Methods and systems for measuring analytes using batch calibratable test strips

Abstract

Systems and methods for measuring an analyte in a fluid sample are disclosed. The systems and methods employ a test strip, which generally includes a substrate, at least one electrical connection, at least one sensing chemical, and at least one additional layer. The test strips can be batch calibrated.

Description

[0001] This application is a divisional application of the invention patent application entitled "Method and System for Measuring Analytes Using Batch Calibrable Test Strips", with an international application date of July 19, 2017, international application number PCT / US2017 / 042830, and national application number 201780056025.5.

[0002] Cross-reference to related applications

[0003] This application claims priority based on U.S. Provisional Application No. 62 / 363,971, filed July 19, 2016, entitled “Methods of And Systems For Test Strip Regeneration and Sample Manipulation For Use With Same”, filed under 35 U.S.SC §119(e), the contents of which are incorporated herein by reference in their entirety.

[0004] This application relates to the following applications: International Patent Application No. PCT / US 15 / 00180, filed December 23, 2015, entitled “MINI POINT OFCARE GAS CHROMATOGRAPHIC TEST STRIP AND METHOD TO MEASURE ANALYTES”, and International Patent Application No. PCT / US 15 / 34869, filed June 9, 2015, entitled “LOW COST TEST STRIP AND METHOD TO MEASURE ANALYTES”, which are included in the appendix and incorporated herein by reference in their entirety. Technical Field

[0005] This invention relates to a gas sensing system comprising: a low-cost, limited-use test strip configured to measure a gas; a system for delivering the gas to the test strip; and a device for controlling and reading the output of the test strip. In other aspects, the invention generally relates to the diagnostic and therapeutic monitoring of patients suffering from chronic respiratory diseases (e.g., asthma and chronic obstructive pulmonary disease) and digestive diseases (e.g., food intolerance or irritable bowel syndrome). Other medical and non-medical applications for gas detection can be used without departing from the spirit of the invention. Examples include, but are not limited to, hydrogen, methane, sulfur dioxide, nitric oxide, nitrogen dioxide, NOx, ozone, ammonia, etc. Further background information has been previously described by the authors. Background Technology

[0006] Many different types of sensors and techniques are available for the detection of gases and analytes well known in this field. The problems associated with these sensors and detection systems have been discussed in the authors' related applications. Some of these disadvantages include cost, complexity, calibration, quality control, shelf life, ease of use, etc. This is certainly not an exhaustive list.

[0007] One of the drawbacks of existing gas sensors is the cost and complexity of calibration. While existing sensors can be mass-produced, each sensor requires calibration. This typically involves establishing calibration profiles across multiple analyte concentrations, temperatures, and humidity levels. Depending on the sensor, calibration can take hours or days, significantly increasing cost. Sensors also require frequent recalibration or quality control to compensate for drifting baselines and / or aging, further adding to their cost. One example is metal-oxide-semiconductor (MOS or CMOS) sensors. These sensors are manufactured on a single wafer in a semiconductor fabrication facility. Once produced, the variability in initial or baseline resistance can vary by a factor of five across the entire wafer, and internal heating elements may require up to 24 hours of constant power to reach a stable baseline. This variability, combined with the nonlinear response to the target analyte, necessitates individual calibration for each sensor to accurately calculate the resistance change and correlate it with the analyte concentration. The ability to mass-produce and mass-calibrate gas sensors compared to existing technologies is a significant improvement, as it reduces the costs associated with production and calibration, allowing sensors to be disposed of after use.

[0008] To address these issues, the applicant has previously described single-use disposable sensors and reusable measurement systems in the PCT patent application incorporated above. Summary of the Invention

[0009] One aspect of the present invention relates to a low-cost test strip and method for measuring analytes in respiratory samples.

[0010] In another aspect of the invention, a system for determining the concentration of at least one analyte in a fluid sample is disclosed, wherein the system includes a test strip as previously described by the authors and an instrument configured to receive a fluid sample from a human user. In some embodiments, the instrument includes a chamber for converting a target analyte into another analyte. In some embodiments, the instrument includes a chamber for altering the physical and / or chemical state of the target analyte. In one embodiment, the chamber converts nitric oxide to nitrogen dioxide for measurement via the test strip. In one embodiment of the invention, the conversion chamber is disposable. In another embodiment, the conversion chamber is configured as a removable cartridge. In another embodiment, the conversion chamber has a limited lifespan. In yet another embodiment of the invention, the conversion chamber is removable and can optionally be replaced by the user.

[0011] In some embodiments, the instrument includes a valve for diverting at least a portion of the expiratory flow path. In other embodiments, the instrument includes a valve for capturing at least a portion of the expiratory gas for analysis. In still other embodiments, the instrument includes a pressure or flow sensor to measure the expiratory flow rate of a human user.

[0012] In some embodiments, the instrument includes another chamber for housing the test strip. In some embodiments, the instrument includes another chamber for buffering the analyte sample prior to measurement. In some embodiments, one or more pumps move the sample between the buffer chamber and the sensor chamber. In another embodiment, the sample is recirculated by a pump. A fan or blower may be a suitable alternative to the pump.

[0013] In some embodiments, the instrument is designed to clean, reset, or recalibrate the test strip baseline or recalibrate the test strip. In one embodiment, the test strip chamber also includes an energy source. In some embodiments, the energy source is UV, RF, or IR (non-exhaustive list). In other embodiments, the chamber includes a magnetic field to alter the binding properties of the analyte to the test strip, or to clean, reset, recalibrate the test strip baseline, or recalibrate the test strip. In other embodiments, the instrument provides additional current or voltage to clean, reset, recalibrate the test strip baseline, or recalibrate the test strip. In some embodiments, the applied energy is designed to remove chemicals before sensing. In some embodiments, this is done to extend shelf life or for calibration purposes. In other embodiments, such processing is performed at multiple time points during analysis. In one embodiment, such processing is performed while at least a portion of the sample is delivered to the test strip.

[0014] In other embodiments, the energy source is designed to alter the chemical state of at least one analyte in the sample. In other embodiments, the magnetic field is designed to alter the electronic, physical, or chemical state of at least one analyte in the sample.

[0015] In other embodiments, a combination of valves, instruments, chambers, and flow measurements is used to accurately measure target analytes by controlling sample delivery to test strips.

[0016] In other embodiments, the chamber includes an inlet and an outlet for the sample to be tested. In other embodiments, the chamber includes only an inlet. In other embodiments, the chamber includes at least one sample inlet.

[0017] In other embodiments, the instrument removes moisture and / or at least one interfering substance from the device. Examples include, but are not limited to, perfluorosulfonic acid tubes, desiccants, energy sources, oxidizing or reducing materials, etc.

[0018] In one aspect, the present invention relates to a system for determining the concentration of at least one analyte in a fluid sample. In some embodiments, the system includes: a chamber adapted to alter the chemical state of at least one analyte in the sample; and a test strip comprising a base substrate, a first electrode pair disposed on the substrate, and an active sensing chemical electrically connected to the first electrode pair, wherein the sensing chemical responds to the chemically altered analyte. In another embodiment, the system includes a second electrode pair disposed on the substrate and a second sensing chemical electrically connected to the second electrode pair. In other embodiments, the first or second sensing chemical may comprise at least one or more of carbonyl groups, nanostructures, functional organic dyes, heterocyclic macrocycles, metal oxides, or transition metals.

[0019] In another embodiment, the analyte molecule binds to the sensing chemical, and the partition coefficient of the bound analyte is less than 0.5 under the desired measurement conditions. In another embodiment, the partition coefficient of the bound analyte converted to the unbound analyte under the desired measurement conditions is less than 0.25. In another embodiment, the partition coefficient of the bound analyte is less than 0.1 under the desired measurement conditions. In another embodiment, the partition coefficient of the bound analyte is less than 0.05 under the desired measurement conditions. In another embodiment, the partition coefficient of the bound analyte is less than 0.01 under the desired measurement conditions.

[0020] In some embodiments, the analyte saturates the sensing chemical after a single exposure. In some embodiments, the analyte saturates the sensing chemical after multiple exposures. In some embodiments, the analyte saturates the sensing chemical after 365 exposures. In some embodiments, the analyte saturates the sensing chemical after 52 exposures. In some embodiments, the analyte saturates the sensing chemical after 12 exposures. In some embodiments, the chemical bond is selected from coordinate bonds, covalent bonds, hydrogen bonds, ionic bonds, and polar bonds. In some embodiments, the sensing chemical includes one or more of carboxyl groups, nanostructures, functional organic dyes, heterocyclic macrocycles, metal oxides, or transition metals.

[0021] In some embodiments, the sensing chemical has a linear shape that forms a bridging electrode pair. In some embodiments, the sensing chemical has a coffee ring shape that forms a bridging electrode pair.

[0022] In some embodiments, the system includes a layer defining a window to expose a sensed chemical to at least one analyte. In some embodiments, the layer contains an adhesive. In some embodiments, the adhesive is a pressure-sensitive adhesive.

[0023] In some embodiments, the system is adapted to sense one or more of nitrogen dioxide, nitric oxide, hydrogen, methane, acetone, sulfur dioxide, carbon monoxide, or ozone.

[0024] In some embodiments, the system includes one or more of a blower, fan, or pump configured to move a fluid sample to the test strip. In some embodiments, the fluid sample is moved to the test strip using expiratory force.

[0025] In some embodiments, the system includes a test strip chamber to contain a test strip in fluid communication with a conversion chamber. In some embodiments, the test strip can be removed from the test strip chamber. In some embodiments, the system is adapted to track the number of times the conversion chamber is used. In some embodiments, one or more of a blower, pump, fan, or exhalation force moves a fluid sample through the conversion chamber. In some embodiments, the fluid sample is recirculated between the conversion chamber and the test strip chamber. In some embodiments, the system includes at least one sensor to determine one or more of humidity, temperature, or pressure.

[0026] In some embodiments, the system includes a microprocessor adapted to determine or accept calibration information regarding the manufacturing batch or lot of test strips.

[0027] In some embodiments, the system includes a dehumidifier adapted to remove moisture from the sample. In some embodiments, the dehumidifier includes a perfluorosulfonic acid tube. In some embodiments, the dehumidifier includes a desiccant. In some embodiments, the desiccant includes silica gel. In some embodiments, the desiccant includes an oxidizing agent.

[0028] In some embodiments, the system includes a filter adapted to remove gases from a sample identified as interfering with the sensor. In some embodiments, the filter includes a perfluorosulfonic acid tube.

[0029] In some embodiments, the conversion chamber is removable. In some embodiments, the conversion chamber includes one or more of an oxidizing agent, a reducing agent, a charge-transfer agent, an adduct, or a complexing agent. In some embodiments, the conversion chamber is configured to oxidize nitric oxide to nitrogen dioxide. In some embodiments, the conversion chamber includes potassium permanganate. In some embodiments, potassium permanganate is suspended on a substrate. In some embodiments, potassium permanganate is suspended on silica gel. In some embodiments, the conversion chamber contains sodium permanganate. In some embodiments, sodium permanganate is suspended on a substrate.

[0030] In some embodiments, the conversion chamber includes one or more of a UV source, an infrared source, a radio frequency source, or a corona discharge power source. In some embodiments, the conversion chamber is adapted to oxidize nitric oxide to nitrogen dioxide. In some embodiments, the sensing chemical is configured to respond to nitrogen dioxide.

[0031] In another aspect, the present invention includes a method for determining the concentration of an analyte in a fluid sample, comprising the steps of: providing a system for determining the concentration of at least one analyte in the fluid sample, the system comprising: a conversion chamber for changing the chemical state of at least one analyte in the sample; and a test strip comprising a base substrate, a first electrode pair disposed on the substrate, an active sensing chemical electrically connected to the first electrode pair, wherein the sensing chemical is responsive to the chemically changed analyte; and measuring at least one of a voltage between the first electrode pairs, a resistance between the first electrode pairs, and a current flowing through the first electrode pairs. In some embodiments, the fluid is a gas. In some embodiments, the test strip is calibrated by at least one of a manufacturing batch, a manufacturing lot, and a sensor location within the batch or lot. Some embodiments also include a step of accepting calibration associated with the test strip. In some embodiments, calibration is accepted by one or more of digital, optical, or manual signals. In some embodiments, the system includes a microprocessor electrically connected to the test strip. In some embodiments, the microprocessor converts analog voltage, resistance, or current into analyte concentration based on calibration.

[0032] In another aspect, the present invention includes a system for determining the concentration of at least one analyte in a fluid sample. The system includes a plurality of test strips, each test strip including: a base substrate; a first electrode pair disposed on the substrate; and an active sensing chemical electrically communicated with the first electrode pair, wherein the sensing chemical is responsive to the analyte, and wherein the sensing chemical is sufficiently uniform to allow calibration information from a subset of the plurality of test strips to be used on the plurality of test strips. In some embodiments, the sensing chemical is disposed in a linear form on the electrode pair, wherein a majority of the sensing chemical between the electrode pairs is concentrated within the line. In some embodiments, the sensing chemical is disposed in a coffee ring form on the electrode pair, wherein a majority of the sensing chemical between the electrode pairs is concentrated within the coffee ring.

[0033] In another aspect, the present invention includes a system for determining the concentration of at least one analyte in a fluid sample, the system comprising: a base substrate; a first electrode pair disposed on the substrate; and an active sensing chemical electrically connected to the first electrode pair, wherein the sensing chemical is responsive to the analyte, and wherein the sensing chemical forms a chemical bond with the analyte having a partition coefficient of less than 0.5 under desired measurement conditions. In some embodiments, the chemical bond is selected from coordinate bonds, covalent bonds, hydrogen bonds, ionic bonds, and polar bonds. In some embodiments, the sensing chemical comprises one or more of a carboxyl group, a nanostructure, a functional organic dye, a heterocyclic macrocycle, a metal oxide, or a transition metal. In some embodiments, the partition coefficient of the bound analyte is less than 0.25 under desired measurement conditions. In some embodiments, the partition coefficient of the bound analyte is less than 0.1 under desired measurement conditions. In some embodiments, the partition coefficient of the bound analyte is less than 0.05 under desired measurement conditions. In some embodiments, the partition coefficient of the bound analyte is less than 0.01 under desired measurement conditions. Attached Figure Description

[0034] In the attached diagram:

[0035] Figure 1A An illustrative example of a system comprising a reaction / conversion chamber, a test strip chamber, a valve, and a flow measurement device according to an embodiment of the present invention is shown.

[0036] Figure 1B Alternative configurations and event sequences of a system including a reaction / conversion chamber, a test strip chamber, and a pump / fan / blower for measuring analytes are shown.

[0037] Figure 2 An illustrative example of a system comprising a chamber, a valve, and a flow measurement device according to an embodiment of the present invention is shown.

[0038] Figure 3 An illustrative example of a system comprising chambers, valves, and flow meters in different configurations, according to an embodiment of the present invention, is shown.

[0039] Figure 4 An illustrative example of a system comprising a reaction chamber, a buffer chamber, a test strip chamber, a valve, and a flow measurement device according to an embodiment of the present invention is shown.

[0040] Figure 5 An illustrative example of a system comprising a reaction chamber, a test strip chamber, a pump, a valve, and a flow measurement device according to an embodiment of the present invention is shown.

[0041] Figure 6A and 6B An illustrative example of a system comprising two sample flow paths according to an embodiment of the present invention is shown.

[0042] Figure 7 An illustrative example of a system comprising two sample flow paths according to an embodiment of the present invention is shown.

[0043] Figure 8 An illustrative example of a test strip chamber reaction chamber comprising an analyte circulator and / or a stirrer, according to an embodiment of the present invention, is shown.

[0044] Figure 9 An illustrative example of a system comprising a test strip chamber containing an energy source or magnetic field, according to an embodiment of the present invention, is shown.

[0045] Figure 10 An illustrative example of a reaction chamber / box according to an embodiment of the present invention is shown.

[0046] Figure 11 An illustrative example of a disposable reaction chamber / box configuration according to an embodiment of the present invention is shown.

[0047] Figure 12 An illustrative example of a disposable reaction chamber / box configuration according to an embodiment of the present invention is shown.

[0048] Figure 13 An illustrative example of a compact configuration of a system having removable and / or disposable test strips and reaction chambers / boxes according to an embodiment of the present invention is shown.

[0049] Figure 14A and 14B An illustrative example of an apparatus having a removable test strip and a reaction chamber / box according to an embodiment of the present invention is shown.

[0050] Figure 15A and 15B An illustrative example of an apparatus having a removable test strip and a reaction chamber / box configuration with a mouthpiece, according to an embodiment of the present invention, is shown.

[0051] Figure 16 A non-exhaustive list of test strip chemicals and layers, as well as coating techniques for sensing chemical additives, is shown.

[0052] Figures 17A-17D The configuration of the test strip, sensing chemical, and layer is shown.

[0053] Figures 18A-18C An example of a sensing chemical configured in a linear shape and electrically connected to an electrode pair is shown.

[0054] Figure 19 An example of a sensing chemical configured in a linear shape and electrically connected to an electrode pair is shown.

[0055] Figures 20A-20B The coffee ring configuration for sensing chemicals was specified.

[0056] Figure 21A This demonstrates the uniformity of the initial or baseline signal of the sensing chemical generated on the test strip prior to sensing.

[0057] Figure 21B The uniformity and linearity of the simulated test strip signals of two batches of sensors within the same manufacturing batch were demonstrated.

[0058] Figure 22A An example of calibration curves derived from a batch of sensors within a manufacturing batch is shown.

[0059] Figure 22B An example of the measured response of a batch of sensors is shown, in which the analog signal is converted into concentration using calibration equations derived from different batches of sensors within the same manufacturing batch.

[0060] Figure 23 Multiple test strips manufactured on a single substrate are depicted.

[0061] Figure 24 The method described involves adding at least one layer to a substrate containing multiple sensors.

[0062] Figure 25 Some embodiments of the questionnaire are described.

[0063] Figure 26 This illustrates an example of combining similar data from multiple patients, sending that data to the cloud for analysis, and generating meaningful information for multiple parties, such as payers, providers, patients, and industry players (i.e., pharmaceutical and medical device companies).

[0064] Figure 27 Some embodiments of a mobile application are described, which collects data in various forms and from different locations from a single patient. This data is then sent to the cloud for storage and analysis.

[0065] Figure 28 Some implementations of medical professionals monitoring data collected from patients are depicted.

[0066] Figure 29 Some embodiments of software monitoring systems are described to proactively alert patients, healthcare professionals, and / or caregivers to trends in their health conditions.

[0067] Figure 30 This is an example of a test strip with a chromatographic layer containing a single sensing chemical.

[0068] Figure 31This is an example of a test strip with a chromatographic layer containing two sensing chemicals and other structural layers.

[0069] Figure 32 This is an example of a test strip with a chromatographic layer that is not integrated with a sensor.

[0070] Figure 33A This is an example of a mixed gas sample that reaches the test strip above the chromatographic layer and begins to pass through the chromatographic layer to reach the sensor.

[0071] Figure 33B yes Figure 33A Continuing with the example.

[0072] Figure 34 A detailed description of the relationship between the percentage of the seven gas mixtures and the percentage of gases diffused through the chromatographic separation layer and time is shown.

[0073] Figure 35A The relationship between a single respiration curve and time is shown on a test strip using a chromatographic layer.

[0074] Figure 35B The time points from which signals can be sampled from a single respiratory curve are shown.

[0075] Figure 36 Gas separation in a 200µm thick chromatographic layer is shown, and the relationship between the gas concentration below the layer and time is expressed.

[0076] Figure 37 Gas separation of a 100µm thick chromatographic layer is shown, and the relationship between the gas concentration below the layer and time is expressed.

[0077] Figure 38 Gas separation in a 50µm thick chromatographic layer is shown, and the relationship between the gas concentration below the layer and time is expressed.

[0078] Figure 39 Gas separation in a 20µm thick chromatographic layer is shown, and the relationship between the gas concentration below the layer and time is expressed.

[0079] Figure 40 The multi-gas signals from the test strip are displayed.

[0080] Figure 41 The multi-gas signals from the test strip are displayed.

[0081] Figure 42 , 43 Figures 44 and 44 demonstrate multi-gas signals from the test strip in response to human respiration. Detailed Implementation

[0082] Figure 1AAn embodiment

[100] of a system for measuring analytes in a gas sample is shown, wherein a patient

[101] inhales through a mouthpiece

[102] connected to an instrument

[112] . The mouthpiece is in fluid communication with a one-way valve

[104] and a scrubber

[103] . The one-way valve

[104] allows gas to pass to the patient only from the external environment. The scrubber

[103] removes certain gases from the incoming ambient air entering the patient's lungs. In one embodiment, the scrubber is configured to remove NO and NO2 from the ambient air. A suitable scrubbing material is activated carbon, but many materials are possible depending on the analyte removal required. Another example is potassium permanganate or potassium permanganate on silica. Yet another example is activated alumina. The patient then exhales through the mouthpiece

[102] and into the fluid path of the instrument

[105] . The flow path may also include structures for dehumidifying or removing certain chemicals from the sample stream. Suitable examples include activated carbon, activated alumina, potassium permanganate, desiccants, perfluorosulfonic acid, or perfluorosulfonic acid tubing, etc. This is not an exhaustive list. The reaction chamber (also referred to herein as the switching chamber)

[106] , described in more detail below, is in fluid communication with the nozzle. Although not shown, the flow path from the nozzle

[102] to the reaction chamber

[106] includes a check valve that allows flow only toward the reaction chamber. A flow measurement device (e.g., a flow meter, pressure sensor, risk tube, flow tube, pitot tube, etc.)

[107] is located in the fluid path of the flow meter

[105] . The flow measurement device

[107] may also be a side flow from the main fluid path. The flow measurement device

[107] may be located near or far from the switching chamber

[106] . As described above, the flow measurement device can measure the pressure and / or differential pressure across the orifice or flow meter. This is not an exhaustive list. A valve

[108] fluidly connected to the reaction chamber and the test strip chamber

[109] allows at least a portion of the sample to be transferred out of the device (e.g., bypassing the test strip

[110] ) or is used in conjunction with another valve

[111] to trap the analyte sample in the test strip chamber

[109] . Many types of valves can be used without departing from the spirit of the invention. The types and functions of valves are well known in the art. In one embodiment, valves

[108] and

[111] are solenoid valves regulated by a controller. In another embodiment, valve

[108] is opened to the atmosphere, and a first portion of the sample is expelled through valve

[108] . In some embodiments, the duration of sample expulsion through valve

[108] is between 0 and 10 seconds. In one embodiment, the duration is less than or equal to 7 seconds. After a predetermined time has elapsed, valve

[108] is closed by the controller, and the sample is introduced into the test strip chamber

[109] . Valve

[111] may begin to open or close to the atmosphere. In one embodiment, when valve

[108] begins to direct airflow into chamber

[109] , the controller opens valve

[111] to the atmosphere.After a predetermined amount of time from the start of exhalation, the controller closes two valves

[108] and

[111] to capture a gas sample in a chamber

[109] with a test strip

[110] . In some embodiments, the system may be configured to circulate the captured gas on the test strip for a predetermined amount of time. In this embodiment, the captured gas may be circulated using any method well known in the art, such as a fan, pump, or blower. In one embodiment, the system is configured to capture at least a portion of the last three seconds of a ten-second exhalation. In yet another embodiment, valve

[108] opens at a set pressure used to expel the sample when valve

[111] closes. In this embodiment, the controller opens regulating valve

[111] to allow the sample to pass through the test strip chamber, thereby closing valve

[108] . In some embodiments, inhalation through the meter is not required, and the patient may only exhale through the device. In these embodiments,

[103] and

[104] are optional. In some embodiments, the test strip chamber does not completely surround the test strip. In this embodiment, the test strip chamber ensures electrical communication between the test strip and the meter. In another embodiment, the test strip chamber ensures that the fluid sample is guided to the precise location of the sensing chemical on the test strip.

[0083] Figure 1B Alternative configurations of flow paths and event sequences between a pump or blower or fan, a switching chamber, and a sensor or sensor chamber are shown. The positions of these elements in the instrument may be aligned with the fluid sample

[115] or the side flow from the main fluid sample path

[114] . The fluid sample

[113] enters the first element

[116] and then passes sequentially through

[117] and

[118] .

[0084]

[116] ,

[117] ,

[118] may consist of pumps / fans / blowers or switching chambers or sensors / sensor chambers in various configurations. Optionally, one or more of these elements may be removed. In some embodiments, the fluid sample is recirculated between at least two elements. In some embodiments, a flow meter and / or any number of valves are placed on the proximal and / or distal sides of the elements, and / or between elements

[116] ,

[117] ,

[118] . In some embodiments, the switching chamber may remove moisture from the sample only. The switching chamber may contain one or more of an oxidant, a reducing agent, a charge transfer agent, an adduct, or a complexing agent. Examples of such materials include the following:

[0085] Oxidizing agents

[0086] • Permanganates (e.g., potassium permanganate, sodium permanganate)

[0087] • Perchlorates (e.g., ammonium perchlorate, perchloric acid)

[0088] • Peroxides (e.g., hydrogen peroxide, magnesium peroxide)

[0089] Nitrates (e.g., ferric nitrate, sodium nitrate, nitric acid)

[0090] Ozone gas

[0091] • Peroxyacid (peroxydisulfuric acid)

[0092] Hypochlorites (e.g., sodium hypochlorite)

[0093] ·reducing agent

[0094] • Metal hydrides (e.g., lithium aluminum hydride, sodium borohydride)

[0095] ·hydrogen

[0096] • Iron(II) compounds (e.g., FeCl2)

[0097] ·oxalic acid

[0098] ·ascorbic acid

[0099] • Charge transfer agent

[0100] • Acids (e.g., citric acid, hydrochloric acid)

[0101] • Alkalis (e.g., sodium hydroxide, ammonia)

[0102] Ion exchange resin

[0103] • Adducts

[0104] Lewis acids (e.g., boranes)

[0105] Lewis bases (e.g., tetrahydrofuran, ammonia)

[0106] Complexing agents

[0107] · ethylenediaminetetraacetic acid

[0108] Heterocyclic macrocyclic compounds

[0109] Organometallic compounds

[0110] In one embodiment, the device is configured to measure environmental levels of nitrogen dioxide and nitric oxide. In a preferred embodiment, the nitric oxide source is human respiration (i.e., fractional exhaled nitric oxide (FeNO) test). In this embodiment, the test strip is sensitive to nitrogen dioxide, and the conversion cartridge is configured to oxidize nitric oxide to nitrogen dioxide. A second conversion cartridge may be provided to record environmental nitrogen dioxide levels. In this embodiment, the conversion cartridge does not oxidize nitric oxide to nitrogen dioxide. The cartridge may be configured as a cavity (i.e., no chemical change of the analyte occurs). In a variant of this embodiment, the conversion cartridge contains a desiccant. In other variants, the conversion cartridge may change some chemical state of the sample without oxidizing nitric oxide to nitrogen dioxide. Suitable applications would be used to measure environmental indoor or outdoor pollution levels known to cause respiratory symptoms and exacerbations in patients with asthma and COPD in the same device, wherein the device measures exhaled nitric oxide, an indicator of the risk of asthma and COPD exacerbations.

[0111] Figure 2 Another embodiment

[200] of a system for measuring an analyte in a gas sample is shown, wherein a transfer valve

[201] is provided between a reaction chamber

[202] and a flow measurement device

[203] . All these components are in fluid communication with the exhaled fluid flow path of an instrument

[204] . A second valve

[205] is located downstream of the reaction chamber

[202] and upstream of the test strip

[207] and the test strip chamber

[206] . Another valve

[208] located downstream of the test strip chamber can be used to trap the analyte or a portion of the analyte in the test strip chamber

[206] . Many combinations are possible without departing from the spirit of the invention. Figure 1A The described embodiments are similar, and these valves can be adjusted between open and closed by a controller, or some valves can open at a set pressure and close when the pressure drops below a threshold. In this way, valves

[205] and

[208] trap the sample in the test strip chamber

[206] .

[0112] Figure 3Another embodiment of a system for measuring an analyte in a gas sample is shown

[300] , wherein a flow measurement device

[301] is located upstream of a reaction chamber

[302] . Flow measurements can be calculated or measured using various types of pressure sensors or flow meters. Examples include, but are not limited to, rotary flow meters, thermal flow meters, acoustic flow meters, Doppler flow meters, hot wire flow meters, differential pressure sensors, mass flow meters, and pressure sensors, all of which are well known to those skilled in the art. Many different configurations and numbers of reaction chambers are possible without departing from the spirit of the invention. Flow can be measured at any number of locations without departing from the spirit of the invention. In one embodiment, the system is configured such that a patient exhales at a flow rate of 50 mL / s plus or minus 10%.

[0113] Figure 4 Another embodiment

[400] of a system for measuring analytes in a gas sample is shown, wherein a flow measurement device

[402] is sampled from a buffer chamber

[401] . In some embodiments, the buffer chamber

[401] is an accumulator for at least a portion of the sample entering. The buffer chamber

[401] may be a static chamber or may be expandable as described in the incorporated application. Sampling from the buffer chamber can be performed by transferring at least a portion of the sample to a pressure sensor or flow meter. The buffer chamber differs from the reaction chamber

[403] in that it is inert. The buffer chamber may be placed upstream or downstream of the reaction chamber. In some embodiments, it may be suitable to use a switching chamber as a buffer chamber as well.

[0114] Figure 5 Another embodiment

[500] of a system for measuring an analyte in a gas sample is shown, wherein a pump or blower

[503] is in fluid communication with a test strip chamber

[504] and at least one other chamber

[501] . The pump can be used to control the flow of the sample from one chamber

[501] to another chamber

[504] . The chamber

[501] can be a buffer chamber or a reaction chamber. In another embodiment, a second chamber (not shown) is located upstream or downstream of the chamber

[501] , such that the two chambers contain at least one buffer chamber and one reaction chamber in fluid communication. In some embodiments, a controller (not shown) controls the pump

[503] to provide a set flow rate of sample gas from the chamber

[501] to the chamber

[504] .

[0115] Figure 6AAnother embodiment

[600] of a system for measuring analytes in a gas sample is shown, wherein the fluid flow path of the instrument

[601] is divided into more than one stream. In one embodiment, the exhaled stream is branched

[602] , wherein one stream

[603] passes through a reaction chamber

[604] in fluid communication with a first test strip chamber

[605] containing a test strip

[606] , while a second stream

[607] is in fluid communication with a second test strip chamber

[608] containing a second test strip

[609] . In one embodiment, the two streams exit the instrument in separate paths

[610] and

[611] . In one embodiment, the sensing chemicals present on both test strips are the same. In another embodiment, the sensing chemicals present on the two test strips are different from each other. In some embodiments, the purpose of the second stream

[607] is to provide a baseline for signal analysis such that the test strip

[606] is exposed to the converted analyte, and the second test strip

[609] is exposed to the same sample without the converted analyte. In one embodiment, the system is configured to uniformly distribute the flow rate between the two streams. In one embodiment, a buffer chamber (not shown) and a pump (not shown) are used to control the flow rate through the two chambers. Alternatively, a blower (whether piezoelectric, fan-type, or other type of blower) can be used instead of a pump.

[0116] Figure 6B Another embodiment

[612] of a system for measuring analytes in a gas sample is shown, which is similar to

[613] except that each bifurcation of the stream

[613] passes through separate reaction chambers (chambers

[614] and

[615] , respectively). Figure 6A The usage shown is

[600] . In some embodiments, the reaction chambers contain the same material. In other embodiments, the reaction chambers contain different materials. In one example, one chamber

[614] contains an oxidant, while chamber

[615] does not contain an oxidant. In one example, reaction chamber

[614] may be filled with KMnO4 on silica, while reaction chamber

[615] may be filled with silica. In some embodiments, such as in combination Figure 6A The flow rates to the two streams are controlled as presented in the described example. In some embodiments, the gas sample can be split into n flow paths to flow through n reaction chambers, which may or may not contain different materials. In this embodiment, the split flow paths can flow to n sample chambers, or they can be recombined or further split into any number of sample chambers. In this embodiment, the sample chambers can contain the same type of test strips, or they can contain different types of test strips, or any combination thereof. An example of a dual-flow-path device is a device for measuring hydrogen and methane for lactose intolerance assessment.

[0117] Figure 7Another embodiment

[700] of a system for measuring analytes in a gas sample is shown, wherein the fluid flow path of the instrument

[701] is split into more than one stream. In one embodiment, the exhaled airflow is branched

[702] , wherein one stream

[703] passes through a reaction chamber

[704] in fluid communication with a first test strip chamber

[705] , which exposes the sample of stream

[703] to a first sensing chemical

[707] on a first test strip

[708] . A second exhaled stream

[706] is in fluid communication with a second test strip chamber

[709] , which exposes the sample of stream

[706] to a second sensing chemical

[710] on the same test strip

[708] . In some embodiments, the sensing chemicals are the same. In other embodiments, the sensing chemicals are different. In some embodiments, the sample is recombined

[711] and passed through the instrument. In some embodiments, a gas sample may be divided into n flow paths to flow through n reaction chambers, which may or may not contain different materials. Examples of fluid samples flowing through multiple reaction chambers, as described above, are possible without departing from the spirit of the invention. Techniques for controlling the flow rate to any one or two streams include any flow described herein with respect to two-stream or single-stream embodiments.

[0118] Figure 8 Another embodiment

[800] of a system for measuring analytes in a gas sample is shown, wherein a chamber

[801] containing a test strip

[802] includes a computer-controlled motorized device for circulating, recirculating, disrupting, agitating, or exciting or otherwise altering the energy or magnetic state of the gas sample

[803] . Various methods can be employed without departing from the spirit of the invention. Examples include, but are not limited to, fans, ultraviolet (UV) energy sources, radio frequency (RF) energy sources, magnetic sources, heaters, coolers, pumps, augers, stirrers, blades, blowers, piezoelectric fans, or blowers, etc. Any combination (including more than one of the same devices) can be made without departing from the spirit of the invention. In one embodiment, the device

[803] accelerates measurement time. In another embodiment, the test strip

[802] consumes or irreversibly binds the target analyte, and the device

[803] is configured to ensure that the test strip

[802] is exposed to the entire sample contained in or trapped in the test strip chamber

[801] . In another embodiment, the device provides sufficient energy to allow the analyte to react. In another embodiment, the device alters the chemical state of the analyte to change the reactivity of the analyte with the test strip.

[0119] Figure 9Another embodiment

[900] of a system for measuring analytes in a gas sample is shown, wherein a chamber

[901] containing a test strip

[902] contains an energy source

[903] . In one embodiment, the energy source is used to clean the sensor. In one embodiment, the energy source is a UV or RF source. Cleaning the sensor may be used for the purpose of removing chemicals from a surface or for stabilizing baseline measurements or for calibration or analyte measurements. In another embodiment, the energy source is used to change the sample. In one embodiment, this can be achieved by applying a current or voltage at a stable or variable rate. Embodiments including one or more energy sources may be used in conjunction with embodiments and techniques disclosed in the incorporated application.

[0120] Figure 10 Another embodiment of a system for measuring analytes in a gaseous sample is shown

[1000] , wherein a reaction chamber

[1001] includes a sample inlet

[1002] and a sample outlet

[1003] . Passing the sample through the reaction chamber alters and / or fundamentally changes the physical, chemical, or electrochemical properties of the sample. Examples include, but are not limited to, oxidation, reduction, ion exchange reactions, coordination reactions, oligomerization reactions, condensation in the gas or liquid phase, volatilization in the solid or liquid phase, dissolution into a carrier gas or liquid, adsorption onto a minor component, formation of a high-energy molecular state (e.g., by stimulation with electromagnetic radiation), molecular polarization of the analyte (e.g., by using a magnetic field), ionization of the analyte (e.g., by using electromagnetic radiation or electron or particle bombardment, or other methods well known to those skilled in the art), etc. In another embodiment, the reaction chamber is designed to heat the sample. In another embodiment, the reaction chamber is designed to alter the chemical composition of the sample and to heat the sample. In one embodiment, the reaction chamber is configured to convert NO to NO2. Oxidation can be carried out by many methods without departing from the spirit of the invention. In another component, the reaction chamber also dehumidifies the sample stream. In some embodiments, the reaction chamber ( Figure 10 , 11 and 12) and sample chamber (e.g. Figure 8 The sample chamber and the test strip chamber are interchangeable and refer to the same structure.

[0121] Figure 11Various embodiments and potential oxidation methods of reaction chambers

[1101] , [1101a], [1101b], and [1101c] are illustrated. In one embodiment, reaction chamber [1101a] contains a catalyst to alter the chemical properties of the sample. In another embodiment, the substrate in reaction chamber [1101a] has been functionalized with a catalyst. In one embodiment, the catalyst is an oxidant. In one embodiment, the reaction chamber contains sodium permanganate or potassium permanganate as a catalyst. In another embodiment, potassium permanganate is located on a silica substrate. In another embodiment, potassium permanganate is located on an activated alumina substrate. In another embodiment, the catalyst is impregnated on a porous substrate. The reaction chamber may also include means containing the catalyst. In one embodiment, a filter, mesh, or metal mesh prevents the catalyst from escaping from the inlet or outlet during patient inhalation / exhalation. In another embodiment, reaction chamber [1101b] contains a heated metal wire or bead catalyst. In another embodiment, reaction chamber [1101c] includes a computer-controlled energy source to apply energy to the sample as it passes through the chamber. Examples include, but are not limited to, UV, UV LEDs, UV bulbs, infrared (IR), RF, corona discharge, etc. In one embodiment, energy is used to generate ozone and oxidize NO to NO2. Various ozone generation methods can be employed without departing from the spirit of the invention.

[0122] Figure 12 Various configurations of the reaction chamber are shown

[1200] ,

[1202] ,

[1204] ,

[1205] ,

[1206] . In one embodiment, the reaction chamber is a disposable cartridge with a limited lifespan. In another embodiment, the cartridge may also include means (not shown) for managing or controlling the number of uses. Examples include RFID, barcodes, fused circuits or fuses, on-cassette memory, etc. In one example, the cartridge's lifespan is designed to match the number of sensors sold in the package. In each of these embodiments, the cartridge is configured to allow fluid samples to enter and exit. In another embodiment, the reaction chamber is part of a sample chamber. In one embodiment, the conversion / reaction chamber contains its own calibration, which can be accepted by the instrument via at least one of optical, digital, or physical signals.

[0123] Figure 13A compact design of a system for measuring an analyte in a gaseous sample according to an embodiment of the present invention is shown. The device

[1300] includes a reaction chamber

[1301] , multiple valves [1302a], [1302b], [1302c], a test strip

[1303] and a test strip chamber

[1304] , and a filter

[1305] to remove chemicals from ambient air. In this embodiment

[1300] , a patient

[1306] inhales ambient air

[1309] through a mouthpiece

[1307] and through the filter

[1305] and a one-way mechanical valve [1302a]. The patient exhales

[1308] through the mouthpiece

[1307] and through a computer-controlled solenoid valve [1302b], expelling the sample into the ambient air. The exhaled breath flow rate (not shown in this embodiment) is measured as previously described. In one embodiment, the flow rate is 50 ml / second ± 10%. In one embodiment, the pressure is between 5 and 20 cm H2O. After a predetermined period of time (e.g., <7 seconds), valve [1302b] is closed to the environment, and fluid is directed to the reaction chamber

[1301] containing the material to oxidize NO in the sample to NO2. The oxidized sample passes through the test strip chamber

[1304] and exits the device through valve [1302c]. Valve [1302c] can be a one-way mechanical valve or a computer-controlled solenoid valve. In the case of a solenoid valve, the initial position can be open or closed, but valve [1302c] is in the open position when valve [1302b] directs the flow to the reaction chamber

[1301] .

[0124] Measurements of the test strip can be performed continuously or at any point or multiple points. In one embodiment, valves [1302b] and [1302c] close after capturing a portion of the sample in the test strip chamber

[1304] for 10 seconds. Valve [1302c] can close electronically, as in the case of a solenoid valve, or mechanically due to a pressure drop, as in the case of a one-way mechanical valve. Alternatively, valve [1302b] can be placed downstream of the reaction chamber

[1301] and upstream of the test strip chamber

[1304] . Alternatively, a buffer chamber (not shown) can be placed upstream or downstream of the reaction chamber.

[0125] Figure 14A and 14B An apparatus

[1403] for measuring an analyte in a gas sample is shown. The apparatus

[1403] includes a removable test strip

[1401] and a reaction chamber / box

[1402] . The apparatus

[1403] also has a lid

[1404] that covers and seals the test strip

[1401] and the reaction chamber / box

[1402] to the apparatus

[1403] . Figure 14A The cover

[1404] is shown in the open configuration, while Figure 14BA lid

[1404] in a closed configuration is shown. The lid

[1404] can be attached to the device

[1403] via a hinge or other known technology. The internal working principle has been described in the previous embodiments (e.g.,

[1300] ).

[0126] Figure 15A and 15B An embodiment of the device

[1500] is shown, which includes a hinged top

[1501] to seal the test strip

[1502] and the reaction chamber / box

[1503] into the device

[1500] . In this embodiment, a separate mouthpiece

[1504] is also connected to the device

[1500] . Figure 15A The lid

[1501] is shown in a closed configuration, with the mouthpiece

[1504] in place, while Figure 15B The lid

[1501] is shown in an open configuration, with the mouthpiece

[1504] removed.

[0127] In some embodiments of the invention, the output of the device is selected from a plurality of endpoints. In one embodiment, the measured resistance or voltage corresponds to at least one of a plurality of analyte concentration ranges. In one embodiment, the output is quantitative or semi-quantitative. In another embodiment, the output is qualitative. In yet another embodiment, the endpoint can be determined based on the patient's age. The endpoint for patients younger than 12 years of age is associated with three analyte concentration ranges: (i) less than 20 ppb (parts per billion), (ii) 20 to 35 ppb, and (iii) analytes greater than 35 ppb. The endpoint for patients older than 12 years of age is also associated with three analyte concentration ranges: (i) less than 25 ppb, (ii) 25 to 50 ppb, and (iii) analytes greater than 50 ppb. In another embodiment, the device can determine the type of output based on input received from one or more sources. In some embodiments, the output is above or below a predetermined analyte concentration. In some embodiments, the preset analyte concentration is selected from a concentration range between 1 and 50 ppb. When the analyte is nitric oxide, the preset analyte concentration can preferably be 20 ppb, 25 ppb, 30 ppb, 35 ppb, 40 ppb, or 50 ppb. When the analyte is methane, the preferred preset analyte concentration is 15 ppm (parts per million) or 20 ppm. When the analyte is hydrogen, the preferred preset analyte concentration is 15 ppm or 20 ppm.

[0128] Test Strip - Overview: At its most basic level, a test strip consists of a substrate / base and a sensing chemical. Embodiments of a test strip include a substrate, components establishing electrical connections (i.e., electrodes), at least one sensing chemical, and optionally at least one additional layer. The configuration and design can be modified based on the target gas and the environment in which the test strip will be placed. The sensing chemical is selected based on the target gas, and the electrodes are configured to measure changes in the properties of the sensing chemical that occur during interaction with the analyte. This one or more layers can be used for a variety of purposes, including but not limited to supporting the sensing material and chemical, sensing the analyte, masking chemical deposits, interlayer bonding, protection from interfering substances, enhancing the selectivity and / or sensitivity of the test strip, and protecting the sensing chemical and spacers. Layers may include features such as windows or holes to allow at least a portion of the fluid sample to pass through. Detailed descriptions of the electrodes, chemicals, and layers are provided below.

[0129] In some embodiments, the test strip is for single use. In some embodiments, the test strip is for multiple uses. In some embodiments, the test strip is for a limited number of uses. In other embodiments, the test strip may be used for fewer than or equal to three uses.

[0130] In one embodiment, the test strip may contain electrodes with a specific configuration or a specific resistance indicating to the device the type of output to be displayed. In another embodiment, a barcode is used to determine the type of output to be displayed. The barcode may be located in any number of places without departing from the spirit of the invention. Examples include, but are not limited to, test strips or packaging. In another embodiment, a chip is inserted into the device to provide information about at least one of a plurality of outputs. In yet another embodiment, the output type is manually entered into the device.

[0131] In another embodiment, the barcode or chip may also enable the device to utilize a specific calibration table. In yet another embodiment, the barcode or chip may contain information related to the calibration table.

[0132] In another embodiment, information about multiple outputs or about calibration is received from a paired mobile computing device.

[0133] Sensing Chemicals on Test Strips: Many sensing chemicals are possible without departing from the spirit of the invention. In one embodiment, the sensing chemical comprises a nanostructure functionalized to bind the analyte, causing a change in resistance across the nanostructure. In other embodiments, the analyte induces a redox reaction on the sensor surface on which the measurement is performed. In yet another embodiment, the analyte causes a change in the electronic environment of the sensing chemical, resulting in a change in the optical properties of the measurement. Nanostructures may include, but are not limited to, carbon nanotubes (single-walled, multi-walled, or several-walled), graphene, graphene oxide, nanowires, etc. Nanostructures can be assembled to form macroscopic features, such as paper, foam, thin films, etc., or can be embedded or deposited on macroscopic structures. Examples of functionalized materials include:

[0134] heterocyclic macrocyclic compounds

[0135] i. Examples include, but are not limited to: crown ethers, phthalocyanines, porphyrins, etc.

[0136] metal oxides

[0137] ii. Examples include, but are not limited to: AgO, CeO2, Co2O3, CrO2, PdO, RuO2, TiO2

[0138] transition metals

[0139] iii. Examples include, but are not limited to: Ag, Cu, Co, Cr, Fe, Ni, Pt, Ru, Rh, Ti

[0140] carbonyl

[0141] iv. Examples include, but are not limited to: carboxylic acids, amides, aldehydes, etc.

[0142] Functional organic dyes

[0143] v. Examples include, but are not limited to: azo dyes, cyanides, fluorides, indigo dyes, photochromic dyes, phthalocyanines, xanthens, etc.

[0144] Functionalized nanostructures (referred to herein as sensing chemicals) are disposed on a substrate to form the basic components of a test strip. Electrodes are connected to the sensing chemicals as described below.

[0145] A sensing chemical is a compound or group of compounds that alters certain physical properties when exposed to an analyte. These physical properties can be converted into electrical signals and measured as at least one of resistance, voltage, or current. A sensing chemical can be active, meaning it is designed to respond to a target analyte or a reference sensing chemical. A reference sensing chemical is a compound or group of compounds that is protected from interaction with at least one analyte or does not respond to at least a target analyte.

[0146] In another embodiment, the sensing chemical is a non-functionalized (i.e., unsensitized) nanostructure. This embodiment can be used in conjunction with functionalized nanostructures, or it can be used independently.

[0147] Auxiliary additives can be used to influence the drying properties and processability of sensing chemicals for deposition onto substrates. Non-limiting examples of deposition methods are listed below. Figure 16 Additives can be used to modify viscosity, surface tension, wettability, adhesion, drying time, gelation, film uniformity, etc. These additives include, but are not limited to, auxiliary solvents, thickeners, salts, and / or surfactants. These additives can be used for one or more purposes. Examples may include, but are not limited to, those mentioned above. Figure 16 Those in:

[0148] i. Thickeners - Polymer and Non-polymer

[0149] 1. Glycerin

[0150] 2. Polypropylene glycol

[0151] ii. Surfactants - Ionic and Nonionic

[0152] 3. Sodium dodecyl sulfate

[0153] 4. Triton X-100

[0154] In some embodiments, the volume of the sensing chemical disposed on the substrate may be less than or equal to 1 ml of material.

[0155] In some embodiments, the sensed chemical irreversibly binds to the target analyte under specified measurement conditions. Examples of irreversible interactions include, but are not limited to, covalent bonds, ion-ion interactions, or non-covalent interactions with large equilibrium constants, such as coordination bonds, dipole-dipole interactions, ion exchange reactions, or hydrogen bonding networks. As used herein, a bond is considered irreversible if there is virtually no signal recovery within a relevant time range of the operating conditions after the sensor ceases exposure to the analyte (i.e., partition coefficient < 0.5). Upon further exposure to a new analyte, the sensor is expected to maintain a certain level of sensitivity. In some embodiments, the condition range includes the conditions the sensor is exposed to during normal operation, such as normal operating levels of temperature, pressure, humidity, exposure, etc. Ideally, with respect to the relevant time scale, an irreversible system will never fully recover to its original baseline. In one embodiment, the sensor recovers less than 10% within twice the sensing time after the sensor is no longer exposed to the analyte. Therefore, if the sensing time is 3 days, the sensor signal of an irreversibly bound system will decrease by less than 10% within 6 days after the sensor ceases exposure to the analyte and will never fully recover to its original baseline. Similarly, if the sensing time is 10 seconds, the signal decreases by less than 10% within 20 seconds after removal from the analyte and never fully recovers to its original baseline. Another way to express irreversible binding is that the binding never reaches a steady-state equilibrium until the number of binding sites has been saturated by the analyte. Instead, the analyte accumulates on the sensor with each additional exposure.

[0156] In some embodiments, when the percentage of bound molecules leaving the sensor surface is, for example, less than 0.5, the analyte is considered irreversibly integrated into the sensing chemical. This percentage is referred to herein as the partition coefficient. The partition coefficient is defined as the proportion of bound analyte molecules that have left the sensor surface after exposure to the analyte at the applied operating temperature. In one embodiment, the partition coefficient is less than 0.5. In another embodiment, the partition coefficient is less than 0.25. In another embodiment, the partition coefficient is less than 0.1. In another embodiment, the partition coefficient is less than 0.05. In yet another embodiment, the partition coefficient is less than 0.01.

[0157] Due to the irreversible nature of chemicals, in some embodiments, a significant portion of the analyte from previous measurements remains on the test strip each time it is used. Therefore, a baseline measurement is performed before each measurement. In some embodiments, an initial baseline measurement is also performed at the point of care or point of use because environmental conditions such as temperature, humidity, and pressure can affect certain types of measurements. After the baseline measurement, the sensor is exposed to the analyte and measurements are taken. The signal can be measured as an absolute or relative change compared to the baseline.

[0158] In some embodiments, the test strip is for single use, meaning that the sensing chemical becomes saturated after a single exposure to the analyte. In some embodiments, the test strip is for multiple use, meaning that the sensing chemical does not become saturated after a single exposure to the analyte. Instead, the sensing chemical accumulates with each exposure and does not become saturated before undergoing multiple exposures. In some embodiments, the analyte saturates the sensing chemical after 365 exposures. In some embodiments, the analyte saturates the sensing chemical after 52 exposures. In some embodiments, the analyte saturates the sensing chemical after 12 exposures.

[0159] Test strip - substrate, electrodes, sensing chemical configuration and layers:

[0160] Various configurations or combinations of the substrate, electrodes, and chemical deposits are possible without departing from the spirit of the invention. The configuration depends on the characteristics of the sensing chemical, the target analyte, and the environment in which the device is located. The sensing chemical can also be coated or covered to prevent specific interactions (e.g., interactions with the analyte) to provide a reference, as in a chemical resistance bridging circuit. Multiple sensing chemicals can be used, or the same chemical substance can be deposited multiple times to serve as a reference for multiplexing or for signal averaging. Figure 17AExamples of various configurations of the substrate, electrodes, sensing chemicals, and layers of a test strip are shown. In one embodiment

[1709] , the test strip comprises a base substrate

[1701] , at least one electrode pair

[1702] , and at least one sensing chemical

[1703] electrically connected to the electrode pair

[1702] , and an optional additional layer

[1704] having a window or a plurality of holes

[1705] that expose at least the sensing chemical during assembly

[1707] . The additional layer

[1704] may serve as a spacer or protective layer. Optionally, the test strip may include a second sensing chemical

[1706] . Optionally, the test strip may not include a second layer

[1708] . Additional layers may be incorporated into the test strip for various reasons depending on the sensing chemical, electrode configuration, interfering substances, and manufacturing process. Examples include, but are not limited to: masking chemical deposits, supporting chemical deposits, protecting against interfering substances, enhancing the selectivity and / or sensitivity of the test strip, acting as a sensing chemical, spacer, protection of the sensing chemical, forming a gas chamber, test strip stiffness, or structural configuration. Layers can consist of porous and non-porous polymers, composites, fibrous materials (such as paper or glass fiber), woven and nonwoven fabrics, membranes, polymers, adhesives, films, gels, etc. For example, in some embodiments, these layers can be modified by chemical treatment or coating and / or mechanical alteration. These layers can be used for one or more purposes. For example, in some embodiments, layers can serve as structural components (e.g., improving rigidity or acting as spacers) and selectively permeable membranes. In another example, layers can serve as structural components (e.g., spacers or protective layers) and further define windows to allow target analytes to reach sensing and / or reference chemicals. Layers can be used in combination to provide selective permeation of target gases while protecting the test strip from interfering substances. In some embodiments, a dielectric layer is present above the electrodes.

[0161] Figure 17B and Figure 17C Examples of various configurations of substrate, electrodes and sensing chemicals on a single layer of the test strip are shown

[1701] to

[1712] and

[1722] to

[1726] .

[0162] In one embodiment

[1701] , the substrate

[1713] includes an electrode

[1714] and a sensing chemical

[1715] deposited across one side of the electrode

[1714] . The reverse side of the substrate

[1716] also includes an electrode and a sensing chemical. The reverse side of the substrate

[1716] can be symmetrical or asymmetrical. Asymmetry can include different sensing chemicals, chemical or electrode configurations, etc. A second sensing chemical

[1717] can be the same as or different from the first sensing chemical

[1715] . This can be used to adjust the sensitivity and selectivity to the target analyte. In another embodiment

[1708] , two test strips

[1732] ,

[1731] are manufactured separately and then assembled onto separate substrates

[1718] to form a finished test strip. This can be done to increase manufacturability if the sensing chemicals are different. In another embodiment

[1709] , where the sensing chemicals are placed side by side, one of the two sensing chemicals

[1721] is covered. In another embodiment

[1710] , the chemical has a linear form. In another embodiment

[1711] , the substrate

[1722] allows gas [1721a] to reach the sensing chemical through it. This allows the test strip to be placed away from the gas flow. Examples of other configurations

[1722] and

[1723] are shown, in which two chemicals are offset on a test strip sharing a single electrode. In one example

[1723] , one of two chemicals is covered. In another embodiment

[1724] , multiple sensing chemicals are shown. In this example, the chemicals may share at least one electrode. In another embodiment

[1725] , at least one chemical is covered. In another embodiment

[1726] , a chemical bridging three electrodes is shown. In this embodiment, the three electrodes may represent a working electrode, a reference electrode, and a counter electrode.

[0163] Figure 17D Embodiments with more complex configurations are shown. In some embodiments

[1727] ,

[1728] , and

[1729] , integrated heaters

[1731] ,

[1733] , and

[1734] are incorporated into the test strip on the same layer as the sensing chemicals [1732a], [1732b], and [1732c] (as shown in

[1728] ) or on a different layer (as shown in

[1727] ). In other embodiments

[1729] , the test strip has additional sensor elements

[1735] and integrated electronics

[1736] on at least one layer. Examples of the additional sensor elements

[1735] may include, but are not limited to, temperature and / or humidity sensors. Examples of the integrated electronics

[1736] may include, but are not limited to, resistors, fuses, capacitors, switches, etc. The test strip may also include components (not shown) for managing or controlling the number of uses. Examples include RFID, barcodes, fused circuits or fuses, memory on the test strip, serial numbers, switches, etc.

[0164] Figure 18A An example of a multi-layered test strip is shown. Multiple layers can be incorporated into a test strip for various reasons depending on the sensing chemistry, electrode configuration, interfering substances, and manufacturing process. Examples include, but are not limited to: masking chemical deposits, supporting chemical deposits, protecting against interfering substances, enhancing the selectivity and / or sensitivity of the test strip, acting as a sensing chemistry, spacers, forming gas chambers, and providing strip stiffness or structural configuration. Layers can consist of porous and non-porous polymers, composite materials, fibrous materials (such as paper or glass fiber), woven and nonwoven fabrics, membranes, polymers, adhesives, films, gels, etc. For example, in some embodiments, these layers can be modified by chemical treatment or coating and / or mechanical alteration. These layers can be used for one or more purposes. For example, in some embodiments, layers can serve as structural components (e.g., improving rigidity or acting as spacers) and selectively permeable membranes. Layers can be used in combination to provide selective permeation of a target gas while protecting the test strip from interfering substances. In some embodiments, a dielectric layer is present above the electrodes.

[0165] As shown in the dual-chamber embodiment

[1821] , the spacer layer

[1825] can also be used to form a single chamber or multiple chambers

[1826] . The spacer layer

[1825] is disposed above the substrate together with the electrodes and sensing chemicals

[1827] . The chambers can be uniformly or differentially coated

[1835] . In one embodiment, differentially coated chambers allow different gases to diffuse into different chambers for sensing by the sensing chemicals. In another embodiment

[1822] , a gas selectivity layer

[1830] is disposed above the substrate together with the electrodes and sensing chemicals

[1827] . A spacer layer

[1825] containing a small single chamber

[1829] is disposed above the gas selectivity layer

[1830] . A moisture barrier layer

[1828] is disposed above the spacer layer and covers the small chamber. In another embodiment

[1823] , two spacer layers

[1825] are used. The two spacer layers can be used to form a larger chamber to allow gas to accumulate on the sensor surface or to separate multiple diffusion layers. The spacer layer can also serve as structural support for the test strip and its layers. A perfluorosulfonic acid layer

[1833] is disposed above the substrate along with the electrodes and sensing chemicals

[1827] . A spacer layer

[1825] is disposed above the perfluorosulfonic acid layer

[1833] . A selective diffusion layer

[1832] is disposed above the first spacer layer

[1825] . A second spacer layer

[1825] is disposed above the selective diffusion layer

[1832] . A foil barrier layer

[1831] is disposed above the second spacer layer

[1825] . In another embodiment

[1824] , a different layer combination is used. A selective permeation layer

[1833] is disposed above the substrate along with the electrodes and sensing chemicals

[1827] . Two selective diffusion layers

[1832] and a plug

[1834] are disposed above the spacer layer

[1825] . In one embodiment, the plug

[1834] serves as a sealing mechanism when the test strip is inserted into the chamber.

[0166] These layers can be designed to be reactive with certain gases.

[0167] These layers can be applied using various coating methods (including but not limited to) Figure 16 (The methods shown) are used for coating.

[0168] Examples of interference may include, but are not limited to: gases, condensed liquids, dissolved solids, particulate matter, humidity, and temperature changes. In the example of measuring nitric oxide in exhaled breath, examples of interference might include:

[0169] Interfering substances used to measure nitric oxide in exhaled breath

[0170] <![CDATA[CO2]]> <![CDATA[H2O]]> <![CDATA[C2H3N]]> <![CDATA[H2O2]]> <![CDATA[C2H4O]]> <![CDATA[H2S]]> <![CDATA[C2H6O]]> <![CDATA[NH3]]> <![CDATA[C3H6O]]> <![CDATA[NO2]]> <![CDATA[C5H8]]> <![CDATA[O2]]> CO pH <![CDATA[H2]]>

[0171] Figure 18BOne embodiment is shown. In this example

[1800] , the test strip includes: a base substrate

[1801] having electrodes

[1806] and sensing chemicals

[1808] and reference chemicals

[1807] ; an optional dielectric layer

[1802] ; a layer covering the reference chemical

[1803] and exposing the sensing chemical

[1810] ; a film layer

[1804] ; and a protective layer

[1805] . The protective layer

[1805] employs a component

[1811] to allow gas flow to the film layer

[1804] . In one embodiment, the film layer

[1804] comprises a siloxane.

[0172] Figure 18C Examples of assembled test strips are shown.

[1812] A fully assembled test strip is depicted. Example

[1813] A test strip with a foil barrier for puncture by a companion device is depicted. Example

[1814] A test strip with a foil barrier including manually removable tabs is depicted. Example

[1815] A test strip with electrodes in a measuring unit rather than on the test strip itself is depicted. In this latter embodiment, when the device and the test strip are mated, the electrodes disposed in the mating device contact the sensing chemicals on the test strip.

[0173] In other embodiments, the heater, additional sensor elements, and integrated electronics described herein are incorporated into the reader instrument.

[0174] In other embodiments, the heater, additional sensor elements, and integrated electronics described herein are incorporated into the reader and / or chamber where the test strip is placed.

[0175] Other examples (not shown) may include electrode configurations suitable for measuring electrochemical reactions (i.e., working electrode, counter electrode, reference electrode).

[0176] In one embodiment, the test strip may include a substrate, at least one electrode, at least one sensing chemical, and optionally at least one layer to protect the sensing chemical from interfering substances. The sensing region may include at least two nanonetworks electrically connected to one or more electrical contacts. One network will act as the active sensing chemical and will be sensitive to a specific set of analytes (e.g., nitric oxide or nitrogen dioxide). Other networks may serve as a reference, a sensor for different analytes, or the same analyte for signal averaging. The reference may be sensitive to a different set of analytes, such that the difference in signal between the active sensing chemical and the reference results in signal sensitivity to a single analyte, a small set of analytes, or a subset of analytes that are highly sensitive to the test strip. In the case of multi-channel analysis, multiple references may exist.

[0177] In another embodiment, the test strip may include a substrate, at least one electrode, at least one sensing chemical, and optionally at least one layer to protect the sensing chemical from interfering substances. The sensing region may include at least two nanonetworks deposited between two or more electrodes. One network will act as the active sensing chemical and will be sensitive to a specific set of analytes (e.g., nitric oxide, nitrogen dioxide, carbon dioxide, hydrogen, or methane). The second network will serve as a reference. This reference may consist of the same sensing chemical as the active nanonetwork and may be covered or uncovered. The test strip and chemical may be configured as a resistive circuit or a bridging circuit.

[0178] In some embodiments, the active and sensing chemicals are premixed before being deposited onto the substrate. In some embodiments, the active and sensing chemicals are deposited in four or fewer steps.

[0179] In some embodiments of the invention, the test strip comprises a chromatographic layer. The chromatographic layer allows at least one analyte in the sample to move through the chromatographic layer at a different rate relative to the movement of other analytes in a variety of analytes (e.g., breath or ambient air).

[0180] One aspect of the present invention provides a system for determining the concentration of at least one analyte in a fluid sample having a plurality of analytes, the system comprising: a base substrate; a first electrode pair disposed on the base substrate; a first sensing chemical responsive to at least one analyte in the sample, wherein the first sensing chemical is electrically connected to the first electrode pair; and a first chromatographic layer disposed on the at least one sensing chemical, wherein at least one of the plurality of analytes moves through the first chromatographic layer at a different rate relative to the movement of other analytes in the plurality of analytes.

[0181] In another embodiment, the system further includes at least one of a barrier layer and a second chromatographic layer disposed on the second sensing chemical, wherein the barrier layer inhibits contact between the second sensing chemical and at least one analyte in the fluid sample, and wherein at least one analyte moves through the second chromatographic layer at a different rate relative to the movement of other analytes in the plurality of analytes. Other aspects of the invention may include any number of chromatographic layers.

[0182] One aspect of the present invention provides a method for determining the concentration of at least one analyte in a fluid sample, the method comprising providing a system comprising: a base substrate; a first electrode pair disposed on the base substrate; a first sensing chemical responsive to at least one analyte in the sample, wherein the first sensing chemical is electrically connected to the first electrode pair; and a first chromatographic layer disposed on the at least one sensing chemical, wherein at least one of a plurality of analytes moves through the first chromatographic layer at a different rate relative to the movement of other analytes of the plurality of analytes; and measuring at least one of a voltage between the first electrode pair, a resistance between the first electrode pair, and a current between the first electrode pair.

[0183] Figure 30 An embodiment of a test strip

[3009] is shown, configured to sense one or more gases using a chromatographic separation layer. The test strip comprises a substrate

[3001] , electrodes

[3002] , at least one sensing chemical

[3003] , and a layer

[3004] containing chromatographic separation material

[3006] . In a preferred embodiment, the chromatographic separation material

[3006] is disposed on the sensing chemical

[3003] bridging the electrode pair

[3002] . The chromatographic separation material may be integrated into another layer or may be a layer itself. If integrated, the layer

[3004] may, for example, provide structural support for the chromatographic material while defining a window

[3005] to allow the analyte to reach the chromatographic layer

[3008] and the sensing chemical

[3003] . A fully assembled test strip

[3007] with a chromatographic layer is shown. Hereinafter, a chromatographic layer refers to any layer containing chromatographic material that allows at least one analyte in a sample to move through the chromatographic material at a different rate relative to the movement of other analytes among a plurality of analytes. Prior to integration, the chromatographic material and any additional layers can be processed in a variety of ways. Examples of processing include, but are not limited to, die-cutting, laser cutting, kissing, surface energy modification (UV radiation, plasma and corona discharge, or by flame or acid treatment or other techniques well known in the art), adhesive spraying, lamination with or without pressure-sensitive adhesives, etc.

[0184] Figure 31An embodiment of a test strip

[3109] is shown, which is configured to sense one or more gases using a chromatographic separation layer. The test strip consists of a substrate

[3101] , electrodes

[3102] , an optional dielectric layer (not shown), two sensing chemicals

[3103] , a layer designed to cover one of the sensing chemicals and expose the second sensing chemical

[3104] , a chromatographic separation layer

[3106] , and a protective layer

[3107] having windows

[3108] for exposing the sensor to a gas or gas mixture. Layers

[3104] and

[3107] can be processed in a variety of ways to form openings

[3108] and

[3105] that expose one of the chemicals for sensing. Examples of processing include, but are not limited to, die-cutting or laser cutting. Layers

[3104] ,

[3106] , and

[3107] can be processed in a variety of ways before being assembled together in the test strip. Examples of processing include, but are not limited to, die-cutting, laser cutting, kissing, surface energy modification (UV radiation, plasma and corona discharge or by flame or acid treatment or other techniques known in the art), spraying with adhesives, etc.

[0185] In another embodiment, the test strip serves only as a chromatographic layer and does not contain a sensing element. Figure 32 In this embodiment, the test strip having a chromatographic layer

[3213] is used in conjunction with another sensor

[3214] . In addition to the test strip, other sensors may include metal oxide (MOS, CMOS, etc.), electrochemical, optical, MEMS, FET, MOSFET, ChemFET, or other types of sensors well known in the art. The test strip

[3213] may be for single use, multiple use, or limited use. It may be disposable or reusable. It may also be for a single patient. An embodiment

[3220] of a test strip used solely as a chromatographic layer is shown. In this embodiment, a chromatographic layer

[3217] is stacked between two substrates

[3216] and

[3218] . The substrates may include windows

[3215] and

[3219] to allow gas to pass through the chromatographic layer

[3217] . Other substrate configurations are also possible without departing from the spirit of the invention. One example is a chromatographic material

[3217] and a structural layer

[3216] . Other examples include, but are not limited to, substrates providing structural support for the chromatographic layer or for integrating the chromatographic layer with a sensor or device.

[0186] In some embodiments, the chromatographic diffusion and / or permeation layer may be composed of an impregnating material, and may consist of porous and non-porous polymers, composite materials, fibrous materials (such as paper or glass fiber), woven and nonwoven fabrics, membranes, polymers, adhesives, films, gels, etc. In some embodiments, for example, in some examples, the surface of said one or more layers may be modified by chemical treatment or coating and / or mechanical alteration. Other examples of materials suitable for chromatographic layers are incorporated herein (test strip-layer). In some embodiments, the layer may contain additional materials or undergo additional processing to make it suitable for manufacture.

[0187] In one embodiment, the chromatographic layer consists of a siloxane or a membrane or thin film containing a siloxane. In one embodiment, its thickness is between 1 μm and 200 μm to facilitate rapid analysis. In another embodiment, the thickness is greater than 200 μm to facilitate delayed analysis (hours or days). In yet another embodiment, the thickness is greater than 1 inch to facilitate analysis over periods of days, weeks, or years.

[0188] In another embodiment, the chromatographic layer is treated with a material to selectively remove chemicals and / or water (including water vapor). Treatments include, but are not limited to, coating, spraying, chemical bonding, etc.

[0189] In another embodiment, the chromatographic layer is designed to prevent water vapor from condensing on the sensing chemical.

[0190] In another embodiment, the chromatographic layer is treated with perfluorosulfonic acid.

[0191] In another embodiment, the chromatographic layer is treated with sulfonic acid.

[0192] In another embodiment, the chromatographic layer comprises siloxane and perfluorosulfonic acid.

[0193] In another embodiment, the chromatographic layer comprises siloxane and sulfonic acid.

[0194] In another embodiment, one of the test strip layers contains sulfonic acid or perfluorosulfonic acid.

[0195] In another embodiment, the chromatographic layer may contain adsorbent particles to modify the chromatographic properties, such as activated carbon, functionalized silica, alumina, clay, diatomaceous earth, mineral carbonates, polymers, and other packing materials well known to those skilled in the art.

[0196] In another embodiment, the chromatographic layer may contain emulsifying components to alter the chromatographic properties, such as emulsified water, oil, gas, organic solvent, polymer, organic molecules, and other biphasic chemicals well known to those skilled in the art.

[0197] Chromatographic detection

[0198] The gas detection methods cited below are based on the selective diffusion and / or permeation properties of chromatographic layers. These methods utilize at least one of the following to separate and analyze the concentration of a single gas or multiple gases, the physical and chemical properties of a material, the thickness of the material, time, temperature, pressure, signal intensity / magnitude and / or signal slope, changes from a single baseline and / or changes relative to multiple baselines, overshoot and / or undershoot relative to a fixed point (e.g., a baseline), changes in the first or second derivative of the signal, changes in signal shape (e.g., full width at half maximum, peak position, curve mode, etc.), ratios of two or more signal characteristics, or changes in any of the aforementioned signal features or chromatographic layer characteristics. Multiple methods may also be used in combination without departing from the spirit of the invention. This method enhances the sensitivity and selectivity of the sensor and allows for complex multipath analysis from a single chemical. Gases that pass through a chromatographic layer and include water vapor should subsequently be analyzed using this method.

[0199] In one embodiment, the test strip is calibrated to one or more target gases. The test strip may also be calibrated relative to gases that may interfere with the target gas. Calibration may include linearizing the sensor signal for one or more gases to convert the signal into an amount of the analyte (e.g., parts per billion or parts per million).

[0200] In one embodiment, the sensor and / or sensing chemical is designed to have different responses to the target gas and the interfering gas.

[0201] In another embodiment, the chromatographic layer is designed to provide both separation and specificity for the sensor and / or sensing chemicals.

[0202] Figure 33A A test strip

[3302] is depicted, in which a chromatographic layer

[3301] is separated for illustrative purposes from a mixture of gas molecules

[3303] above the chromatographic layer. Two types of molecules are depicted, but any number of molecules are possible without departing from the spirit of the invention. Over time, the gas above the chromatographic layer begins to pass through the layer. The properties of the chromatographic layer create a time-based separation, allowing the gas to selectively and predictively pass through the layer to reach the sensing chemical for detection. In one embodiment, as... Figure 33A As shown, gas 1, represented by a dark circle, and gas 2, represented by a light circle (collectively referred to as

[3303] ), reach the test strip

[3302] above the chromatographic layer

[3301] . At zero seconds, as initial conditions, 0% of gas 1 and 0% of gas 2 are located on one side of the chromatographic layer. After 1 second, approximately 43% of gas 1

[3305] and

[3308] , required to reach equilibrium, have passed through the chromatographic layer

[3307] , while 0% of gas 2

[3306] , required to reach equilibrium, has passed through. At 2 seconds ( Figure 33BAt that time, gases 1

[3312] and

[3315] had a 71% equilibrium concentration on the sensor surface of the chromatographic layer

[3314] , while gas 2

[3313]

[3316] has an equilibrium concentration of approximately 40%. At a certain time point, in this example at 100 seconds, gases 1

[3319] and

[3324] and gases 2

[3320] and

[3323] have a 100% equilibrium value below the chromatographic layer

[3321] at the height of the test strip

[3325] . In this case, equilibrium means that the gas diffusion is balanced across the entire membrane, but not about the sensor surface. The substance represented as a gas in this figure can also be any fluid, including liquids. Figure 34 Gas-time separation provided by a chromatographic layer containing a 100 μm thick siloxane is illustrated. In this example, each gas is plotted individually for the gas mixture and expressed relative to its own equilibrium concentration (i.e., at time 0, 100% of the various gases are above the chromatographic layer, while at time > 0, a certain percentage of the various gases have passed through the chromatographic layer close to equilibrium). Figure 34 At time 0

[3406] , the gas reaches above the chromatographic layer of the test strip. At 0.75 seconds

[3401] , the first molecules of gas 1 pass through the chromatographic layer and reach the sensor surface. At 1 second

[3402] , the first molecules of gas 2 pass through the chromatographic layer and reach the sensor. At 2 seconds

[3403] , gas 5 begins to pass through the chromatographic layer. The remaining gases begin to pass through the chromatographic layer at various time intervals between 2 and 3 seconds. Finally, after sufficient time, all gases will reach 100% equilibrium concentration below the chromatographic layer. Figure 34 (Not shown in the image). Any quantity of gas is possible without departing from the spirit of the invention. The sensors or detectors placed adjacent to the chromatographic layer can be any number of gas or liquid sensing devices, and the signals can be, but are not limited to, optical, acoustic, mechanical, or electronic signals. Other embodiments are also possible without departing from the spirit of the invention, such as those signals described elsewhere herein. The signal generated by the sensor at 1 second

[3402] is 20% of the equilibrium concentration of gas 1 compared to 0% of the equilibrium concentrations of gases 2 to 7. At 2 seconds

[3403] , the signal generated by the sensor is 35% of the equilibrium concentration of gas 1 compared to 25% of the equilibrium concentration of gas 2 compared to 0% of the equilibrium concentrations of gases 3, 4, 5, 6, and 7. At 4.25 seconds

[3404] , the signal generated by the sensor is approximately 58% of the equilibrium concentration of gas 1 compared to 50% of the equilibrium concentration of gas 2, and less than 40% of the equilibrium concentrations of gases 3 to 7, and so on. Any number of gases is possible without departing from the spirit of the invention. In one embodiment, the concentrations of gas 1 and gas 2 can be determined by comparing the signals to a calibration table at a given time before the other gases have passed through the chromatographic layer. The signals can be determined from baseline readings when the test strip has adapted to its environment. In another embodiment, the concentration of gas 2 can be determined by enhancing the sensing chemical to more favorably respond to gas 2 rather than gas 1. The system can be calibrated to detect the signal of gas 2 against a control gas 1 or a mixture of other gases that pass through the chromatographic layer prior to gas 2. At a given time, for example... Figure 34 The signal, measured in 2 seconds, represents 25% of the total concentration of gas 2, with only the background of gas 1. The total concentration of gas 2 can be determined by comparing the signal at 25% with the linear output of the signal at 100% in the calibration table. In one embodiment, the test strip and sensing system are calibrated to the gases found in exhaled human breath. In one embodiment, the test strip and sensing chemical control are calibrated against a background of at least one gas (including water vapor) found in exhaled human breath. In another embodiment, the test strip and sensing chemical are designed to respond differently to water vapor and the target gas. Figure 35A and Figure 35B A single respiration curve versus time is shown, recorded and plotted by a sensor with a 100 μm chromatographic layer. The signal represents a relative measurement (e.g., change in millivolts versus time) relative to a baseline measurement. The millivolt signal is compared to a calibration table for quantitative and / or qualitative analysis (e.g., a signal equal to 10 parts per billion of nitric oxide or a signal < 20 parts per billion of nitric oxide). In this example, the gas mixture contains gases found in human respiration that arrive at the test strip at time 0. The target gas to be detected is nitric oxide. At 1 second

[3501] , nitric oxide begins to pass through the chromatographic layer. At 2 seconds

[3502] , the signal is 4.75 mV, which can be shifted by a fraction of a billion. In one embodiment, measurements of the signal are sampled at different times

[3501] ,

[3502] ,

[3503] ,

[3504] to determine the amount of one or more second gases and / or to confirm the initial signal of the sample. In one embodiment, nitric oxide is converted to nitrogen dioxide, and the chromatographic layer and sensor are configured to allow nitrogen dioxide to pass through and be sensed. In one embodiment, a baseline is used to verify the accuracy of the test strip before introducing a gas sample (e.g., a quality control check). In one embodiment, the gas sample interacts with the test strip and sensing chemical further described herein, altering the resistance or other electrical properties of a sensor, for example, measured and displayed in millivolts. In one embodiment, a known current is passed through the test bar electrodes to perform a resistance or voltage measurement. In one embodiment, resistance is measured directly. In one embodiment, the current through the test bar electrode is pulsed. In one embodiment, the signal is converted to the frequency domain. In another embodiment, a test strip and a sensing system measure the liquid. In another embodiment, the test strip and sensing system measure the biological fluid. In another embodiment, a test strip and a sensing system measure respiratory condensate. In another embodiment, the system calibrates each gas in the expected airflow individually and relative to each other. The signal for each gas is linearized, and one or more concentrations can be determined at a given point in time. In another embodiment, the gas that slowly passes through the chromatographic layer is the target gas. For example, in Figure 34 In this process, gas 3 is the target gas, and at each time point, the signals of gas 1 and gas 2 are subtracted or the baseline is reset on that signal until a given percentage of gas 3 has passed through the chromatographic layer. In some embodiments, information for re-baseline setting at each time point regarding a gas mixture of known gases with known concentrations is determined empirically. In another embodiment, the properties of gas separation are altered by increasing or decreasing the ambient temperature on or near the test strip. In another embodiment, the test strip itself is heated or cooled. In another embodiment, the gas concentration is determined before other gases reach the sensor (i.e., through the chromatographic layer). Without departing from the spirit of the invention, any gas in the gas mixture can be measured whenever it passes through the chromatographic layer. Figure 36 , 37 Figures 38 and 39 illustrate the temporal separation of chromatographic layers at different thicknesses. These figures show the concentrations of various gases, expressed as a percentage of diffusion through the chromatographic layer, plotted relative to time. In these figures, one or more gases arrive above the chromatographic layer at time 0. Figure 40 This represents the signal output of one embodiment of a test strip with a chromatographic layer. The sensor is placed in a nitrogen gas stream, which is then exposed to a mixed gas stream consisting of moisture and nitric oxide. Moisture passes through the first gas in the chromatographic layer and causes an increase in the sensor's resistance. Nitric oxide follows and causes a sharp decrease in resistance until nitrogen is reintroduced. In this example, N2 can also be ambient air, and nitric oxide can be oxidized to nitrogen dioxide. Figure 41 Another embodiment of the signal output of a test strip with a chromatographic layer is shown. The sensor is placed in a nitrogen stream, which is then exposed to a mixed stream of moisture, nitric oxide, and carbon dioxide. Moisture is the first gas passing through the chromatographic layer and causes an increase in the sensor's resistance. Nitric oxide follows and causes a sharp decrease in resistance. Carbon dioxide is the third gas passing through the layer, causing a change in the slope until nitrogen is reintroduced. Figure 42 This is an example of a test strip with a chromatographic layer responding to human respiration. The sensor and chromatographic layer are configured to be sensitive and specific to nitric oxide. Moisture is a major known interfering agent in human respiration based on specific sensing chemicals and the test strip configuration. The sensor is baselined in indoor air. A respiratory flow is introduced, and moisture is the first gas passing through the chromatographic layer, causing a sharp initial increase in resistance. The chromatographic layer is designed to exclude other known gases in exhaled breath. Nitric oxide is the second gas impacting the sensor, causing a decrease in resistance. The sensor is then re-exposed to indoor air. Examples of target signal characteristics include, but are not limited to, the initial slope of gas exposure, the slope during gas exposure, the initial slope of the return signal, the slope at the end of gas exposure, slope changes over different times, absolute changes in sensor properties (physical, electro-optical, etc.), baseline-based overshoot or undershoot before and after gas exposure, overshoot or undershoot based on calibration curves, and the regression line as the gas passes through the chromatographic layer. Figure 43 This is an example of a test strip with a chromatographic layer, illustrating the response to human respiration. The sensor is configured to be sensitive to nitric oxide. The chromatographic layer is designed to exclude all interfering substances except for moisture, which is predictably adsorbed and desorbed from the sensor. The sensor is baselined in indoor air. A breathing flow is introduced, and both moisture and nitric oxide pass through the chromatographic layer, resulting in a sharp initial increase in resistance due to the moisture component. The sensor is then re-exposed to indoor air, and an auxiliary baseline is compared to the initial baseline to determine the amount of gas interacting with the sensor. Other examples of target signal characteristics include, but are not limited to, the initial slope of gas exposure, the slope during gas exposure, the initial slope of the return signal, the slope at the end of gas exposure, slope changes over different times, absolute changes in sensor properties (physical, electro-optical, etc.), baseline-based overshoot or undershoot before and after gas exposure, overshoot or undershoot based on a calibration curve, and the regression line as the gas passes through the chromatographic layer. Figure 44This is another example of the response of a test strip with a chromatographic layer to human respiration. The sensing chemical, sensor, and chromatographic layer are configured to be sensitive to nitrogen dioxide, and the conversion chamber in the device is designed to oxidize nitric oxide to nitrogen dioxide. Moisture is a major known interfering agent in human respiration based on the specific sensing chemical and test strip configuration. The sensor establishes a baseline in indoor air

[4401] . A respiratory flow is introduced, and moisture

[4403] is the first gas passing through the chromatographic layer, causing an initial increase in resistance. The chromatographic layer is designed to exclude other known gases in exhaled breath. Nitrogen dioxide is the second gas impacting the sensor

[4404] , resulting in a change in slope relative to humidity

[4403] . In other embodiments, the layer in the test strip oxidizes nitric oxide

[4404] to nitrogen dioxide. In other embodiments, the sensor is sensitive to nitric oxide. Other examples of target signal characteristics include, but are not limited to, the initial slope of gas exposure, the slope during gas exposure, the initial slope of the return signal, the slope at the end of gas exposure, slope changes at different times, absolute changes in sensor properties (physical, electro-optical, etc.), baseline-based overshoot or undershoot before and after gas exposure, calibration curve-based overshoot or undershoot, and the regression line when gas passes through the chromatographic layer. In another embodiment, the test strip and reader can be configured to measure the concentration of gases in respiration or gastrointestinal flatulence, which is the result of the interaction between a substance (e.g., fructose, lactose, sucrose, isotopes, etc.) and a human or animal body. These substances can be inserted, ingested, digested, inhaled, injected, or transmitted through the dermis (i.e., a transdermal patch). Examples include, but are not limited to, hydrogen breath tests (which may also include methane and / or carbon monoxide and / or carbon dioxide measurements) or urea breath tests. Other examples may include substances that interact with cancer, tumors, blood, viruses, bacteria, prions, parasites, etc., to produce the measured gas. In these embodiments, a gas delivery device is optional. Test strips - Sensing chemical deposits, drying formation, and batch calibration Non-limiting examples of deposition methods are listed below Figure 16In a preferred embodiment, an appropriate deposition and drying method is selected such that the sensing chemical forms a uniform electrical pathway between the two electrodes. In some embodiments, this pathway may be a concentrated component containing at least one sensing material and any possible non-volatile additives for the sensing chemical solution. The geometry of the pathway is not critical if the uniformity of the deposit is sufficiently uniform between test strips, resulting in sensor performance meeting the specifications required for accuracy and reproducibility. In practice, thin films cannot achieve sufficient uniformity of the sensing material, leading to variations in baseline resistance and sensor response, thus requiring individual calibration for each sensor. The ideal geometry is to form a uniform linear or coffee-ring shape. Linear and coffee-ring shapes concentrate the sensing material within a small area and can be repeatedly generated, enabling batch calibration of test strip sensors. For example, in some embodiments, in the case of rings, the portion of the ring intersecting the electrode gap should have >80% of the material between the electrodes and be concentrated within <20% of the area of ​​the electrode gap defined by the ring. Similarly, a linear shape should concentrate the material across a region spanning such a gap: its width is, for example, less than 0.5 mm and it traverses the entire gap between the electrodes. In either case, additional material can be placed on the electrode surface (i.e., outside the electrode gap) in any desired manner, since this material does not function when sensing the analyte. The electrode pairs can have any geometry, for example, they can be parallel or crossed arrays. In one embodiment of the invention, the processor uses calibration information to convert an analog signal (e.g., millivolts, resistance, current, etc.) into an analyte concentration. In one embodiment, the analog signal is sent to a mobile computing device, wherein software on the mobile or other computing device contains calibration information to convert the analog signal into an analyte concentration. The processor can receive calibration information from internal memory, an external chip, a SIM card, a USB drive, a paired mobile computing device, or via a mobile or wireless network. In one embodiment, the test strip may contain electrodes with a specific configuration or specific resistance to indicate the calibration of the test strip to the device. In another embodiment, a barcode is used to determine the calibration of the test strip. The barcode can be located in any number of locations without departing from the spirit of the invention. Examples include, but are not limited to, test strips or packaging. In another embodiment, an RFID tag contains calibration information. The RFID tag can be located in any number of locations without departing from the spirit of the invention. Examples include, but are not limited to, test strips or packaging. In another embodiment, a chip or external memory source is inserted into the device to provide the necessary calibration information. In another embodiment, a calibration or code indicating calibration is manually entered into the device. Figure 19An embodiment of a test strip

[1901] and a sensing chemical line

[1902] is shown, wherein the sensing chemical line

[1902] is electrically connected to electrode pairs

[1903] and

[1904] , which are shown in magnification. The line differs from the thin film in that it has clearly defined edges bridging the electrode pairs. For example, the pixel intensity shown as a grayscale value [1902a] corresponds to the sensing chemical line

[1902] . The intensity of [1902a] is distinguishable from that of the base substrate

[1905] with a corresponding intensity [1905a] and

[1906] with a corresponding intensity [1906a]. These lines provide highly consistent conductive paths for transmitting induced current across the electrode and sensor materials. Figure 20A Another embodiment of a test strip

[2001] and a sensing chemical configured in a coffee ring

[2006] is shown. The coffee ring has distinct and distinguishable edges

[2002] ,

[2003] ,

[2004] relative to the film

[2005] , wherein the edges are indistinguishable from the center. There is a continuous edge feature between the ideal coffee ring and the ideal film. The coffee ring approaches the film as the center thickness increases relative to the edge thickness. Better performance is achieved by forming a ring that approximates an ideal coffee ring in which all sensing material is located within an infinitely narrow edge and no material is deposited at the center of the spot. The height profile of the line or ring edge shows a rapidly forming peak with no plateau or local minimum at the peak. Figure 20B An embodiment of a test strip

[2007] and a sensing chemical configured as a coffee ring

[2008] is shown. The sensing chemical

[2008] is electrically connected to electrode pairs

[2009] and

[2010] . The coffee ring differs from the film in that it has clearly defined edges bridging the electrode pairs. For example, the pixel intensity shown as a grayscale value [2008a] corresponds to the coffee ring of the sensing chemical

[2008] , in which the coffee ring bridges the electrode pairs

[2009] and

[2010] in the sensing chemical

[2008] . The intensity of

[2008] shown as [2008a] can be distinguished from the base substrates

[2011] ,

[2012] , and

[2013] , which have corresponding intensities [2011a], [2012a], and [2013a], respectively. In other embodiments, the film may be a suitable configuration for sensing the chemical. The film has a nearly uniform intensity on the portion bridging the electrode pairs. Examples of thin films being superior to lines or coffee rings may include qualitative or semi-quantitative measurements to determine the presence or absence of an analyte. Figure 21AThe initial baseline signals (in millivolts) of two batches of sensors manufactured in the same batch are shown. In this example, the manufacturing batch contains multiple sensors / test strips where the raw materials, sensing chemicals, and sensing chemical geometries are sufficiently uniform such that calibration information from a subset of multiple test strips (e.g., batches within a batch) is applicable to multiple test strips. In this example

[2101] , the x-axis represents 10 individual sensors from a manufacturing batch that has been subdivided into batch 1 and batch 2, while the y-axis represents the corresponding baseline analog signal in mV. The corresponding descriptive statistics

[2103] show a coefficient of variation (CV) of 8.87% for the baseline signal across the two batches. Figure 21B This is the corresponding analog output in millivolts from 10 sensors in a manufacturing batch, which has been divided into batch 1 and batch 2 plotted on the y-axis, while the actual concentrations measured by chemiluminescence are plotted on the x-axis. This example demonstrates a strong correlation (r² > 0.983) between the analog signals of uncalibrated sensors from the same manufacturing batch and the actual analyte concentrations measured by chemiluminescence. In this embodiment, the target analyte is either nitric oxide or nitrogen dioxide. However, it is not a specific type or configuration of chemical, but rather allows for high homogeneity / uniformity among the batch-calibrated sensors. Batch calibration involves selecting a predetermined number of sensors from a manufacturing batch and / or lot and creating a standard curve based on the sensor's response to known concentrations within a relevant range. When the input concentration is unknown, the equation defining the standard curve precisely converts the sensor's analog signal into a concentration. The standard curve, or calibration equation, holds true for at least one set of sensors used in a manufacturing batch or lot. For example, Figure 21A The manufacturing batch was divided into two lots of five sensors (lot 1 and lot 2). Sensors were selected from lot 1 to create calibration curves for lot 2. When lot 2 was exposed to unknown analyte concentrations, the calibration equations from lot 1 were used to convert the analog signal of lot 2 into the measured analyte concentration. Figure 22A This demonstrates batch calibration using four of the five sensors from batch 1 to construct a four-point standard curve. Any number of sensors can be used to construct the standard curve without departing from the spirit of the invention. The y-axis represents the analog signal measured in millivolts from the four sensors in batch 1, while the actual concentration measured by chemiluminescence is plotted on the x-axis. Linear regression yields a fit of Y = -1.67 + 0.1889*X with a correlation coefficient of 1. This equation is rearranged because the actual concentration (x-axis) in the real environment is unknown. The corresponding calibration curve is unknown concentration = (analog signal - intercept) / slope. Other nonlinear calibration equations are also possible without departing from the spirit of the invention, as calibration equations consider environmental parameters such as temperature, pressure, and / or humidity. Figure 22BThis shows the calibration curve obtained based on batch 1. Figure 22A ) Applied to this manufacturing batch (previously in Figure 21A and Figure 21B The remaining five sensors in batch 2 are further subdivided. In this example, the sensors in batch 2 have not yet been individually calibrated and exposed to unknown concentrations of analyte. The calibration curves obtained from batch 1 are used to convert the analog signals into measured concentrations of the sensors in batch 2. In this example, the measured concentrations are plotted on the y-axis, while the actual concentrations measured by chemiluminescence are plotted on the x-axis. The resulting regression equation is Y = 0.3598 + 1.098*X, with a correlation coefficient of 0.999. In another embodiment, a manufacturing batch contains multiple sensors / test strips such that the raw materials, sensing chemicals, and sensing chemical geometries are sufficiently uniform to apply calibration information from a subset of multiple test strips (e.g., batches within a batch) to the multiple test strips. In this example, 40 sensors are manufactured and divided into 4 sub-batches, each containing 10 sensors. Five sensors from each sub-batch are selected to create calibration curves using the same method described previously. The calibration equations obtained from the five selected sensors in each sub-batch are then applied to the remaining five sensors in the corresponding sub-batch. The remaining five sensors in each batch, which are not individually calibrated, are exposed to unknown analyte concentrations. The analog signals are converted to measured concentrations using the corresponding calibration equations (e.g., X = (Y - 1.908) / 0.2943 for the sensors in batch 1). The resulting regression analysis of the measured concentrations plotted against the actual corresponding concentrations is described by the equation Y = 0.7114 + 0.9859 * X, and has a correlation coefficient of 0.986 for the remaining 20 sensors in the original manufacturing batch. Other embodiments of the invention include correlation coefficients greater than 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, and 0.99. For example, in some embodiment systems, the sensing chemical pathway geometry of each of the plurality of test strips is sufficiently uniform such that calibration information from a first subset of calibrated test strips from the plurality of test strips is applied to a second subset of uncalibrated test strips from the plurality of test strips with a correlation coefficient of at least 0.9, wherein the calibration information correlates the electrical signal of the test strip with the measured analyte concentration, and the correlation coefficient measures the accuracy of the measured concentration of the analyte relative to the actual concentration of the analyte. Figure 23 The layout of a mass-produced test strip is shown. A continuous substrate based on roll or sheet

[2301] is provided for chemical deposition. The substrate may already include electrodes

[2302] , or the electrodes may be created during the manufacturing process (i.e., screen printing or laser ablation). Figure 16 Any number of methods and coating techniques listed herein deposit chemicals

[2303] onto a substrate. This is not an exhaustive list. Individual test strips are cut using methods well known in the art (e.g., die-cutting, rotary cutting, laser cutting, etc.)

[2304] . Two chemicals (not shown) can also be deposited on a roll-based or sheet-based substrate. Any number of rows are possible without departing from the spirit of the invention. The sheet containing the electrodes is fed into a machine designed for depositing chemicals. The sheet with the chemicals is then dried by a variety of methods. Examples include, but are not limited to, air drying, convection, heating, infrared, ultraviolet, etc. Those skilled in the art will understand that additional layers may include pressure or heat-sensitive materials that may also be coated onto these layers. The sheet can be cut into smaller strips by any number of methods well known in the art (e.g., die-cutting)

[2304] . Figure 24 A layer

[2401] is shown disposed above a sensing chemical

[2404] , an electrode pair

[2403] , and a substrate

[2402] . This layer has a window

[2405] to allow a target analyte to reach the sensing chemical. In some embodiments, the layer comprises an adhesive. In a preferred embodiment, the layer comprises a pressure-sensitive adhesive. In some embodiments, the layer covering the sensing chemical is substantially permeable to the target analyte. In some embodiments, one of these layers is a barrier layer covering a reference sensing chemical and has a window for exposing the active sensing chemical. In some embodiments, the barrier layer may include an adhesive. Those skilled in the art will understand that any of a number of adhesives will suffice, such as, but not limited to, thermal adhesives or pressure-sensitive adhesives. In some embodiments, a layer may be a membrane layer that selectively permeates at least one analyte. Those skilled in the art will understand that the membrane layer may comprise many different materials, including but not limited to porous polymers, non-porous polymers, composite materials, fibrous materials, fabrics, non-woven fabrics, polymers, adhesives, films, gels, polytetrafluoroethylene, and silicone resins. In some embodiments, a siloxane transfer layer may be used to attach the membrane layer to at least one other layer. The embodiments described herein primarily relate to gas detection; however, the concepts, chemicals, and sensor designs described can also be applied to the detection of other fluids, analytes, etc., without departing from the spirit of the invention. The concepts, chemicals, and sensor designs described herein can also be applied to the detection of other gases, fluids, analytes, etc., without departing from the spirit of the invention. The following list provides examples of such applications. This list is not exhaustive. Industries (not exhaustive): Industrial, automotive, environmental, military, agricultural, veterinary, and medical. In the healthcare industry, specific examples (not an exhaustive list) include: 1) Health diagnostics related to the following areas (not an exhaustive list): clinical chemistry and immunoassay, breath analysis, hematology and hemostasis, urinalysis, molecular diagnostics, tissue diagnostics, point-of-care diagnostics, breath and / or clotting, virology, protein and / or antibody analysis, DNA / RNA, oncology, cardiology and metabolism, infectious diseases, inflammation and autoimmunity, women's health, intensive care and toxicology; 2) Technologies (not an exhaustive list), including: polymerase chain reaction (PCR and qPCR), nucleic acid amplification, ELISA and fluorescence; 3) Specific diseases (not an exhaustive list), including: sexually transmitted diseases, breath tests, digestive system diseases, urine LTE4, MRSA, influenza, virus testing and bacterial testing. The techniques, apparatus, and systems described above have been described with reference to the detection of analytes in a patient's exhaled breath. However, these techniques, apparatus, and systems can also be used in any application that requires the detection of the presence and / or quantity of a specific compound in a gaseous stream, such as applications in the industrial, automotive, environmental, military, fire and safety, agricultural, and veterinary fields. Examples of industrial applications include, but are not limited to, industries such as oil and gas, manufacturing processes, power generation, chemicals, basic materials, mining, and commercial construction. One embodiment of the device is used to detect hazardous gases in coal mines and is worn by miners. In another embodiment, the test strip is configured to measure gases during manufacturing processes requiring high-purity gases for quality control purposes. Examples of automotive applications include, but are not limited to, monitoring air quality in the vehicle's cabin and / or monitoring exhaust flow from the engine. Examples of environmental applications include home security, air pollution, and air quality. In one embodiment, test strips and readers are placed in multiple locations throughout the city, and data is transmitted to a central location to monitor air quality. Examples in agriculture include, but are not limited to, agricultural production and the food packaging and processing industry. In one embodiment, test strips and readers are packaged with food to monitor spoilage. In another embodiment, the test strip is part of an RFID tag, which is packaged with food to monitor spoilage and be read remotely. In yet another embodiment, the test strip and reader are configured to measure the concentration of methane or other gases in livestock waste. In one embodiment in the military, firefighting, and security industries, the test strip is combined with a robot / drone or other component (such as a throwable ball). The test strip is then delivered to an area without the need for human presence to detect the target gas. In another embodiment for medical use, physicians can use the invention to monitor the effectiveness of their prescribed treatments and identify the most effective treatments based on individual patient characteristics. The system provides this information by tracking trends in collected data (i.e., symptoms, biomarkers, etc.) and correlating that information with prescribed treatments. The system can compare treatment outcomes for an entire patient population or a single patient. The system will allow physicians to input characteristics of individual patients, and embodiments of the invention will identify successful and unsuccessful patients and display treatment options. This allows physicians to input characteristics about a given patient and access successful treatment options for that patient population, reducing the need for testing and error. Physicians can also use this invention to determine the root cause of a patient's symptoms. In this embodiment, the system can compare trends in symptoms and biological data, correlate them with prescribed treatments, and examine environmental data and / or prescription usage. Other embodiments use the collected information to compare drug effectiveness, monitor treatment adherence, create risk reports (i.e., for underwriting purposes), or establish payments based on the results. Other embodiments use the collected information to determine the optimal dosage of one or more drugs based on the patient's response to treatment, such as by biomarker values ​​or a combination of information collected by the present invention. Examples of biomarkers include, but are not limited to, serum periostin, exhaled nitric oxide, DPP4, blood eosinophils, blood neutrophils, sputum eosinophils, IgE, or other biomarkers indicating the presence or absence of eosinophils, neutrophils, paucigranulocytic cells, mixed granulocytes, Th2 or Th1 type inflammation. Other embodiments use biomarkers or combinations of biomarkers to predict drug response. Biomarker measurements can be taken at a single time point or across multiple time points. Examples of biomarkers have been described previously, although it is not intended to be an exhaustive list. Examples of drug response can be defined as improvement in lung function, reduction in exacerbations, or a decrease in the need for steroids or rescue medications. Medications can include those therapies designed to treat chronic respiratory diseases. Other embodiments use the collected information to determine patient adherence to or dependence on treatment. Adherence can be determined by measuring one or more biomarkers once or multiple times over time and comparing these measurements to the patient's baseline or well-known biomarker thresholds. Measurements below baseline indicate adherence to treatment. Measurements above baseline may indicate non-adherence to treatment. Examples of biomarkers have been described previously. This is not an exhaustive list. Other embodiments of the invention use the collected information to diagnose or identify steroid-resistant and / or steroid-insensitive asthma. In one embodiment, steroid-resistant or insensitive asthma can be identified by the patient continuing to exhibit asthma symptoms, despite adherence to high doses of steroids and biomarkers or biomarker groups. This embodiment may also include recording the use of biomarkers or biomarker groups to predict response and / or monitor adherence to steroids as the dose is increased throughout treatment. This data may be combined with other information collected by the invention. Other embodiments of the present invention can be used to diagnose or identify specific asthma phenotypes. Other embodiments of the present invention can be used to diagnose or identify the presence or absence of eosinophilic airway inflammation. Other embodiments of the invention can be used to determine the likelihood of a response to biological, oral, or inhaled therapies. Examples of biological therapies include, but are not limited to, those targeting Th2-high or Th2-low inflammation. Specific examples include, but are not limited to, IL-13, IL-4, IL-5, IgE, TLR9, TSLP, etc. Examples of oral and inhaled therapies include CrTH2, leukotriene-modified, corticosteroids, theophylline, muscarinic antagonists, tiotropium bromide, or combination therapies containing multiple active ingredients (e.g., inhaled corticosteroid esters / long-acting β2-agonists or inhaled corticosteroids / long-acting β2-agonists / long-acting muscarinic antagonists, etc.). Treatment can be short-term or long-term. Other embodiments of the invention may use the collected information to determine the level of disease control in a patient or patient population. Other embodiments of the present invention can be used to identify treatment failure of inhaled corticosteroids. In another embodiment of the invention, the collected information can be used to determine the effectiveness or failure of a treatment. Effectiveness can be determined by the ability of a drug to maintain one or more biomarkers at or below baseline readings. Ineffectiveness or failure of treatment can be determined by biomarker measurements above a particular patient's baseline reading. In one embodiment of the invention, the collected information can be used to determine appropriate inhaler technology. In this embodiment, one or more biomarkers can be used to confirm drug deposition or pharmacodynamic effects in the lungs. In one embodiment, exhaled nitric oxide is used as a biomarker to predict response and monitor adherence to and efficacy of inhaled corticosteroids. This information can be combined with other data collected by this invention. Other embodiments use this data to generate data for drug and medical technology research and development, to identify patients for clinical testing, and to communicate with patients and physicians for marketing purposes. Patients can use embodiments of the present invention to view information about the status and progression of their condition over time, and input information about themselves to find effective treatments based on the population in the database. In another embodiment of the invention, trained medical professionals can work in conjunction with system monitoring software to identify trends and proactively intervene before patients develop health problems or consume expensive medical resources (such as emergency room visits). Figure 25 This is an example of the types of information collected from patients. Figure 26 An illustrative embodiment of the invention is shown in which data is collected from individual patients [2604, 2605, 2606] using a mobile application

[2607] [2601, 2602, 2603] and the data

[2608] is sent to a remote database

[2609] that can be analyzed and queried by payers, providers, patients and industries

[2610] . Figure 27 Examples of different types of data collected for each patient, either manually or automatically, are shown. Biological data

[2701] are collected from a single patient

[2711] at home, in a physician's office, or in a pharmacy. Biomarkers, such as exhaled nitric oxide measurements from a breath test

[2704] and periostrin

[2705] and lung function (i.e., vital capacity sensing values ​​

[2706] ) from blood, can be collected from devices connected to computing devices (i.e., telephones, computers, tablets, etc.), and test results can also be entered manually. Other suitable blood biomarkers include blood eosinophils. Additional biomarkers can be collected without departing from the spirit of the invention. Data collected regarding medical history and prescribed treatment

[2702] can be collected at home and / or in a physician's office and supervised by a physician

[2707] . This data can be entered manually or automatically retrieved from medical records. Environmental and symptom data are collected automatically and manually

[2703] . Environmental data

[2708] may include weather, air pollution, and / or allergen indices. Location data can be provided by sensors inside a smartphone and overlaid on environmental data. Particulate matter can be synchronized via a device with embedded sensors located in the patient's home. Symptom data is collected by asking patients between medical visits about the frequency and severity of their symptoms and the extent to which the condition impairs their daily lives

[2709] . All of this information is sent to a remote server for storage and analysis

[2710] . Figure 28A monitoring system for chronic respiratory diseases is shown. As described in this invention, data is collected and transmitted from the patient

[2802] and

[2804] using various methods. As a service, this information is remotely stored

[2803] and monitored by a healthcare professional

[2801] . The healthcare professional is able to communicate with the patient for various reasons related to their health condition

[2805] . Figure 29 A software-based chronic respiratory disease monitoring system is illustrated. Data is collected and transmitted from the patient

[2902] ,

[2903] using the various methods described in this invention. Data is remotely stored and monitored

[2905] and an alarm system is triggered when the patient's information tends to be positive or exceeds a predetermined threshold

[2906] . For example, when the patient's nitric oxide level increases by 10-20% relative to a previous measurement or exceeds 25 or 50 ppb. The threshold may be based on predetermined clinical guidelines and / or patient characteristics (e.g., age, height, weight, etc.). Environmental pollution levels may also trigger an alarm. When an alarm is triggered, healthcare professionals and / or caregivers

[2901] and the individual patient

[2908] may be alerted. Healthcare professionals and / or caregivers are able to communicate with the patient for various reasons related to their health condition

[2907] . Various aspects of the techniques and systems associated with measuring the concentration of analytes in fluid samples and / or performing calibration on the apparatus disclosed in this application can be implemented as computer program products for use with a computer system or, for example, a computerized electronic device using a processor / microprocessor. Such implementations may include a series of computer instructions or logic fixed on a tangible / non-transitory medium (e.g., a computer-readable medium (e.g., a disk, CD-ROM, ROM, flash memory, or other storage or fixed disk)) or transmitted to a computer system or apparatus via a modem or other interface device (e.g., a communication adapter connected to a network via a medium). The medium may be a tangible medium (e.g., an optical medium or an analog communication line) or a medium implemented using wireless technology (e.g., Wi-Fi, cellular, microwave, infrared, or other transmission technologies). This set of computer instructions embodies at least a portion of the functionality described herein with respect to the system. Those skilled in the art will understand that such computer instructions can be written in many programming languages ​​to be used with many computer architectures or operating systems. These instructions can be stored in any tangible memory device (such as semiconductor, magnetic, optical or other memory devices) and can be transmitted using any communication technology (such as optical, infrared, microwave or other transmission technologies). Such computer program products are intended to be distributed as removable media with accompanying printed or electronic documentation (e.g., shrink-wrapped software), pre-installed on computer systems (e.g., on system ROM or a fixed disk), or distributed from servers or electronic bulletin boards on networks (e.g., the Internet or the World Wide Web). Of course, some embodiments of the invention can be implemented as a combination of software (e.g., computer program products) and hardware. Other embodiments of the invention are implemented as entirely hardware or entirely software (e.g., computer program products). It will be apparent to those skilled in the art that this disclosure can be implemented in forms other than those specifically disclosed above, upon reading this disclosure. Therefore, the specific embodiments described above are to be considered illustrative rather than restrictive. Those skilled in the art will recognize or be able to identify many equivalents of the specific embodiments described herein using only conventional experimentation.

Claims

1. A system for determining the concentration of at least one analyte in a fluid sample, the system comprising: A switching chamber, which is suitable for changing the chemical state of at least one analyte in a sample; Test strips, which include: Basic substrate; The first electrode pair is disposed on the substrate; A first sensing chemical is electrically connected to a first electrode pair, wherein the first sensing chemical responds to the chemically altered analyte. The first sensing chemical is formed into a coffee ring. The coffee ring consists of a first part and a second part. The first part is combined with the second part, wherein the first part constitutes less than 20% of the region of the coffee ring, wherein the first part bridges the first electrode pair, and wherein the first part includes more than 80% of the sensing chemical material. The first sensing chemical forms a chemical bond with the chemically altered analyte; And the test strip chamber containing the first sensing chemical, The test strip chamber is suitable for capturing at least a portion of the chemically altered analyte.

2. The system of claim 1, wherein the first sensing chemical comprises one or more of a carboxyl group, a nanostructure, a functional organic dye, a heterocyclic macrocycle, a metal oxide, or a transition metal.

3. The system according to claim 1 further includes a second electrode pair disposed on the substrate and a second sensing chemical electrically connected to the second electrode pair.

4. The system of claim 3, wherein one or more of the first sensing chemical or the second sensing chemical comprises one or more of a carboxyl group, a nanostructure, a functional organic dye, a heterocyclic macrocycle, a metal oxide, or a transition metal.

5. The system of claim 1, wherein the chemically altered analyte molecule binds to the first sensing chemical, and wherein the partition coefficient of the bound analyte is less than 0.5 under the desired measurement conditions.

6. The system of claim 5, wherein the partition coefficient of the bound analyte is less than 0.25 under the desired measurement conditions.

7. The system of claim 6, wherein the partition coefficient of the bound analyte is less than 0.1 under the desired measurement conditions.

8. The system of claim 7, wherein the partition coefficient of the bound analyte is less than 0.05 under the desired measurement conditions.

9. The system of claim 8, wherein the partition coefficient of the bound analyte is less than 0.01 under the desired measurement conditions.

10. The system according to any one of claims 5-9, wherein the chemically altered analyte saturates the first sensing chemical after a single exposure to the analyte.

11. The system according to any one of claims 5-9, wherein the chemically altered analyte saturates the first sensing chemical after repeated exposure to the analyte.

12. The system of claim 11, wherein the chemically altered analyte saturates the first sensing chemical after 365 exposures to the analyte.

13. The system of claim 11, wherein the chemically altered analyte saturates the first sensing chemical after 52 exposures to the analyte.

14. The system of claim 11, wherein the chemically altered analyte saturates the first sensing chemical after 12 exposures to the analyte.

15. The system according to any one of claims 5-9, wherein the chemical bonds are selected from the group consisting of coordinate bonds, covalent bonds, hydrogen bonds, ionic bonds and polar bonds.

16. The system of claim 1, further comprising a layer defining a window to expose the first sensed chemical to at least one chemically altered analyte.

17. The system of claim 16, wherein the layer comprises an adhesive.

18. The system of claim 17, wherein the adhesive is a pressure-sensitive adhesive.

19. The system of claim 1 further includes a chromatographic layer.

20. The system of claim 19, wherein the chromatographic layer comprises an adhesive.

21. The system of claim 20, wherein the adhesive is a pressure-sensitive adhesive.

22. The system of claim 1, wherein the system is adapted to sense one or more of nitrogen dioxide, nitric oxide, hydrogen, methane, acetone, sulfur dioxide, carbon monoxide or ozone.

23. The system of claim 1 further includes one or more of a blower, fan, or pump, said blower, fan, or pump being configured to move a fluid sample to a test strip.

24. The system of claim 1, wherein the fluid sample is moved to the test strip using the force of exhalation.

25. The system of claim 1 further includes a test strip chamber for receiving a test strip in fluid communication with the conversion chamber.

26. The system of claim 25, wherein the test strip is removable from the test strip chamber.

27. The system of claim 25, wherein the system is adapted to track the number of times the conversion chamber is used.

28. The system of claim 25 further includes one or more of a blower, pump, fan, or exhalation force for moving the fluid sample through the conversion chamber.

29. The system of claim 25, wherein the fluid sample is recirculated between the conversion chamber and the test strip chamber.

30. The system of claim 1 further includes at least one sensor for determining one or more of humidity, temperature, or pressure.

31. The system of claim 1 further includes a microprocessor adapted to determine or receive calibration information regarding the manufacturing batch or lot of the test strip.

32. The system of claim 1 further includes a dehumidifier adapted to remove moisture from the sample.

33. The system of claim 32, wherein the dehumidifier comprises a perfluorosulfonic acid tube.

34. The system of claim 32, wherein the dehumidifier comprises a desiccant.

35. The system of claim 34, wherein the desiccant comprises silica gel.

36. The system of claim 34, wherein the dehumidifier further comprises an oxidant.

37. The system of claim 30 further includes a filter adapted to remove from the sample a gas identified as interfering with the at least one sensor.

38. The system of claim 37, wherein the filter comprises a perfluorosulfonic acid tube.

39. The system of claim 1, wherein the conversion chamber is removable.

40. The system of claim 1, wherein the conversion chamber further comprises one or more of an oxidizing agent, a reducing agent, a charge transfer agent, an adduct, or a complexing agent.

41. The system of claim 1, wherein the conversion chamber is configured to oxidize nitric oxide to nitrogen dioxide.

42. The system of claim 1, wherein the conversion chamber comprises potassium permanganate.

43. The system of claim 42, wherein potassium permanganate is suspended on the substrate.

44. The system of claim 43, wherein potassium permanganate is suspended on silica gel.

45. The system of claim 1, wherein the conversion chamber comprises sodium permanganate.

46. ​​The system of claim 45, wherein sodium permanganate is suspended on the substrate.

47. The system of claim 1, wherein the conversion chamber comprises one or more of a UV source, an infrared source, a radio frequency source, or a corona discharge power source.

48. The system of claim 1, wherein the first sensing chemical is configured to respond to nitrogen dioxide.

49. A method for determining the concentration of an analyte in a fluid sample, the method comprising: A system is provided for determining the concentration of at least one analyte in a fluid sample, the system comprising: A switching chamber adapted to change the chemical state of at least one analyte in a sample; and Test strips, which include: Basic substrate; The first electrode pair is disposed on the substrate; A sensing chemical is electrically connected to a first electrode pair, wherein the sensing chemical responds to the chemically altered analyte. The sensing chemical forms a coffee ring. The coffee ring consists of a first part and a second part. The first part is combined with the second part, wherein the first part constitutes less than 20% of the region of the coffee ring, wherein the first part bridges the first electrode pair, and wherein the first part includes more than 80% of the sensing chemical material, wherein the sensing chemical forms chemical bonds with the chemically modified analyte; and The test strip chamber containing the sensing chemical; and At least a portion of the chemically altered analyte is captured in the test strip chamber; and Measure at least one of the voltage between the first electrode pair, the resistance between the first electrode pair, and the current between the first electrode pair.

50. The method of claim 49, wherein the fluid is a gas.

51. The method of claim 49, wherein the test strip is calibrated by at least one of manufacturing batch, manufacturing lot, and sensor location within the batch or lot.

52. The method of claim 49 further includes accepting calibration associated with the test strip.

53. The method of claim 52, wherein the calibration is received by one or more of digital, optical, or manual signals.

54. The method of claim 49, further comprising a microprocessor electrically connected to the test strip.

55. The method of claim 54, wherein the microprocessor converts analog voltage, resistance, or current into analyte concentration based on calibration.

56. Multiple test strips, each used to determine the concentration of at least one analyte in a fluid sample, each test strip comprising: Basic substrate; The first electrode pair is disposed on the substrate; A chemical is sensed, which is electrically connected to a first electrode pair, forming an electrical pathway with a pathway geometry, wherein the sensed chemical responds to an analyte. The sensing chemical forms a coffee ring. The coffee ring consists of a first part and a second part. The first part is combined with the second part, wherein the first part constitutes less than 20% of the region of the coffee ring, wherein the first part bridges the first electrode pair, and wherein the first part includes more than 80% of the sensing chemical material, and wherein the sensing chemical forms a chemical bond with the analyte. The sensing chemical pathway geometry of each of the plurality of test strips is sufficiently uniform such that calibration information from calibrated test strips of a first subset of the plurality of test strips is applied to uncalibrated test strips of a second subset of the plurality of test strips with a correlation coefficient of at least 0.9, wherein the calibration information correlates the electrical signal of the test strip with the measured concentration of the analyte, and the correlation coefficient measures the accuracy of the measured concentration of the analyte relative to the actual concentration of the analyte; as well as The test strip chamber that contains the sensing chemical is located in the chamber. The test strip chamber is suitable for capturing at least a portion of the chemically altered analyte.

57. The plurality of test strips of claim 56, wherein calibration information from calibrated test strips of a first subset of the plurality of test strips is applied to uncalibrated test strips of a second subset of the plurality of test strips with a correlation coefficient of at least 0.

95.

58. The plurality of test strips of claim 56, wherein calibration information from calibrated test strips of a first subset of the plurality of test strips is applied to uncalibrated test strips of a second subset of the plurality of test strips with a correlation coefficient of at least 0.

97.

59. The plurality of test strips according to claim 56, wherein each test strip further comprises a conversion chamber adapted to change the chemical state of at least one analyte in the sample.

60. A system for determining the concentration of at least one analyte in a fluid sample, the system comprising: Basic substrate; The first electrode pair is disposed on the substrate; A sensing chemical is electrically connected to a first electrode pair, wherein the sensing chemical is responsive to an analyte. The sensing chemical forms a coffee ring. The coffee ring consists of a first part and a second part. The first part is combined with the second part, wherein the first part constitutes less than 20% of the region of the coffee ring, wherein the first part bridges the first electrode pair, and wherein the first part includes more than 80% of the sensing chemical material. The sensing chemical forms a chemical bond with an analyte having a partition coefficient of less than 0.5 under the desired measurement conditions; and The test strip chamber that contains the sensing chemical is located in the chamber. The test strip chamber is suitable for capturing at least a portion of the chemically altered analyte.

61. The system of claim 60, wherein the chemical bond is selected from the group consisting of coordinate bonds, covalent bonds, hydrogen bonds, ionic bonds and polar bonds.

62. The system of claim 60, wherein the sensing chemical comprises one or more of carboxyl groups, nanostructures, functional organic dyes, heterocyclic macrocycles, metal oxides, or transition metals.

63. The system of claim 60, wherein the partition coefficient of the bound analyte is less than 0.25 under the desired measurement conditions.

64. The system of claim 63, wherein the partition coefficient of the bound analyte is less than 0.1 under the desired measurement conditions.

65. The system of claim 64, wherein the partition coefficient of the bound analyte is less than 0.05 under the desired measurement conditions.

66. The system of claim 65, wherein the partition coefficient of the bound analyte is less than 0.01 under the desired measurement conditions.

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