WO2024241309A1

WO2024241309A1 - System for pulmonary function test and exhaled gas analyzer

Info

Publication number: WO2024241309A1
Application number: PCT/IL2024/050495
Authority: WO
Inventors: Igor Krivts; Shabtay Negry
Original assignee: Technopulm Ltd
Current assignee: Technopulm Ltd
Priority date: 2023-05-21
Filing date: 2024-05-21
Publication date: 2024-11-28
Anticipated expiration: 2025-11-21
Also published as: IL303095B2; IL303095A; IL303095B1

Abstract

A device for determining at least one pulmonary function characteristic, the device constituted of: a main chamber; a first pressure sensor for measuring pressure within the main chamber; a shutter module; a control unit configured to switch the shutter module between a first state presenting a distal opening of the main chamber with a first effective area, and a second state presenting the distal opening with a second effective area; a sampling chamber; a second pressure sensor for measuring pressure within the sampling chamber; at least one gas sensor for sensing a concentration of a respective gas within the sampling chamber; a pump; a first valve positioned between the main chamber and the sampling chamber; and a second valve positioned between the sampling chamber and the pump, the control unit configured to control the second valve to switch the second valve between an open state and a closed state.

Description

SYSTEM FOR PULMONARY FUNCTION TEST AND EXHALED GAS ANALYZER

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to the field of medical devices, and, more particularly, to a portable system for testing lung functions, and to methods for noninvasive determination of one or more pulmonary function characteristics.

BACKGROUND

[0002] The key function of the respiratory system is to exchange oxygen and carbon dioxide. However, in recent years, the analysis of exhaled air for the presence of certain gas components has become increasingly popular.

[0003] The atmospheric air is a mixture of gases. The main gas components of air are nitrogen ( N₂ , 78.6%, or 786,000 ppm), oxygen (O₂ , 20.9%, or 209,000 ppm), water vapor ( H₂O , 0.5%, or 5,000 ppm) and carbon dioxide (CO₂ , 0.04%, or 400 ppm).

Gas Exchange in the Respiratory System

[0004] The purpose of the respiratory system is to perform gas exchange. Pulmonary ventilation provides air to the alveoli for gas exchange process. At the respiratory membranes, where the alveolar and capillary walls meet, gases move across the membranes, with oxygen entering the bloodstream and carbon dioxide exiting.

[0005] Table 1 represents the amount of the oxygen and carbon dioxide before (inhalation air) and after (exhalation air) gas exchange process.

Table 1

[0006] Basically, the lung gas exchange performance may be estimated by measurement of the CO₂ or O concentrations in the inhalation and exhalation air flow. It is very important to measurement of the CO₂ or O₂ concentration at the final phase of the exhalation process. Then we get the information about the gas exchange process. Carbon Dioxide Monitoring

[0007] Carbon dioxide ( CO₂ ) monitoring is a versatile noninvasive diagnostic tool for continuous assessment of the ventilatory status of patients. Basically, there are two approaches in CO₂ measuring: capnography and capnometry. Capnography refers to the comprehensive measurement and display of CO₂ , including end-tidal, inspired, and the capnogram (real-time CO₂ waveform). Capnometry refers to the measurement and display of CO₂ in numeric form only. In this case, the capnometer displays an end-tidal (ETCO2) and sometimes inspired CO₂ amount. Oftentimes little or no distinction is made between the term capnography and capnometry. Capnography provides instantaneous information about ventilation (how effectively CO₂ is being eliminated by the pulmonary system), perfusion (how effectively CO₂ is being transported through the vascular system) and metabolism (how effectively CO₂ is being produced by cellular metabolism).

[0008] Capnography may enable real-time diagnosis of pathophysiological abnormalities as well as problems related to ventilation. It also allows performing an indirect monitor of the CO₂ partial pressure in the arterial blood. Capnography provides a rapid and reliable detection method compared with pulse oximetry.

[0009] Clinical studies have shown that capnography can be used in the diagnosis of asthma, congestive heart failure, diabetes, circulatory shock, pulmonary embolus, acidosis, and other conditions.

[0010] Infrared, electro-chemical or colorimeter detectors may be used in CO₂ measurement. Today, infrared sensors are most commonly used in this technique.

[0011] Evaluation of the monitoring of the expired oxygen concentration as a diagnostic parameter has been indicated to show very good potential. Analysis of the oxygen concentration has a promise to provide a more sensitive method to estimate ventilation heterogeneities. This performance reflects alveolar regions with longer time constants that may allow better recognition of the presence of poorly ventilated alveolar regions.

[0012] Recently, research has identified emerging opportunities for further clinical research on the use of end-tidal oxygen measurement as an alternative to end-tidal CO₂ and pulse oximetry. Researchers have found potential utility for end-tidal oxygen measurement in ventilation assessment, and emergency department procedures including procedural sedation, assessment of ventilation/perfusion mismatch, pre-oxygenation during rapid sequence intubation, and prediction of central venous oxygen saturation. Nitric Oxide

[0013] Measurement of fractional exhaled nitric oxide (FeNO) is a non-invasive, safe, and simple method of quantifying airway inflammation. FeNO in asthma may have the utility of helping to make a diagnosis, monitoring the patient's compliance with prescribed medications, and predicting pending exacerbations.

[0014] Asthma and COPD affect every age, gender, ethnicity, and socioeconomic status, thus increasing mortality and morbidity burden in society. Nitric oxide (NO) is an important regulator of immune responses and is a product of inflammation in the airways that is over-produced in asthma. The FeNO is an endogenous gaseous molecule which can be measured in the human breath test because of airway inflammation. It has been studied extensively as a biomarker of inflammation and has been incorporated into an algorithm for asthma management.

Monitoring of other Volatile Fractions

[0015] Recently, it has become more and more common to diagnose different types of diseases and monitor the treatment process by measuring volatile fractions (biomarkers) in exhaled air. For example, in the diagnostic process of lung cancer it is helpful to indicate the following volatile biomarkers: methanol; acetone; propanol; and pentane. The development of appropriate sensors and methods for the analysis of volatile biomarkers is an important issue in modern medical practice.

[0016] The performance of the respiratory system is generally examined by pulmonary function tests (PFT), which is a generic term used to indicate a series of noninvasive studies of maneuvers that may be performed using standardized equipment to measure lung function. By assessing lung volumes, capacities, rates of flow and gas exchange, PTF provide information that can help diagnose certain lung disorders and monitoring of the response to therapy.

[0017] Various medical conditions can interfere with ventilation. Such conditions are typically classified as being “restrictive” or “obstructive”. An obstructive condition occurs when air has difficulty flowing out of the lungs due to resistance, causing a decrease flow of air. A restrictive condition occurs when the chest muscles are unable to expand adequately, creating a disruption in airflow. PFT involves several different procedures for obtaining values that can be compared to standards for a large population for comparison purposes.

[0018] There is an unmet medical need for determining characteristics of pulmonary functions. SUMMARY

[0019] Accordingly, it is a principal object of the present invention to overcome at least some of the disadvantages of prior art devices for pulmonary function analysis. This is provided in some examples by a device for determining at least one pulmonary function characteristic, the device comprising a main chamber exhibiting a gas inlet port, a sampling outlet port and a distal opening. [0020] In some examples, the device comprises a first pressure sensor configured to measure pressure within the main chamber.

[0021] In some examples, the device comprises a shutter module facing the distal opening.

[0022] In some examples, the device comprises a control unit configured to switch the shutter module between a first state and a second state, wherein in the first state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a first effective area, and wherein in the second state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a second effective area.

[0023] In some examples, the device comprises a sampling chamber exhibiting a sampling inlet port and a ventilation port.

[0024] In some examples, the device comprises a second pressure sensor configured to measure pressure within the sampling chamber.

[0025] In some examples, the device comprises at least one gas sensor, each of the at least one gas sensor configured to sense a concentration of a respective gas within the sampling chamber;

[0026] In some examples, the device comprises a pump.

[0027] In some examples, the device comprises a first valve positioned between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber.

[0028] In some examples, the control unit is configured to switch the first valve between an open state and a closed state, wherein in the open state the first valve presents a respective gas flow path between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber and in the closed state the first valve blocks the respective gas flow path.

[0029] In some examples, the device comprises a second valve positioned between the ventilation port of the sampling chamber and the pump.

[0030] In some examples, the control unit is configured to control the second valve to switch the second valve between an open state and a closed state, wherein in the open state the second valve presents a respective gas flow path between the ventilation port of the sampling chamber and an inlet of the pump and in the closed state the second valve blocks the respective gas flow path.

[0031] Additional features and advantages of the invention will become apparent from the following drawings and description. [0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise. As utilized herein, “and/or” means any one or more of the items in the list joined by “and/or”. As an example, “x and/or y” means any element of the three-element set {(x), (y), (x, y) } . In other words, “x and/or y” means “x, y or both of x and y”. As another example, “x, y, and/or z” means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z)}.

[0033] Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by anyone of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0034] In addition, use of the “a” or “an” are employed to describe elements and components of examples of the instant inventive concepts. This is done merely for convenience and to give a general sense of the inventive concepts, and “a” and “an” are intended to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.

[0035] As used herein, the term "about", when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +/- 10%, more preferably +/- 5%, even more preferably +/-1%, and still more preferably +/-0.1% from the specified value, as such variations are appropriate to perform the disclosed devices and/or methods.

[0036] The following examples and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, but not limiting in scope. In various examples, one or more of the above-described problems have been reduced or eliminated, while other examples are directed to other advantages or improvements.

[0037] The following examples and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, not limiting in scope. In various examples, one or more of the above-described problems have been reduced or eliminated, while other examples are directed to other advantages or improvements.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings in which like numerals designate corresponding sections or elements throughout. [0039] With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred examples of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how several forms of the invention may be embodied in practice. In the accompanying drawings:

[0040] FIG. 1 illustrates a high-level schematic diagram of a device for determining at least one pulmonary function characteristic, the device comprising a main chamber and a sampling chamber, in accordance with some examples of the disclosure;

[0041] FIGs. 2A - 2B illustrate various high-level perspective views of the device of FIG. 1, in accordance with some examples of the disclosure;

[0042] FIG. 3 illustrates a high-level flow chart of a preparatory cycle of the device of FIGs. 1 - 2B, in accordance with some examples of the disclosure;

[0043] FIG. 4 illustrates a system ventilation phase of the preparatory cycle of FIG. 3, in accordance with some examples of the disclosure;

[0044] FIG. 5 illustrates a sampling chamber pumping phase of the preparatory cycle of FIG. 3, in accordance with some examples of the disclosure;

[0045] FIG. 6 illustrates a high-level flow chart of an operation cycle of the device of FIGs. 1 - 2B, in accordance with some examples of the disclosure;

[0046] FIG. 7 illustrates a high-level graph of the pressure change within the main chamber of the device of FIGs. 1 - 2B, in accordance with some examples of the disclosure;

[0047] FIG. 8 illustrates an operation cycle of the device of FIGs. 1 - 2B, between a first pressure value of the main chamber and a second pressure value of the main chamber, in accordance with some examples of the disclosure;

[0048] FIG. 9 illustrates an operation cycle of the device of FIGs. 1 - 2B, between the second pressure value of the main chamber and a fourth pressure value of the main chamber, in accordance with some examples of the disclosure;

[0049] FIG. 10 illustrates a state of the device of FIGs. 1 - 2B, where the sampling chamber of the device is charged, in accordance with some examples of the disclosure;

[0050] FIGs. 11A - 11B illustrate high-level schematic diagrams of various states of a device for determining at least one pulmonary function characteristic, comprising a single chamber, in accordance with some examples of the disclosure; [0051] FIG. 12 illustrates a high-level graph of the pressure change within the main chamber of the device of FIGs. 11A - 1 IB, in accordance with some examples of the disclosure; and

[0052] FIG. 13 illustrates a high-level flow chart of the operation of the device of FIGs. 11A - 11B, in accordance with some examples of the disclosure.

DETAILED DESCRIPTION OF SOME EXAMPLES

[0053] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure. In the figures, like reference numerals refer to like parts throughout.

[0054] As used herein the terms "subject" and "patient" are interchangeable, and refer to the user of the devices and methods disclosed herein and include a healthy user, in the context of the measured values or a subject having, or being susceptible to have, a pulmonary disease or disorder. The subject may be a person or a mammal.

[0055] As used herein, the terms "about" or "within the range of" mean in the range of, roughly, or around. In general, the terms "about" or "within the range of" are used to modify a numerical value above and below the stated value by 20%. According to some examples, the term "about" or "within the range of" are used to modify a numerical value above and below the stated value by 15% thereof. According to some examples, the term "about" or "within the range of" are used to modify a numerical value above and below the stated value by 10% thereof.

[0056] FIG. 1 illustrates a high-level schematic diagram of a device 100 for determining at least one pulmonary function characteristic. FIG. 2A illustrates a high-level perspective view of device 100 from a first angle and FIG. 2B illustrates a high-level perspective view of device 100 from a second angle. FIGs. 1 - 2B are described together.

[0057] In some examples, device 100 comprises a main chamber 110. In some examples, main chamber 110 comprises a gas inlet port 111; a sampling outlet port 112; and a distal opening 113. The terms "port" and "opening" are used herein interchangeably and are both meant to describe a section of device 100 that allows gas to flow therethrough.

[0058] In some examples, device 100 comprises a first pressure sensor 120. In some examples, main chamber 110 further comprises a pressure port 114. In some examples, first pressure sensor 120 is positioned in front of pressure port 114 such that gas flowing through pressure port 114 is sensed by first pressure sensor 120. Although device 100 is illustrated and described herein in relation to examples where first pressure sensor 120 receives gas via pressure port 114, this is not meant to be limiting in any way. In some examples (not shown), first pressure sensor 120 is positioned within main chamber 110, and pressure port 114 is in some examples not provided.

[0059] In some examples, device 100 comprises a shutter module 130. In some examples, shutter module 130 comprises a first shutter inlet port 131 and a second shutter inlet port 132. In some examples, shutter module 130 comprises a housing 133, first shutter inlet port 131 and second shutter inlet port 132 being respective openings in housing 133. In some examples, housing 133 is generally circular with first shutter inlet port 131 and second shutter inlet port 132 being arranged radially about housing 133 such that first shutter inlet port 131 and second shutter inlet port 132 are arranged on the circumference of a circle. In some examples, shutter module 130 comprises a shutter wheel.

[0060] In some examples, shutter module 130 comprises one of the following two types of rotary actuators: a stepper motor or a rotary solenoid. An example of a suitable stepper motor is model NEMA 14HS10-0404S by STEPPERONLINE. Examples of suitable rotary solenoids are model M341-30-180-R by GEEPLUS, and model 3EVM by LEDEX. In some examples, shutter module 130 comprises a linear solenoid actuator. An example of a suitable linear solenoid is model RD- A622 by GEEPLUS.

[0061] In some examples (not shown), shutter module 130 comprises a switching mechanism configured to switch shutter module 130 between a first state and a second state, as will be described below. In some examples, the switching mechanism comprises a translation mechanism to translate first shutter inlet port 131 and second shutter inlet port 132 between different positions. Particularly, as will be described below, in the first state, first shutter inlet port 131 is in a first position in relation to distal opening 113 and second shutter inlet port 132 is in a second position in relation to distal opening 113. In the second state, first shutter inlet port 131 is in the second position in relation to distal opening 113 and second shutter inlet port 132 is in the first position in relation to distal opening 113. In some examples (not shown), the translation mechanism of the switching mechanism comprises a motor configured to rotate housing 133 such that first shutter inlet port 131 and second shutter inlet port 132 are translated between the first and second positions.

[0062] In some examples, shutter module 130 comprises a first shutter opening 135 and a second shutter opening 136.

[0063] In some examples, as will be described below, in a first state, shutter module 130 presents distal opening 113 of main chamber 110 with a respective gas flow path exhibiting a first effective area Asi. In a second state, shutter module 130 presents distal opening 113 of main chamber 110 with a respective gas flow path exhibiting a second effective area As - In some examples, second effective area As2 is smaller than the first effective area As;, as will be described below. The term "gas flow path", as used herein, means a path that allows gas to flow therethrough.

[0064] In some examples, the total effective area indicates the area through which a passage of exhaled air occurs, where the effective area affects the resistance to gas flow exhalation.

[0065] In some examples, first shutter opening 135 comprises a first set of openings and second shutter opening 136 comprises a second set of openings, as described in US patent S/N 10,687,735, issued June 23, 2020, the entire contents of which incorporated herein by reference.

[0066] Alternatively, in some examples (not shown), shutter module 130 comprises a single adjustable shutter opening, the shutter opening being controlled by control unit 140 to alternately present an opening with a first area and an opening with a second area. In some examples, the second area is smaller than the first area.

[0067] In some examples, device 100 comprises a control unit 140. In some examples, control unit 140 can be implement by one, or a combination, of: a processor; an application-specific integrated circuit (ASIC); a field-programmable gate array (FPGA); or any other suitable control circuitry or mechanism. In some examples, where control unit 140 comprises one or more processors, control unit 140 further comprises a memory having stored therein a plurality of instructions that when ready by the one or more processors cause control unit 140 to perform various functions, as described below.

[0068] In some examples, device 100 further comprises a sampling unit 145, where sampling unit comprises a sampling chamber 150. In some examples, sampling chamber 150 comprises a sampling inlet port 151 and a ventilation port 152.

[0069] In some examples, sampling unit 145 of device 100 comprises a first valve 160. In some examples, first valve 160 comprising an inlet port 161 and an outlet port 162. In some examples, first valve 160 is implemented as a microvalve. In some examples (not shown), first valve 160 is an active valve and comprises a mechanically movable membrane or boss structure, coupled to an actuator, that can close of an orifice, thus blocking the flow path between inlet port 161 and outlet port 162. In some examples, the actuator can be an integrated magnetic, electrostatic, piezoelectric or thermal microactuator, a "smart" phase change actuator (e.g., Shape-memory alloy or rheological material), or an externally applied actuation mechanism, such as an external magnetic field or pneumatic source. In some examples, first valve 160 is a solenoid valve.

[0070] In some examples, first valve 160 is controlled by control unit 140 to alternately open and close first valve 160 such that: when open, gas can flow into first valve 160 through inlet port 161 and flow out of first valve 160 through outlet port 162. In some examples, when open, first valve 160 presents a respective gas flow path between sampling outlet port 112 of main chamber 110 and sampling inlet port 151 of sampling chamber 150. When closed, first valve 160 blocks the respective gas flow path, as will be described below.

[0071] In some examples, sampling unit 145 of device 100 comprises a second pressure sensor 170. In some examples, sampling chamber 150 further comprises a pressure port 153. In some examples, second pressure sensor 170 is positioned in front of pressure port 153 such that gas flowing through pressure port 153 is sensed by second pressure sensor 170. Although device 100 is illustrated and described herein in relation to examples where second pressure sensor 170 receives gas via pressure port 153, this is not meant to be limiting in any way. In some examples (not shown), second pressure sensor 170 is positioned within sampling chamber 150, and pressure port 153 is in some examples not provided.

[0072] In some examples, sampling unit 145 of device 100 comprises at least one gas sensor 180. In some examples, each gas sensor 180 is configured to sense a concentration of a respective gas within sampling chamber 150. In some examples, a plurality of gas sensors 180 are provided, and each of the plurality of gas sensors 180 is configured to sense the concentration of a different gas. In some examples, one or more gas sensors 180 are each configured to sense the concentration of a plurality of different gases. In some examples, the gases comprise one or more of the following gases: CO₂; O₂; NO; H2S; or CO, without limitation.

[0073] In some examples, sampling chamber 150 further comprises a sampling port 154. In some examples, gas sensor 180 (or gas sensors 180) is positioned in front of sampling port 154 such that gas flowing through sampling port 154 is sensed by gas sensor/s 180. Although device 100 is illustrated and described herein in relation to examples where gas sensor 180 (or gas sensors 180) receives gas via sampling port 154, this is not meant to be limiting in any way. In some examples (not shown), gas sensor 180 (or gas sensors 180) is positioned within sampling chamber 150, and sampling port 154 is in some examples not provided.

[0074] In some examples, sampling unit 145 of device 100 comprises a pump 185 exhibiting an inlet 186. In some examples, pump 185 comprises a vacuum pump. In some examples, pump 185 comprises a micro vacuum pump.

[0075] In some examples, sampling unit 145 of device 100 comprises a second valve 190. In some examples, second valve 190 comprising an inlet port 191 and an outlet port 192. In some examples, second valve 190 is implemented as a microvalve. In some examples (not shown), second valve 190 is an active valve and comprises a mechanically movable membrane or boss structure, coupled to an actuator, that can close of an orifice, thus blocking the flow path between inlet port 191 and outlet port 192. In some examples, the actuator can be an integrated magnetic, electrostatic, piezoelectric or thermal microactuator, a "smart" phase change actuator (e.g., Shape-memory alloy or rheological material), or an externally applied actuation mechanism, such as an external magnetic field or pneumatic source. In some examples, second valve 190 is a solenoid valve.

[0076] In some examples, second valve 190 is controlled by control unit 140 to alternately open and close second valve 190 such that: when open, gas can flow into second valve 190 through inlet port 191 and flow out of second valve 190 through outlet port 192. In some examples, when open, second valve 190 presents a respective gas flow path between ventilation port 152 of sampling chamber 150 and pump 185. When closed, second valve 190 blocks the respective gas flow path, as will be described below.

[0077] In some examples, device 100 further comprises a mouthpiece 200. In some examples, mouthpiece 200 comprises an inlet port 201 and an outlet port 202. In some examples, outlet port 202 is connected to gas inlet port 111 of main chamber 110. In some examples, mouthpiece 200 further comprises an anti-bacteriological filter.

[0078] In some examples (not shown), main chamber 100 comprises a diffuser configured to obtain a laminar flow of air exhaled into main chamber 100. In some examples, the laminar exhaled airflow provides accurate measurement of the pressure and allows for an improved accuracy of the estimation of the pulmonary parameters.

[0079] As will be described below, the operation of device 100 is separated into two cycles: a preparatory cycle and an operation cycle. The preparatory cycle consists of two phases: system ventilation; and sampling chamber pumping.

[0080] FIG. 3 illustrates a high-level flow chart of the system ventilation phase and sampling chamber pumping phase. FIG. 4 illustrates the system ventilation phase within the high-level schematic diagram of device 100, where arrows 300 show air flow through device 100. FIG. 5 illustrates the sampling chamber pumping phase within the high-level schematic diagram of device 100, where arrows 310 show air flow through device 100. FIGs. 3 - 5 will be described together. [0081] In stage 1000, the preparatory cycle is initiated. In some examples, in stage 1010, in the system ventilation phase, control unit 140 controls first valve 160 and second valve 190 to be switched to an open state. As described above, in some examples, the open state of first valve 160 presents a respective gas flow path between sampling outlet port 112 of main chamber 110 and sampling inlet port 151 of sampling chamber 150. Similarly, in some examples, the open state of second valve 190 presents a respective gas flow path between ventilation port 152 of sampling chamber 150 and inlet 186 of pump 185.

[0082] In some examples, in stage 1020, control unit 140 activates pump 185, and pump 185 is maintained as activated for a predetermined time T_v (as shown in stage 1030). In some examples, time T_v is about 30 - 60 seconds. In some examples, this cleans all components of device 100 from air remaining from a previous test, as shown by arrows 310. In some examples, once time T_v has been reached, in stage 1040 control unit shuts off pump 185.

[0083] In some examples, in stage 1050, the gas concentration within sampling chamber 150 is measured by the at least one gas sensor 180. In some examples, gas sensor 180 is controlled by control unit 140 to measure gas concentration on demand. Alternatively, gas sensor 180 continuously, or periodically, measures gas concentration, and control unit 140 saves and/or flags measurements at predetermined times, such as in stage 1050.

[0084] In some examples, in stage 1060, control unit 140 activates pump 185, which begins to lower the pressure within sampling chamber 150, as shown by arrows 310 in FIG. 5. Additionally, the vacuum level in sampling chamber 150 is measured by second pressure sensor 170. In some examples, second pressure sensor 170 is controlled by control unit 140 to the pressure within sampling chamber 150 on demand. Alternatively, second pressure sensor 170 continuously, or periodically, measures pressure, and control unit 140 saves and/or flags measurements at predetermined times, such as in stage 1050.

[0085] In some examples, in stage 1070, in the sampling chamber pumping phase, control unit 140 controls first valve 160 to be switched to the closed state, while second valve 190 remains in the open state. As described above, in some examples, the open state of first valve 160 blocks the gas flow path between sampling outlet port 112 of main chamber 110 and sampling inlet port 151 of sampling chamber 150.

[0086] In some examples, in stage 1080 the pressure measurements of second pressure sensor 170 are monitored until the pressure drops to a predetermined vacuum value, denoted Pci- Once Pci is reached, in stage 1090 control unit 140 controls second valve 190 to be switched to the closed state. In stage 1100, control unit 140 shuts off pump 185. This concludes the preparatory cycle in stage 1110.

[0087] FIG. 6 illustrates a high-level flow chart of the operation cycle of device 100, in accordance with some examples. Fig. 7 illustrates a high-level graph of the pressure change within main chamber 110, as measured by first pressure sensor 120, where the x-axis represents time and the y-axis represents pressure values. FIGs. 6 - 7 are described together.

[0088] In stage 2100, the operation cycle is initiated. In some examples, in stage 2110, the pressure value in main chamber 110 is measured by first pressure sensor 120 and stored by control unit 140, and the pressure value in sampling chamber 150 is measured by second pressure sensor 170 and stored by control unit 140. The pressure in main chamber 110 is denoted PM and the pressure in sampling chamber 150 is denoted Pc- [0089] In some examples, the start point of the exhalation process is determined by the

back extrapolation method. Alternatively, the start point can be determined by the pressure threshold, according to which:

where is the atmospheric pressure, and is a predetermined pressure threshold, which in

accordance with some embodiments may be set as Alternatively, other known

methods may be used.

[0090] In the beginning phase of the forced exhalation process, in stage 2120, control unit 140 controls shutter unit 130 to be in the first state, such that the respective gas flow path presented to distal opening 113 of main chamber 110 exhibits a first effective area as described above.

Additionally, control unit 140 switches both first valve 160 and second valve 190 to the closed state.

[0091] In some examples, in stage 2125, the pressure in main chamber 110 is monitored until reaching a respective predetermined pressure value at after passing the maximum pressure

value PMM- In some examples, control unit 140 further determines the point of maximum pressure

as shown in FIG. 7. The maximum point is determined by known methods.

In some examples, the maximum point is determined in real-time.

[0092] FIG. 8 illustrates the operation cycle within the high-level schematic diagram of device 100, between points where arrow 320 shows air flow through device 100.

[0093] The pressure point may be in the range, for example, from

to

where PA is the atmospheric pressure. The level of the pressure

depends on

the effective area values and may be roughly estimated, for example, according to the

following formulas: , where ₂ may be calculated as:

EQ. 1

[0094] In the example shown in FIG. 7, the value of the pressure , which

[0095] In some examples, once the pressure drops to PM2, or to a value within a predetermined range thereof, in stage 2130, control unit 140 control shutter unit 130 to be in the second state, such that the respective gas flow path presented to distal opening 113 of main chamber 110 exhibits a second effective area As2, as described above.

[0096] In stage 2135, the pressure in main chamber 110 is monitored until reaching a respective predetermined pressure value at after passing local maximum pressure point In

some examples, the predetermined pressure value is equal to PM2. FIG. 9 illustrates the

operation cycle within the high-level schematic diagram of device 100, between points

and (t4,PM4), where arrow 330 shows air flow through device 100.

[0097] In some examples, once the pressure drops to PM4, or to a value within a predetermined range thereof, the charging condition of sampling chamber 150 is now prepared. Particularly, the exhalation flow contains the fully gas exchanged air and all device components that participate in the direction of exhaled air have been purified from the presence of the surrounding atmosphere.

[0098] In some examples, in stage 2140, control unit 140 switches first valve 160 to the open state, with second valve 190 remaining in the closed state and shutter module 130 remaining in the second state where the second affective area As2 is presented to distal opening 113 of main chamber 110, as illustrated in FIG. 10. Particularly, FIG. 10 illustrates the state of device 100 in stage 1140 within the high-level schematic diagram of device 100, where arrows 340 show air flow through device 100. As shown, sampling chamber 150 is charged with exhaled air.

[0099] In some examples, in stage 2145, the pressure in sampling chamber 150 is monitored until reaching a respective predetermined pressure value, denoted Pc2, which can be defined as may be in the range of . The time of the charging

process depends on the volume Vc of the sampling chamber 150, the initial pressure Pci in sampling chamber 150 and the effective area Avi of first valve 160. For instance, if the volume of sampling chamber 150 is V_c = 100ml , the absolute initial pressure in sampling chamber is and the effective area of first valve 160 the time of

the charging process is approximately in the range between 0.1 and 0.2 seconds.

[00100] In some examples, once the pressure reaches Pc2, or a value within a predetermined range thereof, in stage 2150 control unit 140 switches first valve 160 to the closed state, as described above in relation to FIG. 9. In some examples, in stage 2160, the one or more gas sensors 180 measure the concentration of the respective one or more gasses within sampling chamber 150. In stage 2170, control unit 140 (see FIG. 1) in some examples ends the storage of the pressure values from main chamber 110 and sampling chamber 150.

[00101] In some examples, in stage 2180, the respective gas concentration within the exhaled air is determined by control unit 140 based on the measurements of stage 1160. In some examples, the calculation of the specific gas concentration, for example CO , , in the exhalation air flow is based on Dalton's law, which asserts that the total pressure of a mixture of gases is equal to the sum of the partial pressures of the individual gases in the mixture. Thus, for example, the CO₂ concentration F_2CO2 in the exhalation air flow may be estimated as:

Where is the CO , concentration in the exhalation air [%], is referenced CO , concentration [%],

P_C1 is the absolute pressure in sampling chamber 150 at the start of the charging process [Pa], and is the absolute pressure in sampling chamber 150 at the end of the charging process

[Pa].

[00102] Similarly, the concentration of other gases in the exhaled air stream can be calculated. In stage 2190, the operation cycle of device 100 ends.

[00103] In some examples, as described below, device 100 is implemented in combination with the principles described in US patent S/N 10,687,735.

[00104] Particularly, as described therein, a device 400 is provided. FIGs. 11 A - 1 IB in the present disclosure illustrate various high-level schematic diagrams of device 400, as will be described below. In some examples, device 400 comprises: a main chamber 110; a pressure sensor 120; a shutter module 130; and a mouthpiece 200. In some examples, mouthpiece 200 further comprises an anti-bacteriological filter. In some examples, a device 400 further comprises a control unit (not shown).

[00105] Thus, in some examples, device 100 comprises device 400 as a first part and comprises sampling unit 145 as a second part. In some examples, device 100 is configured to be operated in one, or both, of two operation modes. In the first operation mode, spirometry and volumetric characteristics of exhaled air are defined, as will be described below. In the second operation mode, the concentration of the volatile components of exhaled air are determined, as described above.

[00106] FIG. 12 illustrates a high-level graph of the pressure change within main chamber 110 during a sequential forced gas exhalation event, in accordance with some examples, where the x-axis represents time and the y-axis represents pressure values. FIG. 13 illustrates a high-level flow chart of the operation of device 400, as described in US patent 10,687,735. FIGs. 11A - 13 are described together. [00107] In stage 1310, the operating cycle of device 400 is started. From that moment, in stage 1320, pressure P _M within main chamber 110 is measured and stored. Shutter module 130, from the beginning of the measurement process, and while not being actuated or toggled, is in a first state, wherein exhaled gas flows to the atmosphere through a first passage, corresponding to the effective area (as shown in stage 1330 and FIG. 11 A). Data processing identifies when first

peak pressure has been reached, after which the control system checks whether the pressure reached the level (in stage 1340) or is within the range of that level. As long as the pressure

has not reached the first peak , or has not reached the level after reaching P_MM , or has

not reached pressures within the range of those levels, shutter module 130 remains in the first state. At the moment the pressure reaches

or is within the range of that level, after reaching first peak pressure , shutter module 130 is switched to a second state, wherein exhaled gas flows

to the atmosphere through second passage, corresponding to the effective area A_s2 (as shown in stage 1350 and FIG. 1 IB). From that point, data processing identifies when second peak pressure P_M3 has been reached, after which the control system checks whether the pressure is within the range of the level P_M5 (as shown in stage 1360). As long as pressure has not reached the second peak P_M3 , or has not reached the level P_{M 5} after reaching P_M3 , shutter module 130 remains in the second state. At the moment that the pressure reaches the level P_{M 5} , after reaching second peak pressure P_M3 , in stage 1370, pressure data storage stops, and the operation cycle of the system ends in stage 1380, which may include the return of shutter module 130 to the first state.

[00108] As described in US patent 10,687,735, typical parameters determined by spirometry include, but are not limited to, any one or more of the following:

1) Spirometry Characteristics defined by forced expiratory flow parameters (spirogram). The main spirometry parameters are: Forced vital capacity (FVC); volume of gas exhaled in the first one second of exhalation (FEV1); forced expiratory flow between 25 and 75 percent of FVC (FEF25-75) i.e. the average expired flow over the middle half of FVC maneuver; and peak expiratory flow (PEF).

2) Lung Volumetric Parameters: Total lung capacity (TLC); residual volume (RV) i.e. the volume of gas remaining in the lung after maximal exhalation; and thoracic gas volume (TGV) i.e., the absolute volume of gas in thorax at any point in time and any level of alveolar pressure.

3) Airway Resistance defined as the ratio of driving pressure to the rate of air flow. Resistance to flow in airways depends on whether the flow (laminar or turbulent), on the dimensions of an airway and on a viscosity of a gas. Total resistance to air flow includes three main components: (a) inertia of respiratory system (contributes negligibly to total resistance), (b) tissue resistance of lungs and chest walls (accounts for approximately 20% of total resistance), and (c) airway resistance ( R_AW ) defined as the ratio of driving pressure to the rate of air flow (80% of total resistance).

4) Lung Compliance, or pulmonary compliance, refers to the extensibility of the lungs. It is expressed as a change in volume divided by a change in pressure. There are two types of lung compliance: static and dynamic. Static compliance of lungs is the change in volume for a given change in transpulmonary pressure with zero gas flow. Dynamic lungs compliance is compliance of lungs at any given time during actual movement of air.

[00109] It is noted, for example, that for analyzing the gas, Nitric Oxide (NO) exhaled gas analysis phase the European Respiratory Society and American Thoracic Society have agreed on procedures for standardized measurements of lower respiratory tract exhaled NO. The importance of measuring NO at a flow rate of 50 mL/s, with the subject inhaling NO-free air, was established, while prolonged inhalation was not required. Typically, a restrictor facilitates an appropriate exhalation, achieving and maintaining 50 mL/s. In this existing technique, the measurement is carried out during dynamic process of the exhalation. Since NO concentrations differ depending upon expiratory flow rate, an expiratory flow rate of 50 mL/s should be maintained during measurements. NO concentrations increase in proportion to reductions in the flow rate, and vice versa. The permissible range for expiratory flow rate is taken to be ±10%, corresponding to the range from 45 to 55 mL/s. High concentrations of NO are produced in the upper airways, such as in the nasal cavity, so it is desired to isolate the lower airway-derived NO from the nasal cavity- derived NO. When exhaling, it is desired to apply an expiratory pressure of 5-15 cmH20, which can close the soft palate by increasing the oral cavity pressure. This procedure prevents the mixing of NO from the upper airways. The above limitations affect the accuracy of measuring NO concentration and complicate the measurement procedure.

[00110] The above proposed system carries out of the measurement of the NO concentration in a static regime where the sample chamber is filled with exhaled air taken at the last stage of exhalation. In this case, exhaled air flow contains the gas that has completely undergone gas exchange in the lungs and is not mixed with gas from the upper respiratory tract. The shutter unit produces a second peak in the change in exhaled air pressure, which blocks the gas in the nose and increases the intensity of filling the sample chamber. This increases the accuracy of NO concentration measurement and simplifies the process. [00111] Certain examples of above-described implementations are enumerated below. It should be noted that one feature of an example in isolation or more than one feature of the example taken in combination and, optionally, in combination with one or more features of one or more examples below are examples also falling within the disclosure of this application.

[00112] Example 1. A device for determining at least one pulmonary function characteristic, the device comprising: a main chamber exhibiting a gas inlet port, a sampling outlet port and a distal opening; a first pressure sensor configured to measure pressure within the main chamber; a shutter module facing the distal opening; a control unit configured to switch the shutter module between a first state and a second state, wherein in the first state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a first effective area, and wherein in the second state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a second effective area; a sampling chamber exhibiting a sampling inlet port and a ventilation port; a second pressure sensor configured to measure pressure within the sampling chamber; at least one gas sensor, each of the at least one gas sensor configured to sense a concentration of a respective gas within the sampling chamber; a pump; a first valve positioned between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber, the control unit configured to switch the first valve between an open state and a closed state, wherein in the open state the first valve presents a respective gas flow path between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber and in the closed state the first valve blocks the respective gas flow path; and a second valve positioned between the ventilation port of the sampling chamber and the pump, the control unit configured to control the second valve to switch the second valve between an open state and a closed state, wherein in the open state the second valve presents a respective gas flow path between the ventilation port of the sampling chamber and an inlet of the pump and in the closed state the second valve blocks the respective gas flow path.

[00113] Example 2. The device of any example herein, particularly example 1, wherein the second effective area is smaller than the first effective area.

[00114] Example 3. The device of any example herein, particularly example 1 or 2, wherein, in an operation cycle, the control unit is configured to: in a first stage, switch the shutter module to the first state, switch the first valve to the closed state and switch the second valve to the closed state; in a second stage, based at least in part on an indication of the first pressure sensor that the pressure within the main chamber has dropped below a first predetermined value, switch the shutter module to the second state; in a third stage, based at least in part on an indication of the first pressure sensor that the pressure within the main chamber has dropped below a second predetermined value, switch the first valve to the open state; in a fourth stage, based at least in part on an indication of the second pressure sensor that the pressure within the sampling chamber has risen above a third predetermined value, switch the first valve to the closed state; and in a fifth stage, based at least in part on an output of the at least one gas sensor during the fourth stage, determine a concentration of the respective at least one gas within exhaled air.

[00115] Example 4. The device of any example herein, particularly example 3, wherein the second stage is further based at least in part on an indication that, prior to the pressure within the main chamber dropping below the first predetermined value, the pressure within the main chamber reached a first peak value.

[00116] Example 5. The device of any example herein, particularly example 4, wherein the third stage is further based at least in part on an indication that, prior to the pressure within the main chamber dropping below the second predetermined value, the pressure within the main chamber reached a second peak value.

[00117] Example 6. The device of any example herein, particularly any one of examples 3

- 5, wherein, prior to the operation cycle, in a pumping stage of a preparatory cycle, the control unit is configured to: activate the pump; and based at least in part on an indication of the second pressure sensor that the pressure within the sampling chamber has reached a predetermined initial value, switch the second valve to the closed state.

[00118] Example 7. The device of any example herein, particularly example 6, wherein, prior to the pumping stage of the preparatory cycle, in a ventilation stage of the preparatory cycle, the control unit is configured to: switch the first valve to the open state and switch the second valve to the open state; activate the pump for a predetermined time period; and following the predetermined time period, the control unit is further configured to: cease operation of the pump, switch the second valve to the closed state, and store an output of the at least one gas sensor, wherein the determination of the concentration of the respective at least one gas within the exhaled air is based at least in part on the stored output of the at least one gas sensor during the ventilation phase.

[00119] Example 8. The device of any example herein, particularly any one of examples 1

- 7, wherein the pump is a vacuum pump.

[00120] Example 9. The device of any example herein, particularly any one of examples 1

- 8, further comprising a mouthpiece connected to the at least one gas inlet port.

[00121] Example 10. The device of any example herein, particularly example 9, wherein the mouthpiece comprises a biological filter. [00122] Example 11. The device of any example herein, particularly any one of examples 1 - 10, wherein the shutter module comprises a first shutter opening and a second shutter opening, and wherein the respective gas flow path of the first state of the shutter module extends to the first shutter opening and the respective gas flow path of the second state of the shutter module extends to the second shutter opening.

[00123] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate examples, may also be provided in combination in a single example. Conversely, various features of the invention, which are, for brevity, described in the context of a single example, may also be provided separately or in any suitable sub-combination or as suitable in any other described example of the invention. No feature described in the context of an example is to be considered an essential feature of that example, unless explicitly specified as such.

[00124] Although the invention is described in conjunction with specific examples thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. It is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other examples may be practiced, and an example may be carried out in various ways. Accordingly, the invention embraces all such alternatives, modifications and variations that fall within the scope of the appended claims.

Claims

1. A device for determining at least one pulmonary function characteristic, the device comprising: a main chamber exhibiting a gas inlet port, a sampling outlet port and a distal opening; a first pressure sensor configured to measure pressure within the main chamber; a shutter module facing the distal opening; a control unit configured to switch the shutter module between a first state and a second state, wherein in the first state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a first effective area, and wherein in the second state the shutter module presents the distal opening of the main chamber with a respective gas flow path exhibiting a second effective area; a sampling chamber exhibiting a sampling inlet port and a ventilation port; a second pressure sensor configured to measure pressure within the sampling chamber; at least one gas sensor, each of the at least one gas sensor configured to sense a concentration of a respective gas within the sampling chamber; a pump; a first valve positioned between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber, the control unit configured to switch the first valve between an open state and a closed state, wherein in the open state the first valve presents a respective gas flow path between the sampling outlet port of the main chamber and the sampling inlet port of the sampling chamber and in the closed state the first valve blocks the respective gas flow path; and a second valve positioned between the ventilation port of the sampling chamber and the pump, the control unit configured to control the second valve to switch the second valve between an open state and a closed state, wherein in the open state the second valve presents a respective gas flow path between the ventilation port of the sampling chamber and an inlet of the pump and in the closed state the second valve blocks the respective gas flow path.

2. The device of claim 1, wherein the second effective area is smaller than the first effective area.

3. The device of claim 1 or 2, wherein, in an operation cycle, the control unit is configured to: in a first stage, switch the shutter module to the first state, switch the first valve to the closed state and switch the second valve to the closed state; in a second stage, based at least in part on an indication of the first pressure sensor that the pressure within the main chamber has dropped below a first predetermined value, switch the shutter module to the second state; in a third stage, based at least in part on an indication of the first pressure sensor that the pressure within the main chamber has dropped below a second predetermined value, switch the first valve to the open state; in a fourth stage, based at least in part on an indication of the second pressure sensor that the pressure within the sampling chamber has risen above a third predetermined value, switch the first valve to the closed state; and in a fifth stage, based at least in part on an output of the at least one gas sensor during the fourth stage, determine a concentration of the respective at least one gas within exhaled air.

4. The device of claim 3, wherein the second stage is further based at least in part on an indication that, prior to the pressure within the main chamber dropping below the first predetermined value, the pressure within the main chamber reached a first peak value.

5. The device of claim 4, wherein the third stage is further based at least in part on an indication that, prior to the pressure within the main chamber dropping below the second predetermined value, the pressure within the main chamber reached a second peak value.

6. The device of any one of claims 3 - 5, wherein, prior to the operation cycle, in a pumping stage of a preparatory cycle, the control unit is configured to: activate the pump; and based at least in part on an indication of the second pressure sensor that the pressure within the sampling chamber has reached a predetermined initial value, switch the second valve to the closed state.

7. The device of claim 6, wherein, prior to the pumping stage of the preparatory cycle, in a ventilation stage of the preparatory cycle, the control unit is configured to: switch the first valve to the open state and switch the second valve to the open state; activate the pump for a predetermined time period; and following the predetermined time period, the control unit is further configured to: cease operation of the pump, switch the second valve to the closed state, and store an output of the at least one gas sensor, wherein the determination of the concentration of the respective at least one gas within the exhaled air is based at least in part on the stored output of the at least one gas sensor during the ventilation phase.

8. The device of any one of claims 1 - 7, wherein the pump is a vacuum pump.

9. The device of any one of claims 1 - 8, further comprising a mouthpiece connected to the at least one gas inlet port.

10. The device of claim 9, wherein the mouthpiece comprises a biological filter.

11. The device of any one of claims 1 - 10, wherein the shutter module comprises a first shutter opening and a second shutter opening, and wherein the respective gas flow path of the first state of the shutter module extends to the first shutter opening and the respective gas flow path of the second state of the shutter module extends to the second shutter opening.