Method and system for delivering a breathable no-enriched gas mixture to a patient

Abstract

The present invention relates to the field of producing nitric oxide (NO)-enriched gas mixtures for the treatment of medical conditions. The claimed invention represents a method and system for delivering a breathable NO-enriched gas mixture to a patient, wherein the breathable NO-enriched gas mixture is generated on-site using plasma chemical conversion, said method and system providing an improvement of the respective technological field by (i) achieving higher accuracy of NO level adjustment and maintenance across a wide range of concentrations; (ii) ensuring a fast response of the system when adjusting NO concentration; (iii) reducing the fraction of undesired side-components, such as NO2 and O2, in the NO-enriched gas mixture.

Description

METHOD AND SYSTEM FOR DELIVERING A BREATHABLE NOENRICHED GAS MIXTURE TO A PATIENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 617,435, filed January 4, 2024; and U.S. Provisional Patent Application No. 63 / 666,175, filed June 30, 2024, the contents of which are all incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to the field of producing nitric oxide (NO)-enriched gas mixtures for the treatment of medical conditions. Specifically, the method and system of the present invention enable on-site production of a pharmaceutical-grade NO and N2 gas mixture (e.g., from ambient air), which is further delivered to the patient in a precisely controlled concentration.BACKGROUND OF THE INVENTION

[0003] As known in the art, nitric oxide (NO) gas, and specifically mixtures of nitrogen (N2) and NO gas, are crucial to many biological systems and can be used to treat various medical conditions via pulmonary delivery. In particular, research has shown that nitric oxide therapy may aid in the treatment of pulmonary arterial hypertension (PAH). PAH is a potentially fatal condition characterized by increased blood pressure in the lungs caused by obstructions in lung arteries. Pharmacological treatment of PAH has not shown sufficient efficiency (about 50% of patients die in 2-5 years depending on the disease state). While the precise mechanisms of disease progression are not entirely clear, several factors were discovered as being implicated in the pathology of PAH. To wit, one of the most important mediators is NO, a lack of which has been found to contribute to pulmonary artery vasoconstriction, vascular remodeling, and right ventricular failure associated with PAH pathology.

[0004] The vasodilator and anti-proliferative actions of NO (and mixtures of NO and N2) make it an attractive tool for pharmacological treatment of PAH. Administration of NO gas by inhalation has been shown to be beneficial to patients with PAH, particularly in children with congenital heart diseases. However, inhaled NO therapies are hampered by high costs, technical difficulties, and inconsistent patient response. Rapid withdrawal of inhaled NO therapy can also have deleterious effects with levels of oxygenation and pulmonaryhypertension returning to levels worse than those seen prior to the commencement of therapy.

[0005] Nitric oxide has other possible applications, e.g., in gene therapy. Currently, genebased therapy is considered a powerful approach for treating pulmonary arterial hypertension. Genetic manipulation may be supplemental to standard pharmacotherapy or be used as a stand-alone treatment. However, genetic material must be transferred into cells and expressed at a desired level to provide therapeutic effect. NO, in turn, may play an important role in improving gene transduction in gene therapies for treating PAH.

[0006] The production of NO and mixtures of NO and N2 for medical applications requires a stable and reliable process in order to ensure that the resulting gas mixtures contain the desired concentrations of the gases of interest.

[0007] There are many known solutions for NO generation, in particular, appliable for medical purposes. In general, these solutions may be divided into two groups: on-demand solutions, wherein the desired mixture is generated in advance and stored in a high-pressure gas tank; and on-site ones, wherein the desired mixture is generated from room air right before the usage. In both approaches, NO is commonly generated by using a controlled electric discharge to generate high-temperature plasma, thereby inducing a plasma chemical conversion, where oxygen and nitrogen in the input mixture react to produce nitric oxide.

[0008] Medical mixtures of NO and N2 are typically manufactured by mixing N2 with pure NO. Compliance with medical requirements for high purity of the final NO and N2 mixtures is considered to be technologically challenging and can result in complex and expensive techniques and methodologies. One of the major problems lies in that nitric oxide may be readily combined with oxygen (O2), e.g., from air, thereby forming toxic and cancerogenic nitrogen oxides gases such as nitrogen dioxide (NO2). NO2 has a very low limit of permissible concentration in inhalable gas, so it should be precisely controlled. Hence, it is crucial to reduce oxygen and NO2 content during the production of NO and N2 mixtures and / or to separate or filter it out therefrom afterwards.

[0009] Furthermore, when providing an on-site respiratory treatment with NO-enriched gas mixture to a patient it is important to provide an accurate maintenance of NO levels automatically across a wide range of concentrations required for various types of therapy. It is further important to ensure a fast response of the system when adjusting NO levels, whichis extremely difficult to achieve especially when operating in a low NO concentration range (e.g., < 100 ppm).

[0010] The existing solutions fall short in maintaining a stable NO concentration within the desired range necessary for medical applications, especially when using on-site plasma chemical conversion. Variations in plasma power and air flow lead to changes in energy input and to undesired fluctuations in NO concentration within the output flow, hindering prompt and accurate adjustment of NO concentration level. Another disadvantage lies in an excessive induction of “parasitic” (i.e. side-reactions) chemical reactions, resulting in incidence of undesired side-components, like NO2 and O2, in the output mixture.SUMMARY OF THE INVENTION

[0011] Accordingly, there is a need for a method and system for delivering a breathable NO-enriched gas mixture to a patient, wherein the breathable NO-enriched gas mixture is generated on-site using plasma chemical conversion, said method and system providing an improvement of the respective technological field by (i) achieving higher accuracy of NO level adjustment and maintenance across a wide range of concentrations; (ii) ensuring a fast response of the system when adjusting NO concentration; (iii) reducing the fraction of undesired side-components, such as NO2 and O2, in the NO-enriched gas mixture.

[0012] In the general aspect, the present invention may be directed to a method of delivering a breathable NO-enriched gas mixture to a patient. Said method may include: receiving, from an input gas mixture supply unit, an input gas mixture including N2 and O2; transferring, the input gas mixture through at least one plasma reactor unit, while generating an electric discharge therein to induce a plasma chemical conversion of at least a portion of the input gas mixture into NO, thereby producing an initial NO-enriched gas mixture; transferring the initial NO-enriched gas mixture through a filter unit to remove at least a fraction of NO2 and / or O2 from the initial NO-enriched gas mixture flowing therethrough, thereby producing a filtered NO-enriched gas mixture; controllably admixing the filtered NO-enriched gas mixture to a breathable air mixture, thereby obtaining the breathable NO- enriched gas mixture having a preset fraction of NO; and delivering the breathable NO- enriched gas mixture to the patient to provide the respiratory treatment thereto.

[0013] In another general aspect, the present invention may be directed to a system for delivering a breathable NO-enriched gas mixture to a patient. Said system may include: an input gas mixture supply unit, configured to provide an input gas mixture comprising N2 andO2; at least one plasma reactor unit configured to receive the input gas mixture and to induce a plasma chemical conversion of at least a portion of the input gas mixture into NO, thereby producing an initial NO-enriched gas mixture; at least one filter unit configured to receive the initial NO-enriched gas mixture and to remove at least a fraction of NO2 and / or O2 from the initial NO-enriched gas mixture, thereby producing a filtered NO-enriched gas mixture; a first pump or valve being in a downstream fluid communication with said at least one filter unit, and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line, said breathable NO-enriched gas mixture supplying line being in a downstream fluid communication with a breathable air supplying unit and in an upstream fluid communication with an airway management device; at least one first sensor configured to determine a concentration of NO in the airway management device; and at least one controller in operative communication with said at least one first sensor and said first pump or valve, said at least one controller being configured to operate said first pump or valve, based on the determined concentration of NO, so as to obtain, in the airway management device, the breathable NO-enriched gas mixture having a preset fraction of NO.

[0014] In some embodiments, said controllably admixing the filtered NO-enriched gas mixture to a breathable air mixture may include: receiving, by at least one controller, a desired value of the preset fraction of NO; and operating, by said at least one controller, at least one first pump or valve being in a downstream fluid communication with the filter unit and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line, said breathable NO-enriched gas mixture supplying line being in a downstream fluid communication with a breathable air supplying unit configured to supply the breathable air mixture, and in an upstream fluid communication with an airway management device, so as to maintain the desired value of the present fraction of NO in the breathable NO-enriched mixture.

[0015] In some embodiments, said controllably admixing the filtered NO-enriched gas mixture to a breathable air mixture further includes operating, by said at least one controller, at least one second pump or valve being in a downstream fluid communication with the input gas mixture supply unit and in an upstream fluid communication with a fluid communication line between the filter unit and the at least one first pump or valve, so as to maintain the desired value of the present fraction of NO in the breathable NO-enriched mixture.

[0016] In some embodiments, said operating the at least one second pump or valve may include: operating, by said at least one controller, said at least one second pump or valve to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a lower predetermined range; and operating, by said at least one controller, said at least one second pump or valve to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a higher predetermined range.

[0017] In some embodiments, the lower predetermined range may be between about 10 ppm and about 100 ppm and the higher predetermined range may be between about 100 ppm and about 1000 ppm.

[0018] In some embodiments, the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture is increased or decreased in a range between about 0 liter / hour and about 500 liter / hour.

[0019] In some embodiments, operating said at least one first pump or valve includes adjusting a volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

[0020] In some embodiments, a volume flow rate of the filtered NO-enriched gas mixture may be between about 50 liter / hour and about 100 liter / hour.

[0021] In some embodiments, a volume ratio between N2 and O2 in the input gas mixture is between 49: 1 and 9:1.

[0022] In some embodiments, the initial NO-enriched gas mixture may include between about 800 and about 5000 ppm of NO, between about 100 and about 500 ppm of NO2, about 89.95% of N2 or more, and between about 0.45 and about 9.95% of O2.

[0023] In some embodiments, the filtered NO-enriched gas mixture may include about 98% N2 or more and between about 500 and about 2000 ppm of NO.

[0024] In some embodiments, the input gas mixture supply unit may be a nitrogen generator comprising a pressure swing adsorption (PSA) system and / or a membrane gas separation system. The method may further include supplying air to the nitrogen generator to produce the input gas mixture. The system may be further configured to provide an air supply to the nitrogen generator to produce the input gas mixture.

[0025] In some embodiments, said at least one plasma reactor unit may include: a reaction chamber having an inlet channel and an outlet channel; a variable power supply in operative connection with a plurality of electrodes installed within the reaction chamber. Said transferring the input gas mixture through said at least one plasma reactor unit may further include: generating a gas flow of the input gas mixture through the reaction chamber via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes, while generating, by the variable power supply, the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture. Said at least one plasma reactor unit may be further configured to generate a gas flow of the input gas mixture through the reaction chamber via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes, while generating, by the variable power supply, the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture.

[0026] In some embodiments, said at least one plasma reactor unit may further include a circulation blower in fluid communication with said inlet and outlet channels of the reaction chamber, thereby forming, together with the reaction chamber, a circulating contour. Said transferring of the input gas mixture through said at least one plasma reactor unit may further include transferring at least a portion of the input gas mixture through the circulating contour. Said at least one plasma reactor unit may be further configured to transfer at least a portion of the input gas mixture through the circulating contour.

[0027] In some embodiments, the filter unit may include: a filter unit housing which defines an inner cavity therein; a pair of inlet and outlet channels coupled to the filter unit housing and being in fluid communication with each other via the inner cavity; a cartridge disposed within the inner cavity, said cartridge comprising a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide, respectively; and at least one heating element. Said transferring of the initial NO-enriched gas mixture through the filter unit may further include: heating the cartridge up to an operational temperature by the at least one heating element; and transferring the initial NO-enriched gas mixture via the inlet and outlet channels through the heated cartridge. The filter unit may be further configured to: heat the cartridge up to an operational temperature by the at least one heating element; and transfer the initial NO- enriched gas mixture via the inlet and outlet channels through the heated cartridge.

[0028] In some embodiments, the method may further include: receiving, by at least one controller, from at least one sensor being in operative communication with the filter unit, a current concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture; and operating, by said at least one controller, the heating element to increase the operational temperature when the received current concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.

[0029] In some embodiments, the metal catalyst may include elemental copper or copper alloy.

[0030] In some embodiments, the system may further include at least one second pump or valve being in a downstream fluid communication with the input gas mixture supply unit and in an upstream fluid communication with a fluid communication line between the filter unit and the at least one first pump or valve; and said at least one controller may be in operative communication with said at least one second pump or valve and may be further configured to operate, based on the determined concentration of NO, said at least one second pump or valve, so as to obtain, in the airway management device, the breathable NO- enriched gas mixture having the preset fraction of NO.

[0031] In some embodiments, said at least one controller may be further configured to: receive a desired value of the preset fraction of NO; and operate at least one of said at least one first pump or valve and said at least one second pump or valve, so as to obtain, in the airway management device, the breathable NO-enriched gas mixture having the preset fraction of NO according to the desired value.

[0032] In some embodiments, said at least one controller may be further configured to: operate said at least one second pump or valve to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a lower predetermined range; and operate said at least one second pump or valve to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a higher predetermined range.

[0033] In some embodiments, the second pump or valve may be configured to increase or decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture in a range between about 0 liter / hour and about 500 liter / hour.

[0034] In some embodiments, said at least one controller may be configured to operate said at least one first pump or valve to adjust a volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

[0035] In some embodiments, said at least one controller may be further configured to: receive, from at least one second sensor being in operative communication with the filter unit, a current concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture; and operate the heating element to increase the operational temperature when the received current concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0037] Fig. 1A is a block diagram, depicting a system for delivering a breathable NO- enriched gas mixture to a patient, according to some embodiments of the present invention;

[0038] Fig. IB is a block diagram, depicting a plasma reactor unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention;

[0039] Fig. 1C is a block diagram, depicting a filter unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention;

[0040] Fig. ID is a block diagram, depicting a filter unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0041] Fig. 2A is an isometric view with a broken-out section of the filtering unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention;

[0042] Fig. 2B is an isometric view with a broken-out section of the filtering module of the filtering unit, according to some alternative embodiments of the present invention;

[0043] Fig. 2C is an isometric view of the filter unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0044] Fig. 2D is another isometric view of the filter unit of the system for delivering a breathable NO-enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0045] Fig. 2E is a front view of the filter unit of the system for delivering a breathable NO- enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0046] Fig. 2F is a back view of the filter unit of the system for delivering a breathable NO- enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0047] Fig. 2G is a side view of the filter unit of the system for delivering a breathable NO- enriched gas mixture to a patient, according to some alternative embodiments of the present invention;

[0048] Fig. 3A is a graph depicting function from a fraction of O2 in an input gas mixture subjected to plasma chemical conversion to a fraction of NO and NO2 in the initial NO- enriched gas mixture, according to some embodiments of the present invention;

[0049] Fig. 3B is a graph of a flow rate in the exhalation line, according to some embodiments of the present invention;

[0050] Fig. 3C is a graph of a flow rate in the inhalation line (breathable NO-enriched gas mixture supplying line), according to some embodiments of the present invention;

[0051] Fig. 3D is a graph of a flow rate in the airway management device, according to some embodiments of the present invention;

[0052] Fig. 3E is an example of a graph of a NO concentration fluctuation in the breathable NO-enriched gas mixture supplying line (flow rate generated by the first pump - 40 liter / hour, concentration of NO before the first pump - 500 ppm, volume of inhalation line- about 300 ml), according to some embodiments of the present invention;

[0053] Fig. 3F is an example of a graph of a NO concentration fluctuation in the breathable NO-enriched gas mixture supplying line (flow rate generated by the first pump - 40 liter / hour, concentration of NO before the first pump - 500 ppm, volume of inhalation line- about 600 ml), according to some embodiments of the present invention;

[0054] Fig. 4 is a flow diagram depicting a method for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention.

[0055] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0056] One skilled in the art will realize the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. Scope of the invention is thus indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

[0057] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention. Some features or elements described with respect to one embodiment may be combined with features or elements described with respect to other embodiments. For the sake of clarity, discussion of same or similar features or elements may not be repeated.

[0058] Although embodiments of the invention are not limited in this regard, discussions utilizing terms such as, for example, “processing,” “computing,” “calculating,” “determining,” “establishing”, “analyzing”, “checking”, “choosing”, “selecting”, “omitting”, “monitoring” or the like, may refer to operation(s) and / or process(es) of a controller, computer, computing platform, computing system, or other electronic computing device, that manipulates and / or transforms data represented as physical (e.g., electronic) quantities within the computer’s registers and / or memories into other data similarly represented as physical quantities within the computer’s registers and / or memories or otherinformation non-transitory storage medium that may store instructions to perform operations and / or processes.

[0059] Although embodiments of the invention are not limited in this regard, the terms “plurality” and “a plurality” as used herein may include, for example, “multiple” or “two or more”. The terms “plurality” or “a plurality” may be used throughout the specification to describe two or more components, devices, elements, units, parameters, or the like. The term “set” when used herein may include one or more items.

[0060] As used herein, the term “fluid communication” refers to a path which allows fluid (e.g., a gas) to flow between two components of the system of the present invention, wherein said two components can be directly or indirectly joined to each other. Similarly, as used herein, the terms “fluidly coupled” or “fluidly connected” are interchangeable and refer to a connection between two components that allows fluid to flow from one component to the other, wherein said connection may be direct or indirect via intermediate components enabling fluid flow therethrough (such via one or more lines).

[0061] In the context of present invention, the term “filter unit” refers to the component of the system for delivering a breathable NO-enriched gas mixture to a patient, wherein this component does not necessarily comprise a controller, although may be controlled by one. E.g., the system may comprise a single controller (or controlling module) that is used for controlling the operation of other units of the system as well (e.g., the operation of the plasma reactor unit).

[0062] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, concurrently, or iteratively and repeatedly.

[0063] The concept of the present invention is further discussed with reference to Fig. 1A.

[0064] Fig 1A depicts system 100 for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention.

[0065] According to some embodiments of the invention, system 100 may be implemented as a hardware module, or a combination of a hardware module and a software module, configured for controlling the operation of hardware components.

[0066] As further described in detail herein, system 100 may be adapted to perform steps of the claimed method of delivering a breathable NO-enriched gas mixture to a patient.

[0067] As shown in Fig. 1A (and further in Figs. IB- ID), arrows may represent a flow of one or more data elements to and from system 100 and / or among modules or elements of system 100. Some arrows have been omitted in Figs. 1A-1D for the purpose of clarity.

[0068] In some embodiments of the present invention, system 100 may include an input gas mixture supply unit, configured to supply an input gas mixture, said input gas mixture comprising N2 and O2. In some embodiments, the input gas mixture supply unit may be nitrogen generator 20. Nitrogen generator 20 may be configured to produce the input gas mixture from air. Air may be supplied to nitrogen generation 20, e.g., via air intake 10.

[0069] Nitrogen generator 20 may be of any type known in the art. E.g., generator 20 may include a pressure swing adsorption (PSA) system.

[0070] PSA is a method used to separate a gas from a mixture of gases (typically air) under pressure according to the molecular characteristics of the gas and affinity for an adsorbent material. PSA systems typically operate in a cyclical process in which beds containing an adsorbent are pressurized to operating pressure with a feed gas, impurities are removed from the feed gas to obtain the input gas mixture, and the beds are regenerated to remove impurities from the PSA system.

[0071] According to some embodiments, nitrogen generator 20 (i.e., a PSA system) comprises: an inlet region for receiving the feed air gas (e.g., ambient air or, optionally compressed air) from air intake 10; at least one treatment zone comprising at least one adsorbent bed (e.g., zeolites, activated carbon, and the like); and at least a first outlet region for recovering the first gas mixture into an output line of generator 20. Means can be provided for controlling the pressure in the treatment zone. According to some embodiments, in the treatment zone the feed of the compressed air (may be compressed using internal compressor of nitrogen generator 20) is passed under pressure through the adsorbent bed (which attracts nitrogen more strongly than oxygen), and therefore a fraction of the nitrogen will stay in the bed, while the gas exiting the treatment zone (via a second outlet region) will be richer in oxygen than the air entering. When the bed reaches the limit of its capacity to adsorb nitrogen, it can be regenerated by decreasing the pressure, thus releasing the adsorbed nitrogen into the first outlet region.

[0072] According to some alternative embodiments, nitrogen generator 20 may include a membrane gas separation system or device as is known in the art.

[0073] According to other alternative embodiments, the input gas mixture supply unit may be a replaceable and / or refillable gas tank, detachably connected to the respective line (as shown in Fig. 1A) and containing the input gas mixture.

[0074] It should be understood that the present invention is not limited to any specific configuration of input gas mixture supply unit (e.g., nitrogen generator 20), and any configuration thereof known in the art may be applied herein, provided that the input gas mixture generated thereby have the desired content.

[0075] The volume ratio of the input gas mixture components may be essential and is discussed in greater detail with reference to Fig. 3A further below.

[0076] In some embodiments, system 100 may further include plasma reactor unit 30. Plasma reactor unit 30 may be in fluid communication with nitrogen generator 20, thereby, be configured to receive the input gas mixture. System 100 may be further configured to transfer the input gas mixture through plasma reactor unit 30. Plasma reactor unit 30 may be further configured to create an electric discharge (a controlled electric discharge (e.g., arc discharge) while the input gas mixture is being transferred therethrough, to induce a plasma chemical conversion (by generating high-temperature plasma) of at least a portion of the input gas mixture into NO, to produce the NO-enriched gas mixture thereby.

[0077] The aspects of plasma reactor unit 30 are discussed in greater detail with reference to Fig. IB further below.

[0078] It is important to recognize that the initial NO-enriched gas mixture obtained through plasma chemical conversion method might require filtration and / or dilution before it is administered to the subject. In some embodiments, the concentration of NO in this mixture may be too high for some specific medical applications.

[0079] Furthermore, in order to make an NO-enriched gas mixture suitable for respiratory treatment, it may be considered advantageous to remove traces of various impurities (e.g., NO2, O2, NOx etc.) therefrom. However, selectively removing residual components like NO2 while minimizing the impact on the desired component’s concentration (such as NO) is a challenging task. The aspects of the residual component removal are further described in greater detail with reference to Figs. 1C and ID, and with reference to Figs. 2A-2G.

[0080] Accordingly, in order to remove traces of residual components from initial NO- enriched gas mixture to obtain a medical grade gas mixture, in some embodiments, system 100 may include at least one filter unit (e.g., filter unit 40) configured to receive the initialNO-enriched gas mixture and to substantially remove NO2 (and optionally additional NOx species) and / or O2 from the initial NO-enriched gas mixture to result in a medical grade gas mixture.

[0081] System 100 may be accordingly configured to transfer the initial NO-enriched gas mixture through filter unit 40 to substantially remove NO2 (and optionally additional NOx species) from the initial NO-enriched gas mixture flowing therethrough, thereby producing a filtered NO-enriched gas mixture.

[0082] In some embodiments, system 100 may include breathable air supplying unit 71 connected via inhalation line 14 and exhalation line 15 with airway management device 72. Breathable air supplying unit 71 may be configured to provide a breathable air mixture to the patient via inhalation line 13 and, and to outtake a gas mixture exhaled by the patient via exhalation line 15 and airway management device 72.

[0083] In some alternative embodiments, system 100 may not necessarily include at least one of breathable air supply unit 71, inhalation line 14, exhalation line 15 and airway management device 72, but instead be connectable thereto. E.g., system 100 may comprise an output line for outputting the filtered NO-enriched gas mixture, wherein said output line may be connectable to inhalation line 14.

[0084] In some embodiments, breathable air supplying unit 71 may be any mechanical ventilation or assisted ventilation machine (also known as “ventilator”) known in the art, configured for fully or partially providing artificial ventilation. In some embodiments, mechanical ventilation may be invasive, involving an instrument to create an airway that is placed inside the trachea. In such embodiments, airway management device 72 may be or may include an endotracheal tube or nasotracheal tube. In some alternative embodiments, mechanical ventilation may be non-invasive, and airway management device 72 may be or may include face or nasal mask, respectively.

[0085] In some embodiments, system 100 may be further configured to controllably admix the filtered NO-enriched gas mixture to a breathable air mixture, thereby obtaining a breathable NO-enriched gas mixture having a preset fraction of NO.

[0086] In particular, in some embodiments, system 100 may include pump 52 (or, alternatively, a valve, also referred herein as the “first” pump or valve) being in a downstream fluid communication with filter unit 40, and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line, said breathableNO-enriched gas mixture supplying line being in a downstream fluid communication with breathable air supplying unit 71 and in an upstream fluid communication with airway management device 72.

[0087] It should be understood that, in some embodiments (including the illustrated embodiment), breathable NO-enriched gas mixture supplying line and inhalation line 14 represent the same element, hence these terms are used herein interchangeably and are indicated using the same reference number: inhalation line 14 or breathable NO-enriched gas mixture supplying line 14, respectively.

[0088] In some embodiments, system 100 may further include sensor 64 (also referred herein as the “first” sensor) configured to determine a concentration of NO in airway management device 72. In order to determine concentration of NO in airway management device 72, in some embodiments, sensor 64 may be operatively connected directly to the inner volume of airway management device 72, or to the inner volume of breathable NO- enriched gas mixture supplying line 14, downstream to the point of connection of breathable NO-enriched gas mixture supplying line 14 with pump 52 (as shown in Fig. 1A).

[0089] In some embodiments, system 100 may further include controller 60 in operative communication with sensor 64 and pump 52. Controller 60 may be configured to receive information about the concentration of NO, determined by sensor 64. Controller 60 may be configured to operate pump 52, based on the determined concentration of NO, so as to obtain, in airway management device 72, the breathable NO-enriched gas mixture having a preset fraction of NO.

[0090] In some embodiments, controller 60 may be further configured to receive a desired value of the preset fraction of NO. In some embodiments, system 100 may include controlling means (not shown) for setting the desired value of the preset fraction of NO, thereby providing a controlling input to the system. In some embodiments, said controlling means may be, e.g., a controlling knob or buttons for setting the desired NO value and a display configured to show the set desired value, or, alternatively, a touchscreen with Graphical User Interface (GUI) means for setting the desired NO value (e.g., virtual knob or buttons).

[0091] In some embodiments, controller 60 may be further configured to operate pump 52, so as to obtain, in airway management device 72, the breathable NO-enriched gas mixture having the preset fraction of NO according to the desired value, received from saidcontrolling means. In order to obtain the preset fraction of NO according to the desired value, controller 60 may be configured to act as a control loop (e.g., to act as a proportional- integral-derivative (PID) controller), by automatically adjusting the volume flow rate through pump 52, while using measurements received from sensor 64 as feedback.

[0092] Thus, system 100 may be configured to obtain and deliver the breathable NO- enriched gas mixture having the preset fraction of NO to the patient, thereby providing a respiratory treatment thereto.

[0093] As can be seen, the present invention offers a solution for delivering a breathable NO-enriched gas mixture to a patient and for providing a respiratory treatment thereto. The solution is characterized by an on-site generation of NO using plasma chemical conversion with further purification of the obtained initial NO-enriched gas mixture from the residual components (such as O2 and NO2) using a respectively configured filter (e.g., filter unit 40).

[0094] Regarding the accuracy of NO level adjustment and maintenance, as well as the system response time when adjusting NO concentration, it is important to consider the limitations of plasma chemical conversion technology. In practical applications, achieving the desired NO level adjustment accuracy (e.g., within ± 10 ppm) by controlling plasma chemical conversion process parameters - e.g., by controlling input gas mixture flow through the plasma reactor unit (e.g., plasma reactor unit 30) and / or varying a power supply of the plasma reactor unit electrodes (discussed in greater details with reference to Fig. IB) - is technologically challenging. Furthermore, achieving a fast response of the system to the requested adjustment of NO concentration, received as an input, solely through controlling the parameters of plasma chemical conversion process is not feasible. In such configuration, the system response can be completed (the output NO concentration in the breathable NO- enriched gas mixture may correspond to the requested adjustment - the new preset NO concentration value) only after the respective gas mixture has passed through the volume of the plasma reactor unit, the filter unit, and all communication lines. This response time is unacceptably slow, especially considering that the patient continuously breathes, and the output NO concentration which needs to be maintained at the desired level, fluctuates accordingly.

[0095] Accordingly, as indicated above, it is suggested herein to controllably admix the filtered NO-enriched gas mixture to the breathable air mixture, thereby obtaining a breathable NO-enriched gas mixture having a preset fraction of NO. In particular, it issuggested to use a pump (e.g., pump 52) or, alternatively, a valve, being in a downstream fluid communication with filter unit 40, and in an upstream fluid communication with breathable NO-enriched gas mixture supplying line 14, and having the volume flow rate through pump 52 (or valve, respectively) controlled by controller 60, based on the concentration of NO in breathable NO-enriched gas mixture supplying line 14, measured by sensor 64.

[0096] By using controllable admixing of the filtered NO-enriched gas mixture to the breathable air mixture, and, specifically, by adjusting a volume flow rate of the filtered NO- enriched gas mixture through the respective pump (e.g., instead of adjusting plasma chemical conversion procedure parameters), higher flexibility and accuracy of the resulting NO concentration control and lower system response time may be achieved. The volume flow rate through the pump may be controlled, e.g., by using a Variable Speed Control pump (e.g., using a Variable Frequency Drive (VFD)). By varying the drive speed, the pump output changes proportionally, allowing precise flow rate control with low latency.

[0097] System 100 (e.g., controller 60) may be further configured to operate pump 52 to generate a stable flow velocity through plasma reactor unit 30 and filter unit 40.

[0098] Furthermore, in the suggested configuration, the parameters of plasma chemical conversion process, as well as those related to subsequent filtration, can remain constant during system operation. Thereby, this approach simplifies overall system operation control, and, specifically, facilitates monitoring of the filtering capacity drop which now can be easily predicted due to constant NO2 and O2 concentration in the initial NO-enriched gas mixture, as well as a stable flow velocity thereof. A decline of filtering capacity may serve as an indicator that system operation should be halted for necessary maintenance, as discussed further with reference to Figs. 2A-2G.

[0099] In order to keep the parameters of plasma chemical conversion process, as well as those related to subsequent filtration constant, in some embodiments, system 100 may further include pump 51 , being in a downstream fluid communication with filter unit 40 and in an upstream fluid communication with pump 52. System 100 may further include flow compensation exhaust line 12, connected to the fluid communication line between pump 51 and pump 52. Thereby, constant volume flow rate of filtered NO-enriched gas mixture downstream to pump 51 may be obtained, while the desired portion thereof may be taken by pump 52, according to the desired concentration of NO in the breathable NO-enriched gasmixture. As the volume flow rate through pump 52 may be lower than the volume flow rate through pump 51, the difference in volume flow rates between pumps 51 and 52 (and the excessive pressure upstream pump 52, obtained in result thereof) may be compensated via exhaust line 12.

[0100] Depending on particular embodiments, exhaust line 12 may be configured to outtake redundant filtered NO-enriched gas mixture from system 100. In some embodiments, the redundant filtered NO-enriched gas mixture may be exhausted into a building ventilation outtake line.

[0101] In some alternative embodiments, system 100 may include or be connectable to a gas tank refilling unit (not shown in Figures). The gas tank refilling unit may be configured to receive the redundant filtered NO-enriched gas mixture. The gas tank refilling unit may include, e.g., a cooler and a high-pressure compressor positioned inline after filter unit 40. The compressor may be configured to compress the redundant filtered NO-enriched gas mixture and the cooler may be configured to decrease the temperature thereof. The gas tank refilling unit may further include means for filling gas tanks with the compressed filtered NO-enriched gas mixture for further usage.

[0102] In yet another alternative embodiment, system 100 may include or be connectable to a plurality of breathable air supplying units 71 and airway management devices 72, connected via a respective plurality of breathable NO-enriched gas mixture supplying lines 14. System 100 may further include a respective plurality of pumps 52 and sensors 64, each connected to a respective line 14, wherein each pump 52 may be operatable by controller 60 to maintain the desired NO concentration in the respective line 14, based on measurements received from respective sensor 64. In such an embodiment, system 100 may have less or even no redundant filtered NO-enriched gas mixture to be exhausted, as the entire volume of the generated filtered NO-enriched gas mixture may be efficiently distributed between the plurality of breathable NO-enriched gas mixture supplying lines 14 and delivered to a respective plurality of patients.

[0103] Due to technological limitations of pumps and plasma reactor units, the abovedescribed configuration of system 100 may effectively provide the output concentration of NO (the concentration of NO in the breathable NO-enriched gas mixture) within a range of about 100 ppm and about 1000 ppm. However, having the lower limit of about 100 ppmmay not be suitable for certain medical applications. E.g., when providing respiratory treatment to newborns, the sufficient range would be from about 10 ppm to about 100 ppm.

[0104] In order to provide a wide range of desired concentrations, while having the desired accuracy of the resulting NO concentration control, as well as a low system response time, the following is suggested.

[0105] In some embodiments, system 100 may further include valve 53 (or, alternatively, a pump, also referred herein as “second” pump or valve) being in a downstream fluid communication with the input gas mixture supply unit (e.g., nitrogen generator 20) and in an upstream fluid communication with a fluid communication line between filter unit 40 and pump 52, thereby forming dilution line 13. Controller 60 may be in operative communication with said valve 53 and is further configured to operate, based on the determined concentration of NO, said at least one second pump or valve, so as to obtain, in airway management device 72 (or, accordingly, in breathable NO-enriched gas mixture supplying line 14), the breathable NO-enriched gas mixture having the preset fraction of NO.

[0106] In some embodiments, controller 60 may be further configured to operate valve 53 (e.g., in combination with the control of pump 52 operation), so as to obtain, in airway management device 72, the breathable NO-enriched gas mixture having the preset fraction of NO according to the desired value (obtained via controlling means, as described above).

[0107] In some particular embodiments, controller 60 may be further configured to determine whether the desired value pertains to a lower predetermined range of NO concentration. In some embodiments, the lower predetermined range may be between about 10 ppm and about 100 ppm. Controller 60 may be further configured to operate valve 53 to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to the lower predetermined range.

[0108] In some embodiments, controller 60 may be further configured to determine whether the desired value pertains to a higher predetermined range of NO concentration. In some embodiments, the higher predetermined range may be between about 100 ppm and about 1000 ppm. Controller 60 may be further configured to operate valve 53 to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to the higher predetermined range.

[0109] Thereby, the suggested solution may provide the breathable NO-enriched gas mixture having wide range of desired NO concentrations, rendering the solution suitable for various medical applications, specifically, for providing respiratory treatment both to newborns and to adults. Furthermore, in the suggested configuration, system 100 maintains both high accuracy of the NO concentration adjustment and control and low system response time across the entire supported NO concentration range.

[0110] It shall be appreciated that, depending on the particular embodiment, valve 53 may be configured to have (i) two discrete states (e.g., open / close); (ii) more than two discrete states; or (iii) continuously adjusted state between “open” and “close” states. When having more than two discrete states, the entire supported NO concentration range may be virtually divided into the respective number of sub-ranges, and controller 60 may be further configured to operate valve 53 to take a state, corresponding to the sub-range to which the inputted desired NO concentration value pertains. In embodiments, where valve 53 may be continuously adjusted, upon receiving a new input - a new desired concentration - controller 60 may be configured to operate valve 53 to achieve a state that allows the new desired concentration to be maintained while pump 52 operates within its normal capacity, if possible. However, if the new desired concentration is either too high or low to be sustained using the aforementioned regime, controller 60 may be configured to further operate pump 52 to increase or decrease its capacity (volume flow rate therethrough) accordingly.

[0111] It shall be appreciated by the person skilled in the art, that in some embodiments, a controllable valve may be used instead of pump 52 to control a desired volume flow rate therethrough. It shall further be appreciated that a pump may be used instead of valve 53 to control a desired volume flow rate therethrough.

[0112] In some embodiments, system 100 may be configured to generate a volume flow rate of the filtered NO-enriched gas mixture (e.g., the volume flow rate generated by pump 51) between about 50 liter / hour and about 100 liter / hour.

[0113] In some embodiments, system 100 may be configured to operate pump 52 to adjust the volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

[0114] In some embodiments, system 100 may be further configured to increase or decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture in a range between about 0 liter / hour and about 500liter / hour (e.g., by operating valve 53). In order to enable the adjustment in such a range, in some embodiments, system 100 may include additional pump positioned downstream to nitrogen generator 20, e.g., in dilution line 13, and configured to generate a volume flow rate therethrough up to about 500 liter / hour.

[0115] Referring now to Fig. IB, aspects of plasma reactor unit 30 are further discussed in greater detail.

[0116] In some embodiments, plasma reactor unit 30 may include reaction chamber 31 having an inlet channel and an outlet channel; variable power supply 32 in operative connection with a plurality of electrodes 31’ installed within reaction chamber 31 and configured to create an electric discharge thereacross upon application of a voltage by power supply 32. Plasma reactor unit 30 may be further configured to generate a gas flow of the input gas mixture through reaction chamber 31 via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes 31’, while generating, by variable power supply 32, the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture. In some embodiments, plasma reactor unit 30 may have an input blower and / or an input control valve (not shown in figures) in order to generate and control a gas flow of the input gas mixture.

[0117] In some embodiments, plasma reactor unit 30 may further include circulation blower 34 in fluid communication with said inlet and outlet channels of reaction chamber 31, thereby forming together with reaction chamber 31 circulating contour 34’. Plasma reactor unit 31 may be further configured to produce the NO-enriched gas mixture further by transferring at least a portion of the first gas mixture through circulating contour 34’. Circulating contour 34’ may further include cooler 33, positioned upstream to blower 34 and configured to decrease the temperature of the initial NO-enriched gas mixture (e.g., below 45 °C), since after plasma chemical conversion the temperature of the NO-enriched gas mixture is too high (e.g., above 200°C) for being recycled to reaction chamber 31 for additional conversion.

[0118] It should be understood that the present invention is not limited to any specific configuration of plasma reactor unit 30, hence, any configuration of plasma reactor unit 30 known in the art may be applied herein, provided that the initial NO-enriched gas mixture generated thereby have the desired abovementioned content.

[0119] After the input gas mixture undergoes the plasma chemical conversion, the subsequent filtration must be performed in order to decrease the content of the residual components.

[0120] Existing methods for selective NO2 removal are based on the use of chemical reagents such as ascorbic acid carried and supported by, e.g., zeolite or silica gel. However, these methods are not applicable for the abovementioned purpose, as they are not selective enough to remove NO2 with insignificant or no effect on NO, and they furthermore do not provide for an efficient removal of O2.

[0121] Hence, the absence of the required solution in the art has motivated the development of a filter assembly (or unit) and method of filtering using the developed filter unit (e.g., filter unit 40), which would provide an improvement of the relevant technological field by increasing efficiency of reducing oxygen and / or gaseous oxide-containing components from product mixtures. In particular, there is a need for a filter unit and method of filtering using the developed filter unit, which would provide an improvement of the relevant technological field by increasing selectivity of reducing NO2 and / or O2 from the initial NO-enriched gas mixture with insignificant or no effect on NO content therein.

[0122] Filter unit 40 is further discussed in detail with reference to Figs. 1C and ID, which are block diagrams, depicting filter unit 40, according to some embodiments of the present invention; and further with reference to Figs. 2A-2G, which are various views of a model of filter unit 40 and its components, according to some embodiments of the present invention.

[0123] In some embodiments, shown in Figs. 1C and 2A, filter unit 40 may include filter unit housing 421 which defines inner cavity 421 A therein; a pair of inlet and outlet channels 422A and 422B coupled to filter unit housing 421 and being in fluid communication with each other via inner cavity 421 A. Filter unit 40 may further include cartridge 423 disposed within inner cavity 421 A. Cartridge 423 may include a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide, respectively. Filter unit 40 may further include heating element 43.

[0124] Filter unit 40 (e.g., by using controller 60) may be further configured to: heat cartridge 423 up to an operational temperature by operating heating element 43 (e.g., using a power source connected to electrodes 43 A and 43B, said power source being in operative connection with controller 60); and operate at least one pump being in fluid communicationwith channels 422A and 422B (e.g., pump 51) to transfer the initial NO-enriched gas mixture via the inlet and outlet channels through heated cartridge 423.

[0125] In some embodiments, filter unit housing 421 may be thermally insulated (e.g., comprise thermal insulation layer 421B, e.g., a layer of polymer, foam, fiberglass material and / or combinations thereof), and heating element 43 may be positioned in inner cavity 421 A, e.g., circumferentially covering its inner surface (as shown in Fig. 2A).

[0126] Referring now to Figs. ID and 2B-2G, some alternative embodiments of filter unit 40 are shown. These embodiments represent filtering unit 40 having higher filtering capacity than filter unit of Figs. 1C and 2A and it may be used, e.g., for a plurality of systems 100 simultaneously.

[0127] In these alternative embodiments, filter unit 40 may include at least two filtering modules arranged successively. More specifically, filter unit 40 may include a plurality of first-stage filtering modules 42 (e.g., six first-stage filtering modules 42) in parallel connection with each other, and second-stage filtering module 42’ in successive connection with first-stage filtering modules 42, as shown in Figs. ID and 2B-2G. Each of filtering modules 42 may include: filtering module housing 421’ which defines inner cavity 421A’ therein; a pair of inlet and outlet channels 422A’ , 422B ’ coupled to filtering module housing 421’ and configured so as to enable the initial NO-enriched gas mixture flow through inner cavity 421A’; and cartridge 423 disposed within inner cavity 421A’, said cartridge 423 comprising a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide. Filter unit 40 may further include heating elements 43’ configured to heat cartridges 423 of first-stage filtering modules 42 up to an operational temperature.

[0128] Second-stage filtering module 42’ may have the same configuration as filter unit 40 shown in Fig. 2A. Specifically, second-stage filtering module 42’ may include: filtering module housing 421, which defines inner cavity 421A therein; a pair of inlet and outlet channels 422A, 422B, coupled to filtering module housing 421 and configured so as to enable the initial NO-enriched gas mixture flow through inner cavity 421 A, after passing first-stage filtering modules 42; and cartridge 423 disposed within inner cavity 421A, said cartridge 423 comprising a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide.Filter unit 40 may further include heating element 43 configured to heat cartridge 423 of second-stage filtering module 42’ up to an operational temperature.

[0129] As can be seen, filtering modules 42 and 42’ may have different configurations in respect of position of heating elements 43 and 43’, respectively.

[0130] E.g., in some embodiments, filter unit 40 may include external housing 44 having a thermally insulated inner space therein. Each of first-stage filtering modules 42 may have thermally conductive filtering module housing 421’ . In such embodiments, filtering modules 42 and heating elements 43’ may be disposed within the thermally insulated inner space (e.g., having a layer of polymer, foam, fiberglass material and / or combinations thereof), thereby enabling the proper heating of all cartridges 423.

[0131] Second-stage filtering module 42’, in turn, may have the same configuration, as shown in Fig. 1C and 2A. E.g., second-stage filtering module 42’ may not have additional external housing. Instead, housing 421 of filtering module 42’ may be thermally insulated (e.g., comprise thermal insulation layer 42 IB), and heating element 43 may be positioned in the inner cavity 421A, e.g., circumferentially covering its inner surface (as shown in Fig. 2A).

[0132] It shall be understood that the provided embodiments of arrangement heating elements 43 and 43’ with respect to filtering module 42’ and 42, respectively, represent a non-exclusive example of such arrangements. Hence, the present invention is not limited in this regard. Furthermore, in some embodiments of the present invention, other known heating methods may be used herein (e.g., including usage of induction heating), hence, such embodiments should also be considered covered by the scope of the present invention.

[0133] In some embodiments, filter unit 40 may further include preheating module 41 arranged inline prior to first- stage filtering modules 42 and configured to preheat the initial NO-enriched gas mixture prior to transferring the initial NO-enriched gas mixture through filtering modules 42. Preheating module 41 may include pipeline 411 covered by thermally insulated housing and having plurality of heating elements 412, configured to heat pipeline 411.

[0134] In some embodiments, the operational temperature for cartridges 423 and 423 ’ is selected from the range of about 400-850 °C.

[0135] It shall be understood that filter unit 40 may comprise a power source (not shown) in operative connection with heating elements 412, 43 and 43’ and with controller 60, andcontroller 60 may be configured to operate voltage and / or current of the power source to change the temperature of respective heating elements 412, 43 and 43’, thereby controlling the operational temperature of respective cartridges. It shall be understood that any appropriate types of heating elements that are known in the art may be used as heating elements 412, 43 and 43’ herein, and the present invention shall not be considered limited in this regard.

[0136] In some embodiments, the metal catalyst of the filtering material of cartridges 423 and 423’ may include elemental copper or copper alloy.

[0137] In some additional or alternative embodiments, the metal catalyst of the filtering material may include silver, silver alloys, iron and iron alloys subjective to oxidation.

[0138] In some embodiments, the filtering material of cartridges 423 and 423’ may include one or more of granules, wires, rods, particles, mesh, fabric, and combinations thereof.

[0139] In some embodiments, housings 421 and 421’ (as shown in Figs. 2A and 2B) may have substantially cylindrical shape, and the filtering material may be a mesh fabric. The mesh fabric may be formed in a roll uniformly filling inner cavity 421 A or 421 A’ of the filtering module housing 421 or 421’, respectively.

[0140] In some embodiments, filter unit 40 may have configuration, as indicated in Figs. 2C-2G, which is provided for clarification purposes only and shall not be considered an exclusive example of configuration. In such configuration, preheating module 41, six first- stage filtering modules 42 and second-stage filtering module 42’ are compactly arranged on the stand (not numbered). First- stage filtering modules 42 are arranged circumferentially, with six heating elements 43’ respectively positioned between adjacent filtering modules 42 and extending along their full length. Preheating module 41 is positioned in the center of the circumferential arrangement of filtering modules 42 and extends in the same direction as modules 42. The entire arrangement of preheating module 41, filtering modules 42, and heating elements 43’ is disposed inside the thermally insulated inner space of external housing 44. Second-stage filtering module 42’, in turn, is positioned under the external housing 44, and extends in the same direction.

[0141] Filter module 40 may be arranged so as to receive the initial NO-enriched gas mixture via an inlet of pipeline 411. Pipeline 411 enters the housing of the preheating module 41 from one side, goes through the housing where it is heated by heating elements 412, andexits preheating module 41 from the other side. Further in the flow direction, pipeline 411 may be connected with six inlet channels 422A’ of respective first-stage filtering modules 42, to direct the gas flow through respective inner cavities 421 A’. Outlet channels 422B’, in turn, may be connected via a pipeline with inlet channel 422A of second stage filtering module 42’, thereby directing the gas flow through inner cavity 421A thereof. Lastly, the filtered NO-enriched gas mixture may be output via outlet channel 422B, after passing through inner cavity 421A of second-stage filtering module 42’.

[0142] The suggested embodiments of filter unit 40 provide for increasing efficiency of reducing oxygen and / or gaseous oxide-containing components from the gas mixture, in particular for high selectivity of reducing NO2 and / or O2 from the initial NO-enriched gas mixture with insignificant or no effect on NO content therein, by using reactions of metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide (e.g., metal catalyst can be made of or including elemental copper or copper alloy) with NO2 and / or O2 at high operational temperatures (e.g., about 400-850 °C).

[0143] E.g., hot cartridge 423 or 423’ may remove O2 and NO2 from the initial NO- enriched gas mixture, consisting of NO, NO2, O2 and N2 by inducing the following chemical reactions:Cu + 1 / 2 O2= CuOCu + NO2= NO + CuO

[0144] The following side-reaction that may also take place, has higher activation energy than reactions above and thus, under the instant operation conditions disclosed herein, is practically negligible:NO + Cu = N + CuO.

[0145] It should be noted that, in order to achieve high efficiency of filtering, yet another aspect is important. During active operation of filter unit 40, surface of filtering material of cartridge 423 and 423’ is getting covered with a solid layer (or even several layers) of CuO, hindering gas diffusion to metal surface, thereby affecting the further conduction of the required chemical reaction. Consequently, with progressive exhaustion of filtering capacity of cartridge 423 and / or 423’ (cartridge degradation), the concentration of undesired components (e.g., O2 and NO2) in the filtered NO-enriched gas mixture starts increasing. This process is unacceptable as it can make the obtained mixture unacceptable for further medical usage.

[0146] As was empirically determined by the inventors, cartridge degradation can be compensated by increasing the operational temperature of preheating module 41 and / or cartridges 423 and 423 ’ .

[0147] To estimate how filtering capacity of cartridge 423 and 423’ is affected by different oxide layer thickness, semi-empirical estimation of oxygen concentration in gas mixture flowing through the cartridge in the presence of copper oxide layer of predefined thickness thereon has been done with respect to the cartridge length. Results of the semi- empirical estimation of oxygen concentration along cartridge length for different operational temperatures and different copper oxide layer thicknesses have demonstrated that thickness of copper oxide layer dramatically affects the reaction rate, as the gas diffusion has to be performed through the oxide layer. It has been determined empirically that this effect can be compensated by increasing operational temperature. For example, the effect of 10 pm oxide layer thickness at 650 °C almost equivalent to 0 pm (new cartridge) at 550 °C.

[0148] Although system 100 or separate components thereof may be operated manually, in order to mitigate the negative effect of cartridge degradation more efficiently, as well as to increase the efficiency of the filtered NO-enriched mixture production process overall, the automatic monitoring and control may be further adapted for these purposes, e.g., in a way described in detail further below.

[0149] In some embodiments, system 100 may further include sensor 61 in operative communication with nitrogen generator 20 or a fluid communication line between first nitrogen generator 20 and plasma reactor unit 30, and configured to determine a concentration of at least one of O2 and N2 in the input gas mixture.

[0150] In some embodiments, system 100 may further include sensor 62 in operative communication with plasma reactor unit 30 or a fluid communication line between plasma reactor unit 30 and filter unit 40, and configured to determine a concentration of at least one of NO, NO2, O2 and N2 in the initial NO-enriched gas mixture.

[0151] In some embodiments, system 100 may further include sensor 63 in operative communication with filter unit 40 or a fluid communication line between filter unit 40 and pump 51, and configured to determine a concentration of at least one of NO, NO2, O2 and N2 in the filtered NO-enriched gas mixture.

[0152] In some embodiments, system 100 may further include sensor 65 in the operative communication with filter unit 40.

[0153] In particular, in some embodiments, such as shown in Fig. 1C and 2A, sensor 65 may be operatively connected with inner cavity 421A, e.g., at a point along the length of cavity 421A, close to outlet channel 422B. Sensor 65 may be configured to determine a concentration of O2 and / or NO2 in a gas mixture obtained after transferring the initial NO- enriched gas mixture through at least a portion of cartridge 423.

[0154] In some alternative embodiments, such as shown in Fig. ID and 2B-2G, sensor 65 may be in operative communication with fluid communication line between first-stage filtering modules 42 and second-stage filtering module 42’, and configured to determine a concentration of O2 and / or NO2 in a gas mixture obtained after transferring the initial NO- enriched gas mixture through first- stage filtering module 42.

[0155] It should be appreciated that sensors 61-65 may be or may include any known types of sensors, configured to measure concentration of the above-indicated components in gas mixtures, e.g., electrochemical gas sensors. In some embodiments, at least one of sensors 61-65 may be or may include a system or device according to patent applications WO 2022 / 123580 Al (“Nitric oxide measurement”) and / or WO 2022 / 123574 Al (“System and method for measuring component concentration”) which are incorporated herein by reference in their entirety. The present invention should not be considered limited in regard to the types of sensors used.

[0156] In some embodiments, controller 60 may further be in operative communication with nitrogen generator 20, plasma reactor unit 30, filter unit 40, and with sensors 61-63 and 65. Controller 60 may be configured to control the operation of nitrogen generator 20, plasma reactor unit 30, and filter unit 40 based on an input from respective sensors 61-63 and 65.

[0157] In some embodiments, controller 60 may be, for example, a central processing unit (CPU) processor, a chip or any suitable computing or computational device. Controller 60 (or, alternatively, one or more controllers or processors, possibly across multiple units or devices) may be configured to request, receive, analyze, calculate and produce various types of data and signals, as well as execute various portions of instruction code, in order to carry out respective steps of methods described herein.

[0158] In particular, in some embodiments, sensor 62 may be configured to determine a concentration of NO in the initial NO-enriched gas mixture; and controller 60 may be further configured to operate variable power supply 32 to change the voltage applied across theplurality of electrodes 31’ so as to keep the concentration of NO in the initial NO-enriched gas mixture between about 800 and about 1000 ppm, based on the input from sensor 62 (the concentration measured thereby), e.g., to increase the voltage when the concentration is lower than 800 ppm and to decrease the voltage when the concentration is higher than 1000 ppm. In some additional or alternative embodiments, controller 60 may be further configured to operate blower 34 to change the flow of the initial NO-enriched gas mixture in circulating contour 34’, based on the input from sensor 62, e.g., to decrease the flow when the concentration is lower than 800 ppm and to increase the flow when the concentration is higher than 1000 ppm.

[0159] In some embodiments, sensor 63 may be configured to determine a concentration of O2 and / or NO2 in the product NO-enriched gas mixture; and controller 60 may be further configured to operate at least one of: (i) heating element 43, (ii) heating elements 43’, and (iii) preheating module 41 (heating elements 412) to increase the operational temperature when the determined concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.

[0160] In some embodiments, controller 60 may be configured to operate at least one of: (i) heating elements 43, (ii) heating element 43’, and (iii) preheating module 41 (heating elements 412) further based on the input from sensor 65.

[0161] E.g., in the embodiment shown in Fig. 1C, controller 60 may be configured to increase the operational temperature of heating element 43 when the determined concentration of O2 and / or NO2 (e.g., obtained from sensor 65), respectively, exceeds a predefined concentration threshold, in order to decrease the concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture.

[0162] In the alternative embodiment shown in Fig. ID, controller 60 may be configured to increase the operational temperature of heating elements 43’ and / or heating elements 412 when the determined concentration of O2 and / or NO2 (e.g., obtained from sensor 65), respectively, exceeds a predefined concentration threshold, in order to decrease the concentration of O2 and / or NO2 in the gas mixture obtained after passing the NO-enriched gas mixture through first-stage filtering module 42. Additionally or alternatively, controller 60 may be further configured to increase the operational temperature of heating element 43, when the determined concentration of O2 and / or NO2 (e.g., obtained from sensor 65) exceeds a predefined concentration threshold, in order to assure that the increased residualcomponents content in the gas mixture obtained after transferring the initial NO-enriched gas mixture through first-stage filtering module 42 will be sufficiently reduced by second- stage filtering module 42’, thereby providing for the desired purity of the filtered NO- enriched gas mixture.

[0163] In some embodiments, the predefined concentration threshold may be 5 ppm for O2 and 0.1 ppm for NO2, which corresponds to the requirements for medical applications.

[0164] Controller 60 and respective heating elements may be configured to increase the operational temperature, e.g., within a range of 400-850 °C.

[0165] Filter unit 40 in the described configuration provides for reliable control of the filter unit operation, thereby assuring the desired selectiveness of filtering and thus further contributing to the improvement of the indicated technological field. By being configured to adjust the operational temperature as described above, controller 60 keeps the concentration of the residual components in the filtered NO-enriched gas mixture below the predefined concentration thresholds, corresponding to the requirements to the filtered NO-enriched mixture.

[0166] The two-stage filtering configuration described above (having the plurality of first-stage filtering modules 42, connected in a parallel manner, and second-stage filtering module 42’, connected in a successive manner, as well as having sensors 63 and 65 connected as indicated above, and controller 60 in operative connection with heating elements 43, 43’ and 412 and with sensors 63 and 65), provides for yet another additional contribution to the improvement of the indicated technological field. In the indicated configuration, the major filtering capacity accounts for first-stage filtering modules 42. Second-stage filtering module 42’, in turn, is used as an auxiliary, reserve means to further assure that no residual components will get into the filtered NO-enriched gas mixture, e.g., when filtering capacity of first-stage filtering modules 42 is getting exhausted.

[0167] In some further embodiments, system 100 (e.g., by means of controller 60) may be further configured to provide a warning indication (e.g., via a visual and / or audio interface) when at least one of the following conditions is met: (a) the operational temperature has reached a predefined temperature limit (e.g., 850 °C), meaning that there is no further ability to compensate cartridge degradation by increasing the operational temperature; (b) a rate of change of the determined concentration of O2 and / or NO2 with respect to an increase of the operational temperature gets below a predefined rate-of-changethreshold, meaning that further increase of the operational temperature does not provide a desired effect on its filtering capacity. Such a warning indication may signal that cartridge capacity has exhausted and that cartridge 423 or 423 ’ , respectively, must be replaced or must undergo regeneration in order to be further used for filtering the initial NO-enriched gas mixture.

[0168] In some embodiments, said filtering capacity and the exhaustion thereof can be calculated from simple stoichiometric calculations based on known computational methods and further based on respective sensor readings, and used for providing warnings, as well as for setting the operational temperature.

[0169] It should be understood that, in order to obtain all the potential capacity of filtering modules having a parallel connection (e.g., as first-stage filtering modules 42), it is critically important to provide a gas flow uniformly distributed between the filtering modules. Otherwise, some filters may have their filtering capacity exhausted earlier than others, leading to the increase of residual components content in the filtered gas mixture (e.g., product NO-enriched gas mixture). This, in turn, may require halting the filtering process to replace / regenerate the degenerated cartridge(s) more frequently and, accordingly, the filtering process and the process of NO-enriched gas mixture production will have lower productivity. As a result, the respiratory treatment process will have to be interrupted more frequently.

[0170] According to some embodiments, cartridges 423 and 423’ may be regenerated upon degradation, in order to restore their filtering capacity. In some embodiments, for cartridge regeneration, a reducing gas, such as methane (CH4) may be used to induce the following chemical reaction:4 CuO + CH4= 4 Cu + CO2+ 2 H2O.

[0171] Alternatively, any reducing gas configured to catalyze reduction of CuO to Cu may be implemented instead of methane.

[0172] Accordingly, in some embodiments, CH4 may be supplied to filter unit 40, e.g., via inlet channels 422A or 422A’, respectively. To induce the chemical reaction, the operational temperature of cartridges 423 or 423’, respectively, may be maintained around approximately 600 °C. It should be understood that, during the regeneration procedure, the flow of initial NO-enriched gas mixture to filter unit 40 should be stopped.

[0173] The output mixture obtained after regeneration may be further removed, e.g., via outlet channels 422B or 422B’, respectively.

[0174] It shall be understood that, for the purpose of clarity, only key components of system 100 are described herein, therefore, the described content of system 100 shall not be considered exhaustive.

[0175] It should be recognized by the person skilled in the art that system 100 may include other components, such as, e.g.: additional pumps, blowers and / or valves (e.g., pump connected upstream to nitrogen generator 20 and / or pump connected upstream to filter unit 40); compressing units; coolers and / or heaters; tanks additional exhaustion and flow compensation output lines; additional sensors (such as, e.g., pressure sensors, temperature sensors, flow sensors) and / or controllers; back-up components, etc. Such additional components may be connected to other components of system 100 and / or communication lines therebetween and be applied as commonly known in the art. For example, in some embodiments system 100 may comprise a plurality of additional controllable pumps (blowers) in operative communication with controller 60; and controller 60 may be further configured to operate at least one of (or a respective) pumps to generate the gas mixture flow through the entire system 100 and / or through specific components thereof of the desired velocity, so as to obtain a desired concentration of said at least one component in the breathable NO-enriched gas mixture. E.g., air intake 10 may be fluidly coupled or comprise one or more pumps configured to create negative pressure in air intake 10 to enable air flow thereto. According to some embodiments, air intake 10 is fluidly coupled to at least one air input pump (not shown), configured to pump air into the system 100. According to some embodiments, system 100 is configured to control the flow rate of air thereinto, optionally via the activation of said air input pump by controller 60.

[0176] It should be further appreciated by the person skilled in the art that such additional elements may be omitted herein for the purpose of clarity, in order to facilitate understanding of essential aspects of the present invention.

[0177] According to some embodiments, the various units or components of system 100 may be in fluid communication with each other via lines such as tubes, pipes, conduits, ducts, or any other known communication appliances in the art.

[0178] Referring now to Fig. 3A, aspects of the input gas mixture content and their effect on the overall process efficiency are further discussed in greater detail.

[0179] Fig. 3A is a graph depicting function from a fraction of O2 in an input gas mixture subjected to plasma chemical conversion to a fraction of NO and NO2 in the respective output mixture (e.g., the initial NO-enriched gas mixture), according to some embodiments of the present invention.

[0180] It was empirically determined by the inventor that, using the plasma chemical conversion method, generation of NO gas from the input gas mixture comprising N2 and O2, depends on the fraction of O2 in the input mixture differently than the generation of NO2. In particular, the most tangible difference can be seen when the volume ratio between N2 and O2 is kept between 49:1 and 9:1, respectively (e.g., when the input gas mixture comprises between about 90 and about 98% of N2; and between about 2 and about 10% of O2, more preferably, between about 4 and about 7% of O2), as shown in the graph of Fig. 3 A.

[0181] Since the essential aspect of NO-enriched gas mixture production efficiency is to maximize the production of the target gas - NO, while minimizing the production of any residual component, such as NO2, by providing the input mixture having O2 and N2 content in the above-indicated range, process of production NO-enriched gas mixture may be significantly improved. The effect of such an improvement is further accentuated by the significant facilitation of the subsequent stages of producing the filtered NO-enriched gas mixture appliable for medical applications. In particular, this facilitation applies, among other things, to the filtering stage, where all the residual components (such as NO2) must be selectively removed from the mixture, i.e., with a minimal effect on the concentration of the desired components therein (such as NO and N2), which is considered a technologically challenging task.

[0182] The achieved effect may be premised by the following aspects of the NO and NO2 formation mechanisms. To generate NO, it is first needed to obtain single atoms of N by dissociation of N2. Dissociation of nitrogen requires comparatively high energy application (about 10 eV), hence, in practice, the obtained concentration of N atoms is quite low. To perform N + O reaction effectively, comparatively small oxygen concentration is needed, as the competitive N + N reaction is slower due to low N atom concentration. As a result, experiments demonstrate significantly higher efficiency of NO generation when O2 concentration in the input gas mixture is up to approximately 4%.

[0183] NO2 formation mechanism is different from the mechanism of NO formation. NO2 is generated by oxidation of NO, hence, NO2 concentration is influenced by O2concentration in the input mixture starting from the very low values thereof in a much more consistent manner. Therefore, as can be seen, concentration of oxygen between 2-10% is optimal, as NO generation is still highly effective, while NO2 generation is not that effective yet.

[0184] Accordingly, in some embodiments, the input gas mixture supply unit (e.g., nitrogen generator 20) is configured to produce an input gas mixture having a volume ratio between N2 and O2 between 49:1 and 9:1. In some embodiments, the input gas mixture supply unit (e.g., nitrogen generator 20) may be configured to provide the input gas mixture comprising between about 90 and about 98% of N2; and between about 2 and about 10% of O2. In some further embodiments, the input gas mixture supply unit (e.g., nitrogen generator 20) may be configured to provide the input gas mixture comprising between about 94 and about 96% of N2; and between about 4 and about 6% of O2.

[0185] Accordingly, by receiving as an input the first gas mixture, comprising the abovementioned fraction of N2 and O2, plasma reactor unit 30 may operate in the improved and more efficient manner, thereby producing the NO-enriched gas mixture with the highest achievable difference in content of the desired components (e.g., NO) and residual components (e.g., NO2), as discussed with reference to Fig. 3A above. Therefore, the induction of undesired chemical reactions may be effectively mitigated while stimulating induction of the desired ones.

[0186] Accordingly, in some embodiments, plasma reactor unit 30 may generate initial NO-enriched gas mixture, which may include between about 800 and about 5000 ppm of NO (theoretical maximum of NO-concentration obtained by the claimed method may be around 30000 ppm (3%)). In some embodiments, a flow rate of a gas mixture transferred through plasma reactor unit 30 may be between about 50 and about 100 liter / hour.

[0187] In some embodiments, plasma reactor unit 30 may be configured to generate the initial NO-enriched gas mixture further including between about 100 and about 500 ppm of NO2, about 89.95% of N2 or more, and between about 0.45 and about 9.95% of O2.

[0188] In some embodiments, filter unit 40 may be further configured to filter the initial NO-enriched gas mixture having the abovementioned content so as to output filtered NO- enriched gas mixture including about 98% N2 or more and between about 500 and about 2000 ppm of NO.

[0189] Referring now to Figs. 3B-3F, the operation of system 100 is further exemplified and explained using a series of graphs.

[0190] Fig. 3B depicts an example of a flow rate in exhalation line 15, according to some embodiments of the present invention.

[0191] Fig. 3C depicts an example of a flow rate in the breathable NO-enriched gas mixture supplying line 14 (inhalation line 14), according to some embodiments of the present invention.

[0192] Fig. 3D depicts an example of a resulting flow rate in airway management device 72, according to some embodiments of the present invention.

[0193] In some embodiments, system 100 may include additional flow sensors configured to measure at least one of the abovementioned flow rates of Figs. 3B-3D. The measured flow rates may be used, by controller 60, for calculation and correction of the flow rate through pump 52 and / or through valve 53, in order to maintain the desired NO concentration in the breathable NO-enriched gas mixture. The low latency of system 100 (which has become available due to the abovementioned configuration) allows timely flow rate corrections, ensuring efficient compensation and mitigation of NO-concentration fluctuations.

[0194] Fig. 3E demonstrates an example of a graph of a NO concentration fluctuation in breathable NO-enriched gas mixture supplying line 14. In this example, the flow rate generated by pump 52 may be about 40 liter / hour, concentration of NO upstream to pump 52 (e.g., measured by sensor 63) may be about 500 ppm, volume of inhalation line 14 may be about 300 ml.

[0195] Fig. 3F demonstrates another example of a graph of a NO concentration fluctuation in breathable NO-enriched gas mixture supplying line 14. In this example, the flow rate generated by pump 52 may be about 40 liter / hour, concentration of NO upstream to pump 52 (e.g., measured by sensor 63) may be about 500 ppm, volume of inhalation line 14 may be about 600 ml.

[0196] As can be seen in Figs. 3E and 3F, inhalation line 14 acts as a buffer volume for the breathable NO-enriched gas mixture. At exhalation stage, the NO concentration increases linearly and, at inhalation stage, drops because of the airflow to the lungs. As can be seen, the process stabilizes within 10-15 seconds after system operation begins.

[0197] It is essential to recognize the significance of minimizing both NO2 and O2 concentrations at the stages preceding the admixture of the filtered NO-enriched gas mixture to the breathable air mixture. As previously mentioned, NO can readily react with O2, thus forming toxic and carcinogenic NO2. It should be noted that volume flow rates at the aforementioned stages are relatively low (e.g., between about 50 and about 100 liter / hour through plasma reactor unit 30; between about 0.1 and about 30 liter / hour through pump 52 etc.). Consequently, the gas mixture passing through lines at these stages remains within system 100 for an extended duration, during which undesirable side reactions may continue to occur. Accordingly, an excessive amount of O2 at these stages can lead to an impermissible increase in NO2 concentration in the resulting mixture (or, as referred herein, a breathable NO-enriched gas mixture). Moreover, as the concentration of NO in the resulting mixture is adjusted by controllably admixing the filtered NO-enriched gas mixture to the breathable air mixture (e.g., by controlling a volume flow rate through pump 52), the decrease of the NO / NO2 concentration ratio before the admixing lowers the upper limit of the NO concentration that can be delivered to the patient without exceeding the maximum permissible concentration for NO2. Given that the maximum permissible NO2 concentration in inhalable gas is very low (e.g., approx. 1 ppm), the imposed limitation may be significant, if not critical.

[0198] It shall further be understood that the volume flow rate in breathable NO-enriched gas mixture supplying line 14 is significantly higher than at the upstream stages (e.g., between approx. 300 and 1000 liter / hour). Accordingly, the O2 content in the breathable air mixture supplied by breathable air supply unit 71 (via line 14) does not have significant effect on the NO2 concentration in the resulting mixture, as there is limited time for side reactions before the resulting mixture is delivered to the patient.

[0199] As can be seen from the present description, the suggested configuration of system 100 provides for an effective reduction of NO2 and O2 concentrations at respective stages of breathable NO-enriched gas mixture production, in particular, by using an input gas mixture having a certain N2 / O2 concentration ratio, as well as by using a filter unit (e.g., filter unit 40) of a specific configuration, as described in detail herein. Thereby, the present invention contributes to the improvement of the relevant technological field by increasing the range of NO concentration adjustment.

[0200] In some embodiments, the following operation parameters of system 100 may be used (provided herein as a non-limiting example). NO concentration if measured in airway management device 72 before inhalation: < 100 ppm. NO2 concentration if measured in airway management device 72 before inhalation (including NO2 obtained by oxidation of NO after the filtered NO-enriched gas mixture is admixed to the breathable air mixture): < 1 ppm (according to the maximum permissible NO2 concentration in the inhalable gas mixture). The volume flow rate through breathable NO-enriched gas mixture supplying line 14 may be approx. 500 liter / hour (for an adult), wherein the volume flow rate of the admixing mixture (e.g., the volume flow rate through pump 52) < 25 liter / hour (< 5% of the volume flow rate through line 14). Accordingly, in order to obtain approx. 100 ppm NO concentration in the breathable NO-enriched gas mixture, the concentration of NO in the filtered NO-enriched gas mixture should be approx. 2000 ppm. In the present configuration, system 100 may provide the filtered NO-enriched gas mixture having < 4 ppm of NO2, while having approx. 3000 ppm of NO (the NO / NO2 ratio: 750 / 1). Thereby, the resulting mixture before being inhaled by the patient (e.g., if measured in airway management device 72) may contain less than, approx., 0.2 ppm of NO2 while containing approx. 100 ppm of NO.

[0201] The following examples provide values of various system 100 operation parameters that were achieved using tests, computations, and mathematical simulations of certain embodiments of system 100.

[0202] Example 1. Plasma reactor unit 30 was configured to generate a pulse electric discharge with a maximum power of 100 W. Nitrogen generator 20 was configured to generate the initial gas mixture of N2 and O2 with residual oxygen concentration of 4%, with a flow rate of 200 liter / hour. A portion of this flow (approximately 60 liter / hour) was being transferred through plasma reactor unit 30. Another portion (approximately 60 liter / hour) was being further transferred via dilution via line 13. Plasma reactor unit 30 was being operated to generate the initial NO-enriched gas mixture with NO of 2000 ppm (the residual NO2 concentration was approximately 150 ppm). Then, a portion of the flow from plasma reactor unit 30 was being transferred by pump 51 to pump 52 which was being operated to inject this flow through inhalation line 14 to airway management device 72 - a face mask. Pumps 51 and 52 were being operated to vary the flow therethrough between approximately 1.2 liter / hour and 15 liter / hour. This flow was being admixed to the breathable air mixture flow of 300 liter / hour, which was being directed to the mask. Before activating dilution line13 (valve 53 were closed), by adjusting volume flow rate through pumps 51 and 52, NO concentration in the breathable NO-enriched gas mixture supplying line varied in the range between 8 and 100 ppm. After valve 53 was opened and dilution line 13 was activated, the range of NO-concentrations in the breathable NO-enriched gas mixture, obtained by adjusting volume flow rate through pumps 51 and 52, changed to 0.1 - 25 ppm. Thereby, it was determined that the full range of NO-concentration may be adjusted within the range of 0.1 - 100 ppm. During the adjustment, the response time of system 100 was no more than a few seconds. The content of NO2 concentration in the filtered NO-enriched gas mixture was below 0.1 ppm, while O2 concentration was below 10 ppm.

[0203] Example 2. For this example, plasma reactor unit 30 was configured as a DC high-voltage plasma generator with a maximum power of 200 W. The input gas mixture supply unit was configured as a membrane nitrogen concentrator generating the input gas mixture of N2 and O2 with residual O2 concentration of 6% and a flow rate of 200 liter / hour. A portion of the input gas mixture flow (approximately 60 liter / hour) was being transferred to plasma reactor unit 30. Another portion of approximately 60 liter / hour was being used for further dilution via dilution line 13. The generated initial NO-enriched gas mixture comprised approximately 4000 ppm of NO and approximately 350 ppm of NO2. After the initial NO-enriched gas mixture was transferred through filter unit 40, NO2 concentration was significantly reduced, down to 0.1 ppm and O2 concentration was reduced to approximately 10 ppm. Then, the filtered NO-enriched gas mixture was being directed by pump 51 to pump 52, which, in turn, was being operated to inject this flow through inhalation line 14 to airway management device 72 - a face mask. Pumps 51 and 52 were being operated to vary the flow therethrough between approximately 1.2 liter / hour and 15 liter / hour. This flow was being admixed to the breathable air mixture flow of 500 liter / hour, which was being directed to the mask. Before activating dilution line 13 (valve 53 were closed), by adjusting volume flow rate through pumps 51 and 52, NO concentration in the breathable NO-enriched gas mixture supplying line varied in the range between 10 and 120 ppm. After valve 53 was opened and dilution line 13 was activated, the range of NO- concentrations in the breathable NO-enriched gas mixture, obtained by adjusting volume flow rate through pumps 51 and 52, changed to 0.15 - 30 ppm. Thereby, it was determined that the full range of NO-concentration may be adjusted within the range of 0.15 - 120 ppm. During the adjustment, the response time of system 100 was no more than a few seconds.

[0204] Referring now to Fig. 4, a flow diagram is presented, depicting a method for delivering a breathable NO-enriched gas mixture to a patient, according to some embodiments of the present invention.

[0205] As shown in step S 1005, the method may include receiving, from an input gas mixture supply unit (e.g., nitrogen generator 20, as shown in Fig. 1A), an input gas mixture comprising N2 and O2.

[0206] As shown in step S1010, the method may include transferring, the input gas mixture through at least one plasma reactor unit (e.g., plasma reactor unit 30, as shown in Figs. 1 A and IB), while generating an electric discharge therein to induce a plasma chemical conversion of at least a portion of the input gas mixture into NO, thereby producing an initial NO-enriched gas mixture.

[0207] As shown in step S1015, the method may include transferring the initial NO- enriched gas mixture through a filter unit (e.g. filter unit 40, as shown in Figs. 1A, 1C, ID, and 2A-2G) to remove at least a fraction of NO2 from the initial NO-enriched gas mixture flowing therethrough, thereby producing a filtered NO-enriched gas mixture.

[0208] As shown in step S1020, the method may include controllably admixing the filtered NO-enriched gas mixture to a breathable air mixture (e.g., by using controller 60 to operate pump 52 and valve 53, as shown in Fig. 1A), thereby obtaining the breathable NO- enriched gas mixture having a preset fraction of NO.

[0209] As shown in step S 1025, the method may further include delivering the breathable NO-enriched gas mixture to the patient (e.g., using breathable air supply unit 71 and airway management device 72, as shown in Fig. 1A) to provide the respiratory treatment thereto.

[0210] In some further embodiments, said controllably admixing the filtered NO- enriched gas mixture to a breathable air mixture may comprise: receiving, by at least one controller (e.g., controller 60, as shown in Fig. 1A), a desired value of the preset fraction of NO (e.g., via controlling means, as discussed above); and operating, by said at least one controller (e.g., controller 60, as shown in Fig. 1A), at least one first pump or valve (e.g., pump 52 as shown in Fig. 1A) being in a downstream fluid communication with the filter unit (e.g., filter unit 40, as shown in Fig. 1A) and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line (e.g., inhalation line 14), said breathable NO-enriched gas mixture supplying line being in a downstream fluid communication with a breathable air supplying unit (e.g., breathable air supply unit 71, asshown in Fig. 1A) configured to supply the breathable air mixture, and in an upstream fluid communication with an airway management device (e.g., airway management device 72, as shown in Fig. 1A), so as to maintain the desired value of the present fraction of NO in the breathable NO-enriched mixture.

[0211] In some further embodiments, said controllably admixing the filtered NO- enriched gas mixture to a breathable air mixture further comprises operating, by said at least one controller (e.g., controller 60, as shown in Fig. 1A), at least one second pump or valve (e.g., valve 53 as shown in Fig. 1A) being in a downstream fluid communication with the input gas mixture supply unit (e.g., nitrogen generator 20, as shown in Fig. 1A) and in an upstream fluid communication with a fluid communication line between the filter unit (e.g., filter unit 40, as shown in Fig. 1A) and the at least one first pump or valve (e.g., pump 52, as shown in Fig. 1 A), so as to maintain the desired value of the present fraction of NO in the breathable NO-enriched mixture.

[0212] In some additional embodiments, said operating the at least one second pump or valve (e.g., valve 53, as shown in Fig. 1A) comprises: operating, by said at least one controller (e.g., controller 60), said at least one second pump or valve (e.g., valve 53, as shown in Fig. 1A) to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a lower predetermined range; and operating, by said at least one controller (e.g., controller 60, as shown in Fig. 1A), said at least one second pump or valve (e.g., valve 53, as shown in Fig. 1A) to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a higher predetermined range.

[0213] In some additional embodiments, said operating said at least one first pump or valve (e.g., pump 52, as shown in Fig. 1A) comprises adjusting a volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

[0214] In some additional embodiments, the method may further comprise supplying air (e.g., via air intake 10) to the nitrogen generator (e.g., nitrogen generator 20, as shown in Fig. 1A) to produce the input gas mixture.

[0215] In some embodiments, said transferring the input gas mixture through said at least one plasma reactor unit (e.g., plasma reactor unit 30, as shown in Fig 1A, 1C, ID and 2A- 2G) may include: generating a gas flow of the input gas mixture through the reactionchamber (e.g., reaction chamber 31, as shown in Fig. IB) via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes (e.g., electrodes 31’, as shown in Fig. IB), while generating, by the variable power supply (e.g., variable power supply 32, as shown in Fig. IB), the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture.

[0216] In some embodiments, said transferring the input gas mixture through said at least one plasma reactor unit (e.g., plasma reactor unit 30, as shown in Fig. 1A) further comprises transferring at least a portion of the input gas mixture through the circulating contour (e.g., circulating contour 34’ as shown in Fig. IB).

[0217] In some embodiments, transferring the initial NO-enriched gas mixture through the filter unit (e.g., filter unit 40, as shown in Figs. 1A, 1C, ID and 2A-2G) may further include heating the cartridge (e.g., cartridge 423, as shown in Figs. 1C-1D and 2A-2B) up to an operational temperature by the at least one heating element (e.g., heating element 43 or 43’ as shown in Figs. 1C-1D and 2A-2G); and transferring the initial NO-enriched gas mixture via the inlet and outlet channels (e.g., channels 422A, 422B or 422A’, 422B’ as shown in Figs. 2A-2G) through the heated cartridge.

[0218] In some embodiments, the method may further include receiving, by at least one controller (e.g., controller 60, as shown in Fig. 1A), from at least one sensor being in operative communication with the filter unit (e.g., sensor 63 and / or 65 being in operative connection with filter unit 40, as shown in Figs. 1A, 1C and ID), a current concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture; and operating, by said at least one controller (e.g., controller 60, as shown in Fig. 1A), the heating element (e.g., heating element 43 and / or 43’, as shown in Figs. 1C-1D and 2A-2G) to increase the operational temperature when the received current concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.

[0219] As can be seen from the provided description, the claimed invention represents a method and system for delivering a breathable NO-enriched gas mixture to a patient, wherein the breathable NO-enriched gas mixture is generated on-site using plasma chemical conversion, said method and system providing an improvement of the respective technological field by (i) achieving higher accuracy of NO level adjustment and maintenance across a wide range of concentrations; (ii) ensuring a fast response of the system whenadjusting NO concentration; (iii) reducing the fraction of undesired side-components, such as NO2 and O2, in the NO-enriched gas mixture.

[0220] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Furthermore, all formulas described herein are intended as examples only and other or different formulas may be used. Additionally, some of the described method embodiments or elements thereof may occur or be performed at the same point in time.

[0221] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

[0222] Various embodiments have been presented. Each of these embodiments may of course include features from other embodiments presented, and embodiments not specifically described may include various features described herein.

Claims

CLAIMS1. A method of delivering a breathable NO-enriched gas mixture to a patient, comprising: receiving, from an input gas mixture supply unit, an input gas mixture comprising N2 and O2; transferring, the input gas mixture through at least one plasma reactor unit, while generating an electric discharge therein to induce a plasma chemical conversion of at least a portion of the input gas mixture into NO, thereby producing an initial NO-enriched gas mixture; transferring the initial NO-enriched gas mixture through a filter unit to remove at least a fraction of NO2 and / or O2 from the initial NO-enriched gas mixture flowing therethrough, thereby producing a filtered NO-enriched gas mixture; controllably admixing the filtered NO-enriched gas mixture to a breathable air mixture, thereby obtaining the breathable NO-enriched gas mixture having a preset fraction of NO; and delivering the breathable NO-enriched gas mixture to the patient to provide a respiratory treatment thereto.

2. The method of claim 1, wherein said controllably admixing the filtered NO- enriched gas mixture to the breathable air mixture comprises: receiving, by at least one controller, a desired value of the preset fraction of NO; and operating, by said at least one controller, at least one first pump or valve being in a downstream fluid communication with the filter unit and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line, said breathable NO-enriched gas mixture supplying line being in a downstream fluid communication with a breathable air supplying unit configured to supply the breathable air mixture, and in an upstream fluid communication with an airway management device, so as to maintain the desired value of the present fraction of NO in the breathable NO- enriched mixture.

3. The method of claim 2, wherein said controllably admixing the filtered NO- enriched gas mixture to a breathable air mixture further comprises operating, by said at least one controller, at least one second pump or valve being in a downstream fluidcommunication with the input gas mixture supply unit and in an upstream fluid communication with a fluid communication line between the filter unit and the at least one first pump or valve, so as to maintain the desired value of the present fraction of NO in the breathable NO-enriched mixture.

4. The method of claim 3, wherein said operating the at least one second pump or valve comprises: operating, by said at least one controller, said at least one second pump or valve to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a lower predetermined range; and operating, by said at least one controller, said at least one second pump or valve to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a higher predetermined range.

5. The method of claim 4, wherein the lower predetermined range is between about 10 ppm and about 100 ppm and the higher predetermined range is between about 100 ppm and about 1000 ppm.

6. The method according to any one of claims 3-5, wherein the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture is increased or decreased in a range between about 0 liter / hour and about 500 liter / hour.

7. The method according to any one of claims 2-6, wherein operating said at least one first pump or valve comprises adjusting a volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

8. The method according to any one of claims 1-7, wherein a volume flow rate of the filtered NO-enriched gas mixture is between about 50 liter / hour and about 100 liter / hour.

9. The method according to any one of claims 1-8, wherein a volume ratio between N2 and O2 in the input gas mixture is between 49:1 and 9:1.

10. The method according to any one of claims 1-9, wherein the initial NO-enriched gas mixture comprises between about 800 and about 5000 ppm of NO, between about 100 and about 500 ppm of NO2, about 89.95% of N2 or more, and between about 0.45 and about 9.95% of O2.

11. The method according to any one of claims 1-10, wherein the filtered NO- enriched gas mixture comprises about 98% N2 or more and between about 500 and about2000 ppm of NO.

12. The method according to any one of claims 1-11, wherein the input gas mixture supply unit is a nitrogen generator comprising a pressure swing adsorption (PSA) system and / or a membrane gas separation system; and wherein the method further comprises supplying air to the nitrogen generator to produce the input gas mixture.

13. The method according to any one of claims 1-12, wherein said at least one plasma reactor unit comprises: a reaction chamber having an inlet channel and an outlet channel; a variable power supply in operative connection with a plurality of electrodes installed within the reaction chamber; and wherein transferring the input gas mixture through said at least one plasma reactor unit comprises: generating a gas flow of the input gas mixture through the reaction chamber via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes, while generating, by the variable power supply, the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture.

14. The method of claim 13, wherein said at least one plasma reactor unit further comprises a circulation blower in fluid communication with said inlet and outlet channels of the reaction chamber, thereby forming, together with the reaction chamber, a circulating contour; and wherein transferring the input gas mixture through said at least one plasma reactor unit further comprises transferring at least a portion of the input gas mixture through the circulating contour.

15. The method according to any one of claims 1-14, wherein the filter unit comprises: a filter unit housing which defines an inner cavity therein; a pair of inlet and outlet channels coupled to the filter unit housing and being in fluid communication with each other via the inner cavity;a cartridge disposed within the inner cavity, said cartridge comprising a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide, respectively; and at least one heating element; and wherein transferring the initial NO-enriched gas mixture through the filter unit comprises: heating the cartridge up to an operational temperature by the at least one heating element; and transferring the initial NO-enriched gas mixture via the inlet and outlet channels through the heated cartridge.

16. The method of claim 15, further comprising: receiving, by at least one controller, from at least one sensor being in operative communication with the filter unit, a current concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture; and operating, by said at least one controller, the heating element to increase the operational temperature when the received current concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.

17. The method according to any one of claims 15 and 16, wherein the metal catalyst comprises elemental copper or copper alloy.

18. A system for delivering a breathable NO-enriched gas mixture to a patient, comprising: an input gas mixture supply unit, configured to provide an input gas mixture comprising N2 and O2; at least one plasma reactor unit configured to receive the input gas mixture and to induce a plasma chemical conversion of at least a portion of the input gas mixture into NO, thereby producing an initial NO-enriched gas mixture; at least one filter unit configured to receive the initial NO-enriched gas mixture and to remove at least a fraction of NO2 and / or O2 from the initial NO-enriched gas mixture, thereby producing a filtered NO-enriched gas mixture; a first pump or valve being in a downstream fluid communication with said at least one filter unit, and in an upstream fluid communication with a breathable NO-enriched gas mixture supplying line, said breathable NO-enriched gas mixture supplying line being in a downstream fluid communication with a breathable air supplying unit and in an upstream fluid communication with an airway management device; at least one first sensor configured to determine a concentration of NO in the airway management device; and at least one controller in operative communication with said at least one first sensor and said first pump or valve, said at least one controller being configured to operate said first pump or valve, based on the determined concentration of NO, so as to obtain, in the airway management device, the breathable NO-enriched gas mixture having a preset fraction of NO.

19. The system of claim 18, further comprising at least one second pump or valve being in a downstream fluid communication with the input gas mixture supply unit and in an upstream fluid communication with a fluid communication line between the filter unit and the at least one first pump or valve; wherein said at least one controller is in operative communication with said at least one second pump or valve and is further configured to operate, based on the determined concentration of NO, said at least one second pump or valve, so as to obtain, in the airway management device, the breathable NO-enriched gas mixture having the preset fraction of NO.

20. The system according to any one of claims 18 and 19, wherein said at least one controller is further configured to: receive a desired value of the preset fraction of NO; and operate at least one of said at least one first pump or valve and said at least one second pump or valve, so as to obtain, in the airway management device, the breathable NO-enriched gas mixture having the preset fraction of NO according to the desired value.

21. The system of claim 19, wherein said at least one controller is further configured to: operate said at least one second pump or valve to increase a volume flow rate of a portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a lower predetermined range; andoperate said at least one second pump or valve to decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture, when the desired value pertains to a higher predetermined range.

22. The system of claim 21, wherein the lower predetermined range is between about 10 ppm and about 100 ppm and the higher predetermined range is between about 100 ppm and about 1000 ppm.

23. The system of claim 22, wherein the second pump or valve is configured to increase or decrease the volume flow rate of the portion of the input gas mixture to be admixed to the filtered NO-enriched gas mixture in a range between about 0 liter / hour and about 500 liter / hour.

24. The system according to any one of claims 18-23, wherein said at least one controller is configured to operate said at least one first pump or valve to adjust a volume flow rate therethrough between about 0.1 liter / hour and about 30 liter / hour.

25. The system according to any one of claims 18-24, wherein a volume flow rate of the filtered NO-enriched gas mixture is between about 50 liter / hour and about 100 liter / hour.

26. The system according to any one of claims 18-25, wherein a volume ratio between N2 and O2 in the input gas mixture is between 49:1 and 9:1.

27. The system according to any one of claims 18-26, wherein the initial NO-enriched gas mixture comprises between about 800 and about 5000 ppm of NO, between about 100 and about 500 ppm of NO2, about 89.95% of N2 or more, and between about 0.45 and about 9.95% of O2.

28. The system according to any one of claims 18-27, wherein the filtered NO- enriched gas mixture comprises about 98% N2 or more and between about 500 and about 2000 ppm of NO.

29. The system according to any one of claims 18-28, wherein the input gas mixture supply unit is a nitrogen generator comprising a pressure swing adsorption (PSA) system and / or a membrane gas separation system, and the system is further configured to provide an air supply to the nitrogen generator to produce the input gas mixture.

30. The system according to any one of claims 18-29, wherein said at least one plasma reactor unit comprises: a reaction chamber having an inlet channel and an outlet channel;a variable power supply in operative connection with a plurality of electrodes installed within the reaction chamber; and wherein said at least one plasma reactor unit is further configured to generate a gas flow of the input gas mixture through the reaction chamber via the inlet channel and the outlet channel to transfer the input gas mixture through a gap between the plurality of electrodes, while generating, by the variable power supply, the electric discharge thereacross, thereby producing the initial NO-enriched gas mixture.

31. The system of claim 30, wherein said at least one plasma reactor unit further comprises a circulation blower in fluid communication with said inlet and outlet channels of the reaction chamber, thereby forming, together with the reaction chamber, a circulating contour; and wherein said at least one plasma reactor unit is further configured to transfer at least a portion of the input gas mixture through the circulating contour.

32. The system according to any one of claims 18-31, wherein the filter unit comprises: a filter unit housing which defines an inner cavity therein; a pair of inlet and outlet channels coupled to the filter unit housing and being in fluid communication with each other via the inner cavity; a cartridge disposed within the inner cavity, said cartridge comprising a filtering material comprising a metal catalyst configured for reducing NO2 to NO and undergoing oxidation upon exposure to O2 to form a metal oxide, respectively; and at least one heating element; and wherein the filter unit is further configured to: heat the cartridge up to an operational temperature by the at least one heating element; and transfer the initial NO-enriched gas mixture via the inlet and outlet channels through the heated cartridge.

33. The system of claim 32, wherein said at least one controller is further configured to:receive, from at least one second sensor being in operative communication with the filter unit, a current concentration of O2 and / or NO2 in the filtered NO-enriched gas mixture; and operate the heating element to increase the operational temperature when the received current concentration of O2 and / or NO2, respectively, exceeds a predefined concentration threshold.

34. The system according to any one of claims 32 and 33, wherein the metal catalyst comprises elemental copper or copper alloy.

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