicontinuous measurement or monitoring of one or more patient respiratory biomarkers.

[0216]

[0217] The device 1, 101, 201, 301 may be configured to be a reusable or a disposable device.

[0217]

[0218] Referring now to Figures 9 and 10, the above-described device 1 has utility in a system 1001 for minimally invasive measurement of a respiratory biomarker to inform patient respiratory state and / or respiratory therapy. The system 1001 comprises a minimally-invasive sensor device 1003 configured to measure a respiratory biomarker of relevance to a respiratory condition and / or of relevance to respiratory therapy and a respiratory therapy system 1005. The system 1001 may include a display for communicating information to a clinician.

[0218]

[0219] Figure 10 schematically illustrates an example respiratory system 1005, including a respiratory apparatus, and one or more components. The one or more components may be for example any combination of: one or more conduits (for example inspiratory conduit 1021, expiratory conduit 1035), a patient interface 1033, and a Wye-piece 1031. The one or more components may form part of a conduit system. In some examples, the one or more components may form part of the respiratory system but may not be part of the conduit system.

[0220] The respiratory apparatus may comprise a flow generator 1023 (such as a ventilator or blower, for example) and a humidifier 1025. In other examples, the respiratory apparatus comprises only the humidifier 1025, or only the flow generator 1023. The respiratory apparatus (for example as part of a respiratory system) may be configured to provide a form of respiratory therapy, such as, for example, high flow therapy, or a continuous, variable, or bi-level positive airway pressure (PAP), or another form of respiratory therapy.

[0219]

[0221] Gases may be transported in the conduit system of Figure 10 as follows: the flow generator 1023 may connect to a gases source to receive a flow of gases. The flow generator 1023 may draw in a flow of gases from the ambient environment. The flow of gases passes from the flow generator 1023 through a supply conduit 1037 to the humidifier 1025, which humidifies the gases.

[0220]

[0222] The flow generator 1023 may be, for example, a ventilator or a blower. The flow generator 1023 may be separated from the humidifier 1025 (for example be in separate housings which may optionally be coupled together) or integrated with the humidifier 1025 in a single housing.

[0221]

[0223] The humidifier 1025 connects to an end 1027 of a conduit, such as inspiratory conduit 1021, via a port 1029. The inspiratory conduit 1021 is connected to a patient 1013 through a patient interface 1033, optionally using a wye-piece 1031. An optional expiratory conduit, such as expiratory conduit 1035, also connects to the patient interface 1033 through the wye-piece 1031. The expiratory conduit 1035 may be configured to direct exhaled gases away from the patient 1013. In the example shown in Figure 10, expiratory conduit 1035 returns exhaled gases from the patient 1013 to the flow generator 1023. In another example, the inspiratory conduit 1021 connects directly to the patient interface 1033 without a Wye-piece 1031. In such an implementation, exhaled gases may flow to the ambient environment, without requiring an expiratory conduit.

[0222]

[0224] Inspiratory conduit 1021 can include electrically conductive elements such as heater and / or sensor elements 1039. Similarly, expiratory conduit 1035 can optionally include heater and / or sensor elements 1041.

[0223]

[0225] Further, the Wye-piece 1031 and patient interface 1033 can also optionally include heater and / or sensor elements. As will be explained in further detail below, the heater and / or sensor elements 145, 147 can be wires.

[0224]

[0226] As shown in the example respiratory system of Figure 10, dry or relatively dry gases enter the flow generator 1023, for example, through a vent 1043. A fan 1045 may improve gas flow into the flow generator 1023 by drawing air or other gases through the vent 1043. The fan 1047 may be, for instance, a variable speed fan, where an electronic controller 1049 controls the fan speed. The electronic controller 123 may also be controlled by a second electronic controller 1051, or vice versa, in some implementations.

[0225]

[0227] When present, various styles or types of humidifiers may be used in combination with other elements of the respiratory system. The humidifier 1025 can include a humidification chamber 1053 containing a volume of water 1055 or other suitable humidifying liquid, for example, a "pass-over" type humidifier. Other humidifier types are also contemplated, such as a humidifier including a wicking or other suitable absorbent material for holding humidification fluid. Other humidifier types may include humidifiers in cannula. A suitable humidifier may comprise a humidifier chamber and / or medium to hold humidification fluid. The humidification chamber 1053 can be removable from the humidifier 1025. In one example, where the humidifier may be a pass-over type humidifier, the humidification chamber 1053 may include a heat-conductive base (for example, an aluminium or steel base) contacting or associated with a heater plate 1057 on the humidifier 1025. The examples in the present disclosure describe a heater plate as a heater of the humidifier and a heater wire as a heater of the conduit.

[0226]

[0228] The humidifier 1025 may also include electronic controls. In Figure 10, for example, the humidifier 1025 includes an electronic, analog, or digital controller 1051. The controller 1051 may be a microprocessor-based controller executing computer software commands stored in associated memory. In response to humidity, temperature or other feedback values provided via a user interface 1060 and / or integrated sensors, the controller 1051 may determine heat, flow, pressure and / or other variables used to provide humidified gases to a patient (also referred to as a user) according to target operating parameters. User interface 1060 can be one or more hardware buttons and / or a display or touch screen display. The respiratory apparatus e.g. humidifier 1025 can provide audio and / or visual feedback to the user.

[0227]

[0229] Bi-directional arrow 1054 shows a communication connection between flow generator 1023 and humidifier 1025. The communication connection 128 may allow for the transmission of information between the humidifier 1025 and the flow generator 1023. Additionally, or alternatively, the communication connection 1054 provided may allow for the transmission of one or more control signals, between the humidifier and the flow generator. For example, the communication connection 128 provided may be provided between the controller 1051 of the humidifier and the controller 1047 of the flow generator. In some examples, this communication connection may be bi-directional, however in other examples it may be a one-way (either from the flow generator to the humidifier, or from the humidifier to the flow generator). The communication connection may be a wired or wireless connection.

[0228]

[0230] Any suitable patient interface may be used. Patient interface is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (that is, it is not to be limited to a special or customized meaning) and includes, without limitation, masks (such as tracheal mask, face masks, and nasal masks), endotracheal tubes, tracheostomy tubes, cannulas, and nasal pillows. Patient interface may be selected based on, for example, type of respiratory therapy, patient population and / or patient / clinician preferences.

[0231] A temperature sensor 1061 may be incorporated in or connected to inspiratory conduit 1021 near the Wye-piece 1031, or directly to the Wye-piece 1031 or the patient interface 115. The temperature sensor 1061 monitors the temperature of the flow of gases near or at the patient interface 1033. The temperature sensor may be a colorimetric sensor as described in more detail below.

[0229]

[0232] A heating wire may be used to adjust the temperature of the patient interface 1033, the Wye-piece 1031, and / or the inspiratory conduit 1021 to maintain the temperature of the flow of gases above the saturation temperature (that is the dew point temperature of the flow of gases), thereby reducing the opportunity for unwanted condensation, and / or to deliver the gases at a temperature which is well suited to the gases being provided to the patient. As shown in Figure 10, exhaled gases are optionally returned from the patient interface 1033 to the gases source 1023 via the expiratory conduit 1035.

[0230]

[0233] The respiratory system 1005 of Figure 10 can also provide oxygen (02) or an 02 fraction to the patient through port 1059. The respiratory system 1005 of Figure 10 can receive 02 from a remote source and / or by blending atmospheric air with incoming 02 from the remote source. The blending of atmospheric air and incoming 02 can occur via a Venturi or a similar inlet located in gases source 1023 or humidifier 1025.

[0231]

[0234] The minimally-invasive sensor device 1003 may comprise the wearable device 1, 101, 201, 301 described above, or another microneedle device. The sensor device 1003 may comprise a capnography-type sensor or transcutaneous-type sensor. The sensor device 1003 may comprise a transmitter 1007 to communicate a signal 1008 indicative of the respiratory biomarker.

[0232]

[0235] Measurements such as etCO2 obtained by capnography and TCCO2 obtained using a transcutaneous-type sensor device are generally less accurate than measurements obtained with a microneedle device but may have utility, for example for monitoring trends in a patient's respiratory condition.

[0233]

[0236] A remote, off patient device 1009 may be configured to receive the wireless signal 1007 from the transmitter 1007. In other examples, the off patient device 1009 may receive the signal via a wired connection. The remote device 1009 comprises a display such as a screen to display data received from the sensor device 1003. For example, the display could be a stand-alone monitoring display, a hospital monitoring hub, or the display of a respiratory device. The display may be any suitable electronic display such as an LED screen.

[0234]

[0237] The minimally invasive sensor 1003 may be configured to provide data in a continuous or semi-continuous manner. The minimally invasive sensor 1003 may be configured to provide data in real time. Therefore, the data displayed on the remote device 1009 is real-time data and indicative of a patient's current state.

[0235]

[0238] The system 1001 can generate patient specific information and display this in a graphical or other visua I ly / cl inicia n accessible form. The displayed information may include comparison with previous known patient data set(s), which can be collected using the current system or otherwise input into system. The system 1001 can generate and display this data with a speed / timeliness that is much more clinically useful that existing methods with long lead times. Relevant patient information is measured and displayed, in near realtime such that the clinician is receiving data that is relevant to current clinical status of patient.

[0236]

[0239] The data displayed may comprise a measurement or estimation of one or more respiratory biomarkers. Some example respiratory biomarker(s) may include: pH, PaCO2, PaO2, CO32-, HCO3-, and Base excess (BE), glucose, lactate, oxygen content (O2CT), and oxygen saturation (O2Sat).

[0237]

[0240] The display may be configured to display an alert or indicator to notify a clinician if a measured analyte is outside a desired range. Suitable indicators may include, for example, a colour change of the displayed data, an alert symbol, or a coloured light. An audible alert may be provided when a value or a combination of values is outside of a target range. In some systems, the remote device 1009 may send a notification to the clinician 1011, for example to a pager or other mobile device.

[0238]

[0241] The display may utilise colour coding, graphical plots, flashing of numbers or symbols, for example, to display readings and to communicate where the clinician's attention should focus.

[0239]

[0242] In an example embodiment, the remote device 1009 is configured to alert the clinician 1011 if a measured respiratory biomarker is outside of a respective target range. For example, if pH is outside of the range 7.35-7.45, if PaCO2 is outside of the range 4.7-6 kPa, PaO2 is outside of the range 11-13 kPa, HCO3- is outside of the range 22-26 mEq / L, or if Base excess (BE) is outside of the range -2 to +2 mmol / L. It will be understood that these ranges are examples only and that target ranges may vary between patients.

[0240]

[0243] PaCO2 may be useful for monitoring adequacy of respiratory therapy. PaCO2 measurements or estimations may assist to diagnose lung and breathing problems, both alone and in combination with other measurements.

[0241]

[0244] In some cases, a combination of two or more measurements may be required or useful to determine if a respiratory biomarker reading is outside of a clinically acceptable range and / or to determine a likely cause of the adverse reading. The indicator to alert the clinician may be activated if one or more values indicate an adverse respiratory state.

[0242]

[0245] For example, a measured pH outside of the clinically acceptable range may indicate an acidotic or alkalotic state, but not necessarily if that state is due to respiratory factors. If a patient 1013 is retaining CO2, blood may become more acidic from an increased concentration of carbonic acid. If a patient is ventilating excessive CO2, the blood may become more alkalotic. Therefore, pH in combination with PaCO2 can indicate hypercapnic respiratory failure, for example with a PaCO2 > about 6 kPa alongside a pH < about 7.35.

[0243]

[0246] As another example, a PaO2 measurement alone may be useful to a clinician's assessment of whether a patient is hypoxic or hypoxaemic. When considered in combination with a reliable PaCO2 measurement that is communicated to the clinician in a timely manner, PaO2 can assist a clinician to distinguish between types 1 & 2 respiratory failure or other conditions. The example system 1001 is advantageously able to measure and display these measurements in near real-time such that the clinician is able to act on current data that is relevant to the current status of the patient.

[0244]

[0247] Figure 11 shows an example display 1009 that provides a visual display 1073, 1075 of PaO2 and PaCO2 levels. In this example, the display 1009, communicates to a clinician whether the patient is within or outside of threshold ranges for each measurement.

[0245]

[0248] Communicating accurate respiratory biomarker data relevant to a patient's respiratory state to a clinician in a clear and a continuous or semi-continuous manner assists them to make timely, patient specific decisions with respect to the respiratory therapy they provide to the patient. This patient specific information may enable a clinician to provide the most appropriate and effective respiratory therapy to a patient. It may enable a clinician to modify respiratory therapy as required. It may allow a clinician to assess the effectiveness of a therapy for a given patient or patient group that may improve future patient outcomes.

[0246]

[0249] In some embodiments, as shown in the example of Figure 11, the remote device 1009 may be configured to display a respiratory therapy instruction or recommendation 1071 to a clinician based on the transmitted signal, which they can use for guidance. This may be in addition to displaying the measured values or as an alternative.

[0247]

[0250] If the display 1009 is on or is otherwise linked to the respiratory therapy system 1005, the recommended action can be initiated automatically, or upon confirmation or authorisation by the clinician.

[0248]

[0251] The therapy recommendation may include one or more of the following :

[0249] • If respiratory therapy should be started

[0250] • A recommended type of respiratory therapy

[0251] • If another type of respiratory therapy type is recommended

[0252] • If a setting of the respiratory therapy should be adjusted, for example a gas flow rate, pressure, humidity, tidal volume, FiO2, PEEP, ventilation mode, or other setting of respiratory therapy, which may be dependent on the type of respiratory therapy provided.

[0253] • If respiratory therapy should be ceased.

[0254]

[0252] For example, for a patient 1013 receiving a respiratory therapy, detection that the patient is hypercapnic may cause the system to recommend a change in respiratory therapy to decrease dead space. For example, the display 1009 may prompt the clinician 1011 to increase a flow rate of the respiratory therapy or to increase pressure support (for example, by increasing pressure or changing from a flow-based therapy to a pressure-based therapy).

[0255]

[0253] The remote device 1009 may comprise a processing module to process the received signal 1008. The processing module may process the signal to easily readable data to enable a clinician to make decisions about a patient's care. The processing module may include an algorithm to process the received signal and determine recommendations to display to a clinician based on data transmitted from the sensor. The algorithm may compare sensed data to predetermined acceptable data ranges. There may be different data ranges for different patient groups, and / or the desired ranges may be selected or preprogrammed by a clinician.

[0256]

[0254] In the example shown in Figure 9, the respiratory therapy module 1005 includes an example respiratory device having a flow generator FG and a humidifier H arranged to provide humidified gases to a patient via a patient interface PI. However, other respiratory devices and configurations of the respiratory therapy module are envisaged and would be understood by a person skilled in the art.

[0257]

[0255] The respiratory therapy module may optionally additionally include a controller C in communication with a receiver 115, wherein the controller C is configured to alter settings of the respiratory therapy module based on the transmitted signal 1016.

[0258]

[0256] The respiratory therapy module 1005 may include an interface I such as a display configured to display patient parameters, recommendations, and / or settings of the respiratory therapy module. In some embodiments respiratory therapy module 1005 may comprise the processing module, configured to process the received signal 1016. The processing module may process the signal to display easily readable data on the interface I to enable a clinician to make decisions about a patient's care. The processing module may include an algorithm to process the received signal and determine recommendations to display on the interface I to a clinician based on data transmitted from the sensor.

[0259]

[0257] In some embodiments, the controller C is configured to receive a signal 1016 from the sensor device 1003 and automatically, or upon confirmation or authorisation by the clinician, modify one or more settings of respiratory therapy module 1005 in response to the received signal. The controller C may include a processor to process the received signal 1016. In this embodiment, the system is a closed loop system.

[0260]

[0258] The controller C may be configured to automatically or on instruction or confirmation by a clinician, modify the one or more parameters of respiratory therapy based on the respiratory biomarker estimation or measurement(s). For example, the controller may be configured to modify a setting of the respiratory therapy module if one or more respiratory biomarker is outside of a respective target range. The target ranges may be the clinically acceptable described above, or ranges input by a clinician. The target ranges may be specific to a particular patient population, or patient specific.

[0261]

[0259] The controller may be configured to do one or more of the following :

[0262] • Commence respiratory therapy, for example, by starting the flow generator FG and / or the humidifier H

[0263] • Increase or decrease a gas flow rate, for example by changing a setting of the flow generator FG • Increase or decrease one or more of pressure, humidity, tidal volume, FiO2, PEEP, ventilation mode, or other setting of respiratory therapy, which may be dependent on the type of respiratory therapy provided

[0264] • Cease respiratory therapy by turning off the flow generator and humidifier.

[0265]

[0260] The system 1001 shown in Figure 9 includes a remote device 1009 in communication with the sensor device 1003 for displaying information to a clinician, and a respiratory module 1005 having a receiver 1015 and controller C in communication with the sensor device 1003. The controller C may be configured to modify settings of the respiratory therapy module 1005. Some systems may not transmit data to a remote device 1009, and instead transmit the sensor signal 1016 only to the respiratory therapy module 1005. In some embodiments the respiratory therapy module may have a screen to display data from the sensor 1003.

[0266]

[0261] In some embodiments the respiratory therapy module 1005 may not comprise a controller C or receiver 1015. In some embodiments the respiratory therapy module 1005 may not comprise a display 1009. The settings of the respiratory therapy may be changed manually by a clinician 1011 based on data displayed by the remote device 1009 or by the respiratory therapy module.

[0267]

[0262] Figures 12 and 13 illustrate a method 2001 of estimating or measuring a respiratory biomarker and selecting and / or modifying one or more parameters of respiratory therapy based on a respiratory biomarker such as PaCO2, for example. The method 2001 may use one of the systems 1001 and / or the device 1, 101, 201, 301 described above, or may use an alternative sensor 2003 and / or system.

[0268]

[0263] In a first example, for a patient receiving no respiratory therapy, after energising the sensor 2003, at time Tl, a reading 2005 indicative of one or more target analytes and / or other biomarker is obtained from the patient sensor. This reading may be processed 2007 to estimate a respiratory biomarker or other respiratory marker. The raw or processed signal may be transmitted 2009, wirelessly or non-wirelessly from the sensor.

[0269]

[0264] The transmitted signal may be received 2011 by a receiver on a remote device. The received signal may be processed or further processed at the remote device prior to being displayed in some form on a screen of the remote device. The signal may be displayed as a numerical measurement and / or a graphical or colour symbol to indicate whether the measurement is within a target range or whether it is high or low. In some embodiments, a recent history of the measurement may be shown, for example in the form of a graph.

[0270]

[0265] In a next step 2013, the estimation of a respiratory biomarker (or other respiratory biomarker(s)) is assessed against an acceptable threshold range of the biomarker for the patient. This assessment may be carried out automatically using an algorithm. A clinician may utilise the measurement of the respiratory biomarker along with other patient information to make decisions on patient care.

[0271]

[0266] If the respiratory biomarker estimation is outside the threshold range, it is deemed 'unsatisfactory' and a recommendation is displayed for a respiratory therapy action such as starting respiratory therapy. This may include recommendations for the type of respiratory therapy and the parameters of the therapy.

[0272]

[0267] If the respiratory biomarker estimation is acceptable a decision 2015 can be made as to whether respiratory therapy is required. A decision to commence respiratory therapy may also be made if the respiratory biomarker is measured over time trending in the wrong direction but still within an acceptable range. If there is an observable trend in the wrong direction, other factors may be considered which influence the decision-making process. The system may communicate details, based on the measured patient respiratory parameters, about therapy type and recommended therapy parameters. A clinician may decide to commence a first level of therapy as a preventative measure taking individual patient parameters into consideration.

[0273]

[0268] If the decision is that commencing respiratory therapy is required, the recommended action is displayed 2017. The clinician may start the therapy.

[0274]

[0269] If no respiratory therapy is required, the patient continues to be monitored and the method repeats. The respiratory biomarker may be monitored continuously or semi- continuously throughout the method 2001.

[0275]

[0270] Referring now to Figure 13, which illustrates a monitoring method for a patient receiving respiratory therapy. In a first step 2021 of administering respiratory therapy, a type of respiratory therapy is selected along with operating settings. Examples of operating settings include: gas flow rate, operating pressure, humidification settings, humidity level, patient interface type, operating pressure, pressure support, inspiratory positive airway pressure (IPAP), expiratory positive airway pressure (EPAP), positive end-expiratory pressure (PEEP), tidal volume, fraction of inspired oxygen (FiO2). These settings may be selected by the clinician based on the clinician's knowledge and experience, may be suggested or instructed by the display on the remote device. One or more settings may be set by a controller.

[0276]

[0271] Monitoring of the patient's respiratory biomarker(s) such as PaCO2, for example, may be continued 2023 at a time interval T2. This biomarker data may be used to determine 2025 the status of the patient's respiratory biomarker, for example by comparing against an acceptable threshold range of that biomarker for the patient.

[0277]

[0272] Other respiratory biomarkers that may be monitored in this method 2001 in addition or instead of PaCO2 include carbonate (COs2-), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

[0278]

[0273] In a next step 2025, the estimation of the respiratory biomarker (such as PaCO2, for example) is assessed against an acceptable threshold range of the biomarker for the patient. This assessment may be carried out automatically using an algorithm. A clinician may utilise the measurement of the respiratory biomarker along with other patient information to make decisions on patient care.

[0274] The assessment may incorporate an input 2026 of supplementary information in addition to the measured respiratory biomarker. Supplementary information may include, for example, patient data and / or information about therapy the patient is receiving. Examples of supplementary information include current respiratory settings, gender, height, breathing pattern, body weight, BMI (body mass index), age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders e.g. asthma, COPD, other comorbidities, and other chronic disorders e.g. cardiac disorders. A clinician may utilise the supplementary information along with measurement of the respiratory biomarker(s) to make decisions on patient care.

[0279]

[0275] The supplementary information may be provided, or obtained, from the patient's medical records, clinician observations, or measurements recorded from one or more monitors. Such monitors may include cardiometers, capnometers, oximeters, thermometers, sphygmomanometers, pulse meters, glucometers, or lactate analysers. Supplementary information may be automatically provided by the one or more monitors, e.g., via wireless or wired communication.

[0280]

[0276] If the respiratory biomarker estimation is outside the threshold range, it is deemed 'unsatisfactory'. An action is then taken 2029 to adjust one or more of the respiratory therapy operating settings. This may include cessation of respiratory therapy, changing a mode of respiratory therapy, or maintaining the current therapy. The nature of the recommended adjustment may be calculated using an algorithm. The adjustment may be a manual decision by a clinician based on their reading of the displayed measurement, optionally along with other patient information, and / or taking into consideration recommendations displayed by the system.

[0281]

[0277] Adjustments to respiratory therapy may comprise changing a mode of therapy and / or a change to one or more parameters of the respiratory therapy. The mode of respiratory therapy may be selected from: invasive or non-invasive respiratory therapy; flow-based therapy including high flow therapy (including nasal high-flow therapy), low flow therapy; oxygen therapy; pressure-based therapy (including positive airway pressure and continuous positive airway pressure); continuous mandatory ventilation; synchronised intermittent mandatory ventilation; pressure support ventilation; continuous positive airway pressure; airway pressure release ventilation; bilevel positive airway pressure; pressure- regulated volume control; mandatory minute ventilation; adaptive support ventilation; proportional assist ventilation; and neurally adjusted ventilatory assist. One or more predetermined threshold ranges may be provided to assist with decisions regarding the recommended therapy mode. A respiratory biomarker value may be considered unsatisfactory if it falls outside the predetermined threshold range. An unsatisfactory respiratory biomarker value may trigger a recommendation towards an adjustment 2029 of the mode of therapy.

[0282]

[0278] Adjustment between different modes of therapy may be automatic, may require clinician confirmation or authorisation, for example via a display, or may be manual. The system 2001 may communicate to the clinician that a change is required, for example via an alarm or display, whereupon the clinician takes steps to change therapy type.

[0283]

[0279] The system may include a controller configured to operate respiratory therapy device in a plurality of therapy modes, each therapy mode comprising one or more therapy parameters. The one or more therapy parameters may be based at least in part on one or more signals received by the controller.

[0284]

[0280] In one example, if measurements 2023 from the sensor device indicate a patient is hypercapnic, settings of the respiratory therapy system may be adjusted 2029 to increase the flow rate and / or increase pressure support to the patient.

[0285]

[0281] The system may include a predetermined time period, T3 for which to maintain therapy before considering adjusting the therapy. At time T3, respiratory biomarker(s) measurements from the sensor device provide input into a decision 2027 as to whether respiratory therapy is to be maintained, for example at current therapy type, settings, for example, or if therapy adjustment is recommended.

[0286]

[0282] If the respiratory biomarker estimation is assessed 2025 as acceptable, an action 2031 is then taken to maintain respiratory therapy.

[0287]

[0283] The patient continues to be monitored continuously or semi-continuously throughout the respiratory therapy.

[0288]

[0284] The above-described system and method advantageously provide minimally- invasive, real time monitoring of clinically relevant respiratory biomarkers and use these to provide information, instructions, and / or recommendations to a clinician. This method may improve the efficacy of respiratory therapy provided to a patient and enable a clinician or system to be more responsive to changes in a patient's condition.

[0289]

[0285] Figure 14 provides a further example system 3001 utilising a bi-level positive airway pressure machine, display, or other respiratory system 3005. Respiratory biomarker information 3023, such as estimated PaCO2 in this example, may be input to adjust minute ventilation in a bi-level positive airway pressure machine control. This respiratory therapy alternates inhalation and exhalation pressures and / or flows to a patient 3013, to encourage more efficient breathing.

[0290]

[0286] Respiratory biomarker information 3023 is input into the machine, display or system 3005, which provides a recommended action and adjustment of minute ventilation. A decision 3025 is then made as to whether an adjustment is required. The adjustment 3027 of minute ventilation, if required, can be performed by a clinician or a closed loop control based on the recommended action.

[0291]

[0287] Minute Ventilation (MV) may be adjusted 3025 by adjusting, for example, tidal volume (TV) (using MV = TV x respiratory rate or deadspace). The system may enable monitoring respiratory rate to ensure a patient's spontaneous breathing doesn't fall below a certain threshold when tidal volume is increased. Minute ventilation may be adjusted differently per patient and could depend on the condition of the patient's lungs.

[0288] Tidal volume may be controlled by controlling the pressure support of the respiratory system. Pressure support can be controlled by adjusting the inspiratory flow / pressure and expiratory flow / pressure.

[0292]

[0289] Machine / display should receive / display the recommended action and adjustment of minute ventilation can be performed by a clinician / the closed loop control

[0293]

[0290] Figure 18 shows steps of a method 4001 for determining a therapy recommendation. Respiratory therapy may be adjusted or controlled based on the therapy recommendation determined by method 4001. Respiratory therapy may be controlled in relation to commencing respiratory therapy, ceasing respiratory therapy, adjusting characteristics of the gases flow (including flow rate, temperature, gases concentration, humidity, pressure, for example), changing a mode of respiratory therapy, or maintaining the current therapy.

[0294]

[0291] In a first step, a device of the present disclosure, worn by a patient, senses an analyte 4003 and generates a signal indicative of a respiratory biomarker concentration in the patient. The device may comprise a patch, sensor, plurality of microneedles, and communication module, each of which is described herein. The device may further comprise one or more other features of a device described herein. The generated signal corresponds to a current value of the biomarker as detected by the device.

[0295]

[0292] The signal is transmitted 4005 by the communication module, and the signal is received 4007 by a separate device comprising, at least, a processor and a display. The separate device may be an off patient device as described herein. The device may be configured for wired transmission of the detected signal to the separate device. Where the separate device is remote from the device worn by the patient, the communication module may comprise a transmitter and the signal may be transmitted from the transmitter wirelessly and received by a receiver of the separate device.

[0296]

[0293] The separate device processes 4009 the received signal, determines 4013 a current value of the biomarker (i.e., corresponding to the value of the biomarker as detected by the device), and compares 4015 the current value with a predetermined threshold range. Based on the comparison of the current value and predetermined threshold range, the separate device determines 4017 a therapy recommendation.

[0297]

[0294] In addition to processing 4009 the signal, the separate device may store 4011 a signal information on a memory. Signal information may include the current value, the corresponding biomarker value and its corresponding time of measurement. A plurality of the values may be compiled to produce a patient specific historical trend of biomarker information for the patient.

[0298]

[0295] The determination 4017 of a therapy recommendation may further incorporate an assessment of supplementary information other than the current value of the biomarker. The supplementary information may be provided to the separate device by an input 4019 to the separate device. Supplementary information may be information relating to current respiratory settings, gender, height, breathing pattern, body weight, BMI, age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders e.g. asthma, COPD, other comorbidities, and other chronic disorders e.g. cardiac disorders. The separate input 4019 may be sent to the separate device from the patient's medical records, clinician observations, or measurements recorded from one or more monitors. Such monitors providing input may include cardiometers, capnometers, oximeters, thermometers, sphygmomanometers, pulse meters, glucometers, or lactate analysers. Supplementary information may be automatically input to the separate device by the one or more monitors, e.g., via wireless or wired communication.

[0299]

[0296] The separate device may display 4021 information on the display (e.g., to the patient and / or a clinician) related to the current value and / or therapy recommendation. The therapy recommendation may include an indication to adjust gas flow rate, pressure support, tidal volume, fraction of inspired oxygen, or therapy mode, for example. The recommended action may be initiated automatically, or upon confirmation or authorisation by the clinician.

[0300]

[0297] The separate device may be configured to display or otherwise generate an alert or indicator to notify a clinician if a current value of the respiratory biomarker is outside the predetermined threshold range.

[0301]

[0298] Embodiments of a device, system, and method have been described by way of example only and modifications may be made thereto without departing from the scope of the disclosure.

Claims

1. CLAIMS1. A device for minimally-invasive sensing of a respiratory biomarker, the device comprising: a patch having a sensor arranged to contact a target body fluid and arranged to form an electrochemical cell therewith, the sensor being selective for at least one target analyte; a power source; and a circuit configured to output a signal representative of a concentration of the target analyte in the target fluid.

2. The device as claimed in claim 1, wherein the sensor is configured to measure two or more target analytes in the target fluid.

3. The device as claimed in claim 2, wherein the target analyte is utilised in a calculation to estimate one or more respiratory biomarkers.

4. The device as claimed in claim 3, wherein the respiratory biomarker comprises one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

5. The device as claimed in any one of claims 1 to 4, wherein the sensor comprises one or more working electrodes.

6. The device as claimed in any one of claims 1 to 5, comprising a plurality of microneedles.

7. The device as claimed in claim 6, wherein one or more of the plurality of microneedles comprises a bevelled tip.

8. The device as claimed in claim 6 or 7, wherein one or more of the plurality of microneedles are configured to penetrate through a patient's stratum corneum.

9. The device as claimed in any one of claims 6 to 8, wherein one or more of the plurality of microneedles comprises an electrode.

10. The device as claimed in any one of claims 6 to 9, comprising one or more working electrodes, one or more counter electrodes, and one or more reference electrodes.

11. The device as claimed in claim 10, wherein the one or more working electrodes is functionalised to select for a respective target analyte.

12. The device as claimed in any one of the claims 1 to 11, wherein the target analyte is a target ion.

13. The device as claimed in any one of claims 1 to 12, wherein the device is configured to measure potentiometric pH.

14. The device as claimed in claim 13, wherein one or more working electrodes select for H+ions.

15. The device as claimed in claim 10 or 11, wherein one or more working electrodes select for COs2-ions.

16. The device as claimed in any one of claims 1 to 15, comprising a substrate for placing in contact with a patient's skin.

17. The device as claimed in claim 16, wherein the substrate is flexible.

18. The device as claimed in any one of claims 16 to 17, wherein the device comprises a plurality of microneedles protruding from the substrate.

19. The device as claimed in any one of claims 16 to 18, wherein the substrate comprises a conductive layer arranged to electrically connect the circuit with the respective electrodes.

20. The device as claimed in any one of claims 1 to 18, comprising a transmitter arranged to transmit a signal indicative of one or more outputs of the circuit.

21. A respiratory interface or headgear therefore, comprising the device of any one of claims 1 to 20.

22. A system for minimally-invasive measurement of a respiratory biomarker comprising a minimally-invasive sensor configured to measure a signal indicative of the respiratory biomarker, and a communication module configured to communicate a signal indicative of a concentration of the respiratory biomarker to a remote device; wherein the remote device is configured to display data based on the transmitted signal.

23. The system as claimed in claim 22, wherein the remote device comprises a monitoring display, a hospital monitoring hub, or a respiratory therapy device.

24. The system as claimed in claim 22 or 23, wherein the respiratory biomarker is blood partial pressure of carbon dioxide for respiratory therapy (PaCOz).

25. The system as claimed in any one of claims 22 to 24, wherein the remote device is configured to process the transmitted signal and display a respiratory therapy recommendation to clinician based on the transmitted signal.

26. The system as claimed in any one of claims 22 to 25, comprising a respiratory therapy module and a controller, wherein the controller is configured to alter at least one setting of the respiratory therapy module based on the transmitted signal.

27. A system for measurement of a respiratory biomarker, comprising a minimally- invasive sensor device configured to measure the respiratory biomarker; and a communication module to communicate an output signal indicative of the respiratory biomarker to a remote device, wherein the remote device is configured to provide a respiratory therapy recommendation to modify one or more parameters of a respiratory therapy module.

28. The system as claimed in claim 27, wherein the respiratory therapy recommendation is displayed on a clinician interface.

29. The system as claimed in claim 27 or 28, wherein the respiratory therapy recommendation is automatically transmitted to the respiratory therapy module.

30. The system as claimed in any one of claims 27 to 29, wherein the respiratory therapy recommendation is initiated automatically by the respiratory therapy module.

31. The system as claimed in any one of claims 27 to 30, wherein the remote device comprises one or more of: a monitoring display, a hospital monitoring hub, or a respiratory therapy device.

32. The system as claimed in any one of claims 27 to 31, wherein the respiratory therapy recommendation includes one or more of: whether respiratory therapy should be started or stopped; selection of a type of respiratory therapy; whether the type of respiratory therapy should be changed; changing one or more settings of the respiratory therapy.

33. The system as claimed in any one of claims 27 to 32, wherein the sensor device is configured to monitor the respiratory biomarker continuously.

34. The system as claimed in claim any one of claims 27 to 33, comprising a controller, wherein the controller is configured to alter at least one setting of the respiratory therapy based on the output signal.

35. The system as claimed in claim any one of claims 27 to 34 wherein the respiratory biomarker is selected from: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

36. The system as claimed in claim any one of claims 27 to 35, wherein the decision regarding the modification of one or more respiratory therapy parameters is made based on two or more respiratory biomarker measurements.

37. The system as claimed in claim any one of claims 27 to 36, wherein sensor device comprises: a patch having a sensor arranged to contact a target body fluid and arranged to form an electrochemical cell therewith, the sensor being selective for at least one target analyte; a power source; and a circuit configured to output a signal representative of a concentration of the target analyte in the target fluid.

38. The system as claimed in claim any one of claims 27 to 37, wherein the sensor device is configured to measure two or more target analytes in the target fluid.

39. The system as claimed in claim 38, wherein the target analytes can be utilised in a calculation to estimate one or more respiratory biomarkers.

40. The system as claimed in claim 39, wherein the respiratory biomarker comprises one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

41. The system as claimed in any one of claims 27 to 40, wherein the sensor device comprises one or more working electrodes.

42. The system as claimed in any one of claims 27 to 41, wherein the sensor device comprises a plurality of microneedles.

43. The system as claimed in claim 42, wherein at least one of the plurality of microneedles comprises an electrode.

44. The system as claimed in any one of claims 42 to 43, wherein the sensor device comprises one or more working electrodes, one or more counter electrodes, and one or more reference electrodes.

45. The system as claimed in claim 44, wherein at least one working electrode is functionalised to select for a respective target analyte.

46. The system as claimed in any one of claims 42 to 45, configured to measure potentiometric pH.

47. The system as claimed in claim 46, wherein one or more working electrodes select for H+ions.

48. The system as claimed in any one of claims 41 to 47, wherein one or more working electrodes select for CCh2' ions.

49. The system as claimed in any one of claims 27 to 48, wherein the circuit comprises an integrated circuit on the device.

50. The system as claims in any one of claims 27 to 48, wherein the circuit is remote from the device and electrically attached to the device via leads.

51. The system as claimed in any one of claims 27 to 50, comprising an electrochemical sensing module, in communication with a signalling module, the signalling module comprising the power source, the transmitter, and being configured to process and transmit a signal from the sensing module.

52. The system as claimed in any one of claims 27 to 51, wherein the device comprises a plurality of microneedles protruding from the substrate.

53. The system as claimed in any one of claims 27 to 52, wherein the substrate comprises a conductive layer arranged to electrically connect the circuit with the respective electrodes.

54. The system as claimed in any one of claims 27 to 53, comprising a transmitter arranged to transmit a signal indicative of one or more outputs of the circuit.

55. The system as claimed in claim 54, wherein the transmitter is configured to transmit a wireless signal.

56. A method of assessing a patient for a respiratory condition, comprising obtaining one or more signals representative of one or more target analyte concentrations from the device of any one of claims 1 to 20, and determining one or more respiratory biomarker measurements based on the one or more signals.

57. The method as claimed in claim 56, further comprising assessing a value of the biomarker against an acceptable threshold range of the biomarker for the patient.

58. The method as claimed in claim 56 or 57, further comprising determining if a patient is hypercapnic based on the respiratory biomarker measurement.

59. The method as claimed in any one of claims 56 to 58, wherein the one or more signals are obtained continuously.

60. The method as claimed in any one of claims 56 to 59, wherein the one or more respiratory biomarker is selected from one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

61. The method as claimed in any one of claims 56 to 60, comprising determining two or more respiratory biomarker measurements.

62. The method as claimed in any one of claims 56 to 61, comprising displaying a value or an indication of the one or more biomarkers on a display.

63. A method of treating a patient for a respiratory condition, comprising : applying the device of any one of claims 1 to 20 to a patient; assessing the patient for a respiratory condition, comprising obtaining one or more signals representative of one or more target analyte concentrations from the device and determining one or more respiratory biomarker measurements based on the one or more signals; and modifying of one or more parameters of respiratory therapy based on the one or more respiratory biomarker measurement.

64. The method of claim 63, wherein a controller modifies the one or more parameters of respiratory therapy based on the respiratory biomarker measurement.

65. The method as claimed in any one of claims 63 to 64, wherein modifying of one or more parameters of respiratory therapy occurs if the respiratory biomarker value is outside the threshold range.

66. The method as claimed in any one of claims 63 to 65, wherein modifying of one or more parameters of respiratory therapy occurs if the respiratory biomarker value is within the threshold range but trending towards a limit of the range.

67. The method as claimed in any one of claims 63 to 66, wherein the one or more parameters of respiratory therapy includes one or more of: whether respiratory therapy is provided to the patient; a type of respiratory therapy; and one or more settings of the respiratory therapy.

68. A method for controlling a respiratory therapy device providing respiratory therapy to a patient, comprising: receiving a signal indicative of at least one respiratory biomarker concentration of the patient, from a wearable device comprising a plurality of microneedles in contact with the patient's skin; obtaining supplementary information; determining a recommended adjustment to a respiratory therapy setting using a therapy adjustment algorithm based on the received signal and the supplementary information; andcausing a respiratory therapy device to implement the recommended adjustment to the respiratory therapy setting.

69. The method of claim 68, wherein the respiratory biomarker comprises one or more of partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

70. The method of claim 68 or 69, wherein the supplementary information comprises one or more data on the patient, selected from: current respiratory settings, gender, height, breathing pattern, body weight, BMI, age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders, other comorbidities, and other chronic disorders e.g. cardiac disorders.

71. The method as claimed in any one of claims 68 to 70, wherein the wearable device comprises a patch comprising a plurality of microneedles arranged in one or more microneedle regions, wherein one or more microneedle region comprises a plurality of microneedles extending from the substrate and functionalised to selectively detect a different target analyte in a body fluid.

72. The method as claimed in any one of claims 68 to 71, wherein the therapy adjustment algorithm compares the received respiratory biomarker concentration to a predetermined threshold range.

73. The method as claimed in any one of claims 68 to 72, wherein the recommended adjustment is a recommended adjustment of any of: commencement or respiratory therapy, cessation of respiratory therapy, changing a respiratory therapy setting, changing a mode of respiratory therapy, or changing the type of respiratory therapy.

74. The method as claimed in any one of claims 68 to 73, wherein the recommended adjustment comprises an adjustment of at least one of: gas flow rate, pressure support, tidal volume, fraction of inspired oxygen, or therapy mode.

75. The method as claimed in any one of claims 68 to 74, wherein the respiratory therapy device is selected from the group consisting of: a ventilator, a flow-controlled device, a pressure-controlled device, a positive airway pressure device, a continuous positive airway pressure device, a bi-level positive airway pressure device, or a high-flow therapy device.

76. The method as claimed in any one of claims 68 to 75, further comprising displaying the recommended adjustment and the respiratory biomarker concentration on a clinicianfacing display.

77. A system for respiratory therapy management, comprising: a first device, wearable by a patient, configured to generate a signal indicative of at least one respiratory biomarker concentration from a patient; a communication module configured to transmit the signal to a device; and a second device, separate from the first device, comprising a display and a processor, wherein the second device is configured to:receive the signal; process, on the processor, the signal to determine a current value of the at least one respiratory biomarker; compare the current value to a predetermined threshold range; determine a therapy recommendation based on the comparison; and display, on the display, the current value of the at least one respiratory biomarker and the therapy recommendation.

78. The system as claimed in claim 77, wherein the first device comprises a microneedle-based sensor patch configured to detect the respiratory biomarker in a target fluid.

79. The system as claimed in claim 77 or 78, wherein the first device comprises the device of any one of claims 1 to 20.

80. The system as claimed in any one of claims 77 to 79, wherein the target fluid is interstitial fluid.

81. The system as claimed in any one of claims 77 to 80, wherein the respiratory biomarker is selected from one or more of: partial pressure of carbon dioxide (PaCO2), pH, partial pressure of oxygen (PaO2), oxygen saturation (O2Sat), oxygen concentration, carbonate (COs2-), bicarbonate (HCO3-), base excess (BE), glucose, and lactate.

82. The system as claimed in any one of claims 77 to 81, wherein the second device is further configured to receive supplementary information.

83. The system as claimed in any one of claims 77 to 82, wherein the supplementary information is selected from: current respiratory settings, gender, height, breathing pattern, body weight, BMI, age, respiratory rate, heart rate, blood pressure, skin colour, temperature, known respiratory disorders, other comorbidities, and other chronic disorders e.g. cardiac disorders.

84. The system as claimed in any one of claims 77 to 83, wherein the therapy recommendation indicates an adjustment to at least one of: gas flow rate, pressure support, tidal volume, fraction of inspired oxygen, or therapy mode.

85. The system as claimed in any one of claims 77 to 84, wherein the display is configured to present an alert if the current value of the respiratory biomarker is outside the predetermined threshold range.

86. The system as claimed in any one of claims 77 to 85, wherein the remote device is configured to store on a memory a plurality of current values corresponding to respiratory biomarker data.

87. The system as claimed in any one of claims 77 to 86, wherein the therapy recommendation is implemented automatically by a respiratory therapy device, or upon confirmation by a clinician.

88. A microneedle patch for multi-analyte detection, comprising: a flexible substrate configured for placement on a patient's skin;two or more microneedle regions on the substrate, each microneedle region comprising a plurality of microneedles extending from the substrate and functionalised to selectively detect a different target analyte in a body fluid; and a circuit configured to receive signals from the microneedles of each region and output data indicative of the concentration of each respective target analyte.

89. The microneedle patch as claimed in claim 88, wherein the target analyte is a target ion.

90. The microneedle patch as claimed in claim 88 or 89, wherein the target ion is selected from COs2', HCOs' ions or H+.

91. The microneedle patch as claimed in any one of claims 88 to 90, wherein the microneedles in each region are functionalised to be selective for the target analyte.

92. The microneedle patch as claimed in any one of claims 88 to 92, wherein the circuit comprises a signal conditioning module configured to filter and amplify the signal(s) received.

93. The microneedle patch as claimed in any one of claims 88 to 92, wherein the circuit is configured to output data in real time or at predetermined intervals.

94. The microneedle patch as claimed in any one of claims 88 to 93, further comprising a wireless transmitter configured to transmit the output data to a remote device.

95. A microneedle patch for customisable analyte sensing, comprising: a flexible substrate configured for placement on a patient's skin; one or more microneedle arrays removably mounted on the substrate; wherein the one or more microneedle arrays are configured to detect a selected target analyte in a body fluid; and a circuit configured to receive signals from the one or more microneedle arrays and output data indicative of the concentration of each detected target analyte.

96. The microneedle patch as claimed in claim 95, wherein the one or more microneedle arrays is selected from a set comprising a first microneedle array and a second microneedle array, wherein the first microneedle array is interchangeable with the second microneedle array, and wherein the first microneedle array and the second microneedle array comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles.

97. The microneedle patch as claimed in any one of claims 95 or 96, wherein each microneedle array is functionalised to selectively detect a target analyte.

98. The microneedle patch as claimed in claim 97, wherein the target analyte is a target ion.

99. The microneedle patch as claimed in claim 98, wherein the target ion is selected from CO32’, HCO3‘ ions or H+.

100. A microneedle patch for analyte detection, comprising: a flexible substrate configured for placement on a patient's skin; one or more distinct microneedle regions on the substrate, the one or more microneedle regions comprising a plurality of microneedles extending from thesubstrate and comprising one or more working electrodes functionalised to selectively detect a target analyte in a body fluid; a reference electrode array comprising microneedles, the reference electrode array being electrically connected to the working electrodes in the at least two microneedle regions; and a circuit configured to receive signals from the working electrodes and the reference electrode array, and to output data indicative of the concentration of each respective target analyte.

101. The microneedle patch of claim 100, comprising two or more distinct microneedle regions on the substrate.

102. The microneedle patch as claimed in claim 100 or 101, wherein the target analyte is a target ion.

103. The microneedle patch as claimed in any one of claims 100 to 102, wherein the target ion is selected from COs2', HCOs' ions or H+.

104. The microneedle patch as claimed in any one of claims 100 to 103, wherein the microneedles in each region are functionalised to be selective for the target analyte.

105. The microneedle patch as claimed in any one of claims 100 to 104, wherein the circuit comprises a signal conditioning module configured to filter and amplify the signal(s) received.

106. The microneedle patch as claimed in any one of claims 100 to 105, wherein at least one of the microneedle regions is removably mounted on the substrate.

107. The microneedle patch as claimed in claim 106, wherein the one or more microneedle region is selected from a set comprising a first microneedle region and a second microneedle region, wherein the first microneedle region is interchangeable with the second microneedle region, and wherein the first microneedle region and the second microneedle region comprise a different number, shape, analyte selectivity, and / or arrangement of microneedles.

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