Nitric oxide sterilization devices and methods

Abstract

Sterilization systems and methods presented herein include a reaction container in which nitric oxide is generated on-demand from a nitric oxide donor in solution. So generated nitric oxide is moved via a negative pressure gradient from the reaction container through a surge vessel into a sterilization chamber, and residual nitric oxide is subsequently adsorbed or catalytically destroyed.

Description

NITRIC OXIDE STERILIZATION DEVICES AND METHODSCross Reference to Related Applications

[0001] This application claims priority to copending US provisional patent application No. 63 / 438,445, which was filed January 11, 2023, and which is incorporated by reference herein..Field of the Invention

[0002] The field of the invention is devices, systems, and methods for sterilization of objects using nitric oxide as a gaseous sterilant, and especially as it relates to on-demand generation and delivery of nitric oxide at low or sub-atmospheric pressure.Background of the Invention

[0003] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0005] Sterilization of medical devices and equipment is paramount for their safe use and the most common methods of sterilization include steam autoclaving and irradiation. However, not all medical devices, equipment, and biologies can withstand such harsh conditions, and other sterilization methods must be used. To circumvent these difficulties, sterilization can be performed using selected gases, and ethylene oxide is the most commonly used sterilizing gas for items such as surgical kits, catheters, cardiac implants, stents, IV sets, etc. Unfortunately, ethylene oxide possesses several physical and health hazards that merit special attention. According to the Occupational Safety & Health Administration of the U.S. Department of Labor, acute exposures to ethylene oxide gas may result in respiratory irritation and lung injury, headache, nausea, vomiting, diarrhea, shortness of breath, and cyanosis. Chronic exposure hasbeen associated with the occurrence of cancer, reproductive effects, mutagenic changes, neurotoxicity, and sensitization. Indeed, the Environmental Protection Agency has classified ethylene oxide as a carcinogen.

[0006] To avoid some of the problems with ethylene oxide, various alternative sterilizing gases have been used. For example, formaldehyde can be generated from formalin and has been employed as a sterilizing gas at relatively high concentrations (e.g., 8-16 mg / 1). While significantly less flammable than ethylene oxide, formaldehyde gas is generated / used at an operating temperature of about 70-75 °C, which precludes its use with thermally sensitive material or equipment. Alternatively, hydrogen peroxide vapor can be used as a sterilizing gas. Hydrogen peroxide vapor is typically generated by vacuum vaporization. Among other benefits, hydrogen peroxide vapor typically has a rapid cycle time (e.g., 30-45 minutes), can be effective at low temperature (e.g., 20 °C), and produces environmentally safe by-products (water, oxygen). In addition, hydrogen peroxide vapor has generally fair material compatibility and ease of operation. However, hydrogen peroxide vapor can be reactive with selected polymers and has not been cleared by the FDA for sterilization of medical devices. On the other hand, ozone can be used as a sterilizing gas, which is relatively effective, even at low temperatures. Unfortunately, ozone is chemically very unstable and may be reactive with biologies. Furthermore, generation of quantities sufficient for sterilization typically requires dedicated equipment.

[0007] More recently, sterilization has also been reported where nitric oxide gas was employed as the sterilant as is described in WO 2022 / 164894. Here, nitric oxide is generated from a nitric oxide donor compound that is then subjected to conditions leading to the release of nitric oxide. In typical examples, the donor compound is immobilized on or within a carrier, which is in proximity to the object that is to be sterilized. Notably, such systems and methods circumvent most of the difficulties associated with hydrogen peroxide or ethylene oxide sterilization. However, use of a donor compound in proximity to the objects is difficult to scale to larger operations. To increase scale, nitric oxide gas could theoretically be used from a bulk source. However, replacement of a nitric oxide donor compound with commercially available compressed nitric oxide gas is undesirable as nitric oxide at elevated pressure readily disproportionates to N2O and NO2.

[0008] Thus, even though various compositions and methods of sterilization of various objects using a sterilizing gas, including nitric oxide, are known in the art, all or almost all of themsuffer from several drawbacks. Therefore, there remains a need for improved devices, systems, and methods for sterilization of objects using nitric oxide as gaseous sterilant.Summary of The Invention

[0009] The inventive subject matter is directed to various devices, systems, and methods for sterilizing objects using nitric oxide as a sterilizing gas in which nitric oxide is generated under controlled reaction conditions from a precursor solution, and in which the so generated nitric oxide is moved through a sterilization system that includes a sterilization chamber via a negative pressure gradient. Finally, residual nitric oxide after sterilization is destroyed or otherwise removed from the exhaust of the sterilization system using a suitable filter or reactor.

[0010] In one aspect of the inventive subject matter, the inventor contemplates a nitric oxide generator that includes a reaction that is container configured to maintain a solution containing a nitric oxide donor and a metering system that is configured to provide to the solution the nitric oxide donor or one or more reagents that generate the nitric oxide donor in the solution. Contemplated nitric oxide generators will further include an energy source that is coupled to the reaction container and that is configured to provide energy to the solution in an amount sufficient to decompose the nitric oxide donor to thereby produce nitric oxide. A control circuit is operationally coupled to the metering system and one or more sensors such that the control circuit controls operation of the sensors as a function of nitric oxide donor concentration in the solution, the one or more reagents, and / or a concentration or quantity of the produced nitric oxide.

[0011] In some embodiments, the nitric oxide generator will be configured to protect the solution containing the nitric oxide donor from ambient light, and / or the container may be configured to allow introduction and replacement of atmospheric oxygen from the container by an inert gas. It is further contemplated that the solution will be an aqueous solution that may or may not contain a metal ion chelator. Preferably, but not necessarily, the solution will have a pH of equal or less than 4.0 (e.g., pH 2-4 or 3-5). In further embodiments, the nitric oxide donor will comprise a nitrosothiol group, and / or the one or more reagents will include an organic thiol compound and a nitrite, and wherein the nitric oxide donor is generated in the solution in situ by a reaction of the organic thiol compound with the nitrite.

[0012] Where desired, the metering system may comprise a liquid pump or a screw drive that is configured to dispense the nitric oxide donor or the one or more reagents into the solution.In further contemplated embodiments, suitable energy sources include a light source, a heater, an ultrasonic emitter, and / or an impeller, while suitable sensors include a pH sensor, a UV-VIS sensor, a nitric oxide sensor, and / or a gas flow meter.

[0013] Additionally, it is contemplated that the nitric oxide generator will be fluidly coupled to a source of inert gas (e.g., nitrogen gas), and / or that the generator will be fluidly coupled to a surge vessel. Moreover, it is contemplated that the generator may be fluidly coupled to a sterilization chamber and / or may be fluidly coupled to a vacuum pump.

[0014] Therefore, the inventor also contemplates a method of generating nitric oxide that includes a step of reacting in a container an organic thiol compound and a nitrite to thereby generate a solution comprising a nitric oxide donor, and a further step of providing energy to the solution in the reaction container to decompose at least some of the nitric oxide donor to thereby generate nitric oxide. In yet another step, the generated nitric oxide is then moved from the reaction container using a negative pressure gradient, and the nitric oxide donor is replenished by feeding additional organic thiol compound and nitrite to the solution.

[0015] It is also contemplated that the solution may comprise a metal ion chelator and / or will have a pH of equal or less than 4.0 (e.g., pH 2-4 or 3-5). Preferably, but not necessarily, the headspace over the solution will be flushed with an inert gas, typically while solution is protected from ambient light. It is still further contemplated that the energy in such methods will be provided in form of light energy, heat energy, mechanical energy, and / or ultrasound energy. Where desired contemplated methods may further comprise a step of measuring a nitric oxide concentration in the reaction container.

[0016] Most typically, the generated nitric oxide is moved from the reaction container into a surge vessel and from there into a sterilization chamber. Moreover, it is generally preferred that the generated nitric oxide is moved through at least part of the system using a vacuum pump. As will be readily appreciated, contemplated methods may further include a step of measuring a concentration of the nitric oxide, wherein the nitric oxide donor is replenished in response to a measured nitric oxide concentration in the solution. Still further, it is contemplated that residual nitric oxide is, after use as a sterilant, adsorbed or catalytically destroyed.

[0017] Therefore, in still another aspect of the inventive subject matter, the inventor also contemplates a sterilization system for sterilization of an object using gaseous nitric oxide thatcomprises a reaction container that is fluidly coupled to a surge vessel and a sterilization chamber such that nitric oxide produced in the reaction chamber moves from the reaction container through the surge vessel to the sterilization chamber. Such systems will include an energy source coupled to the container and configured to provide energy to a solution in the container in an amount sufficient to decompose the nitric oxide donor in the solution to thereby produce nitric oxide, and further include a vacuum pump fluidly coupled to the sterilization chamber such that the vacuum pump draws the nitric oxide from the container, the surge vessel and the sterilization chamber to a nitric oxide adsorbent or catalyst.

[0018] Most typically, the reaction container will comprise one or more ports configured to receive a nitric oxide donor or one or more reagents that generate the nitric oxide donor, and / or suitable energy sources include a light source, a heater, an ultrasonic emitter, or an impeller. In further embodiments, contemplated sterilization systems may further include a plurality of nitric oxide sensors that measure nitric oxide concentrations in one or more of the reaction container, the sterilization chamber, and an exhaust of the vacuum pump, and / or a sensor that measures concentration of the nitric oxide donor in the reaction container.

[0019] Consequently, and viewed from a different perspective, the inventors contemplates a method of sterilizing an object using nitric oxide that includes a step of generating in a reaction container nitric oxide from a solution containing a nitric oxide donor, a further step of moving the generated nitric oxide from the reaction container to a sterilization chamber using a negative pressure gradient, and a still further step of maintaining a sterilizing nitric oxide concentration in the sterilization chamber for a time sufficient to sterilize the object.

[0020] Typically, but not necessarily, the nitric oxide donor comprises a nitrosothiol group and may be generated in the solution from a reaction between an organic thiol compound and a nitrite. It is also contemplated that the nitric oxide is generated from the nitric oxide donor by photolytic decomposition of the nitric oxide donor, and that the so generated nitric oxide is moved from the reaction container to the sterilization chamber via a surge vessel (which will typically have a volume that is greater than the volume of the sterilization chamber).

[0021] In still further aspects of the inventive subject matter, the negative pressure gradient is generated using a vacuum pump that is downstream of the sterilization chamber. Moreover, it is contemplated that the sterilizing nitric oxide concentration is between 1-50 ppb, or above, and / or that the sterilizing nitric oxide concentration is maintained for a time of between 10-120min and / or at a temperature of between 0-50 °C or between 20-50 °C. As noted above, it is also contemplated that residual nitric oxide is, after use as a sterilant, adsorbed or catalytically destroyed.

[0022] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.Brief Description of The Drawing

[0023] FIG.l is an exemplary schematic illustration of a nitric oxide sterilization system according to the inventive subject matter.Detailed Description

[0024] The inventor has discovered systems, devices, and methods of sterilizing objects using nitric oxide as a sterilant in which the nitric oxide is generated on-demand in a reaction container, and in which the so generated nitric oxide is moved through a sterilization chamber using a negative pressure gradient. Residual nitric oxide after sterilization is then adsorbed or catalytically destroyed. Advantageously, the systems, devices, and methods presented herein allow for rapid sterilization at large scale at low temperatures (e.g, between 0 and 50 °C, or between 0 and 70 °C, and in some cases even higher) and short cycle times while being conceptually simple, effective, and economically attractive.

[0025] In one exemplary embodiment as schematically illustrated in FIG.l, a sterilization system comprises a reaction container 250 in which nitric oxide is generated on-demand, which is then moved via valve 170 to a surge vessel (or nitrogen bladder) 180 from which nitric oxide is then moved to the sterilization chamber 200. Residual nitric oxide then leaves the sterilization chamber and is catalytically oxidized in a hopcalite fdter 210. Residual odor can be removed in an activated charcoal fdter 230.

[0026] In this context, it should be appreciated that the gas stream containing nitric oxide is not subject to compression and as such avoids significant issues associated with disproportionation of nitric oxide (NO), 3NO — NO2 + N2O. Earlier kinetic studies by others have revealed that disproportionation reaction is strongly dependent on the pressure of nitricoxide. For example, at 200 atm, the mole fractions of NO2 and N2O can become as high as 12- 13% only after 10 days (see e.g. , Free Radic Res. 2003 Feb;37(2): 171 -7). Instead, it is generally preferred that the nitric oxide is moved by a negative pressure gradient that is generated by a vacuum (or suction) pump 220 that is located downstream of the sterilization chamber. For example, the negative pressure gradient is generated in some embodiments by a vacuum pump that at least temporarily reduces pressure in the sterilization chamber to about 10 Torr to so draw the nitric oxide (typically in a carrier gas) from the reaction container to the sterilization chamber as depicted in FIG.l. Upon exit of the nitric oxide from the sterilization chamber, the nitric oxide is drawn into and catalytically oxidized in a hopcalite fdter. The vacuum pump exhaust can then be routed through an activated charcoal fdter for removal of odorous compounds.

[0027] While not limiting to the inventive subject matter, it is generally preferred to include a surge vessel, between the nitric oxide reaction container and the sterilization chamber that can act as a nitric oxide reservoir. Most typically, the surge vessel will have a capacity for nitric oxide that is at least equal or significantly larger (e.g., at least 1.5x, or at least 2. Ox, or at least 3. Ox, or at least 5. Ox) than the capacity of the sterilization chamber. In some embodiments, the surge vessel may have an inner volume of at least 1 m3, or of at least 3 m3, or of at least 5 m3, or have an inner volume of less than 2 m3, or have an inner volume of between 10-500 cm3, or have an inner volume of between 100-5,000 cm3.

[0028] With further reference to FIG.l, nitric oxide is preferably generated on-demand from a precursor solution 120 in a reaction container, and it is still further generally preferred that the precursor solution contains a nitrosothiol compound. Moreover, it is also preferred that the concentration of the nitrosothiol compound in the solution can be maintained by generating the nitrosothiol compound in situ from reactants that are fed to the solution. In some embodiments, the precursor solution may be an aqueous solution at a relatively acidic pH (e.g., pH 4.0) and may further include a metal ion chelator (e.g, EDTA) to so increase chemical stability of the nitrosothiol compound. To that end, the solution may be buffered, or the pH may be actively controlled using a control system that can feed acid or base to the solution as needed to maintain a setpoint or pH band for the solution.

[0029] Among other suitable reagents, contemplated nitrosothiol compounds can be generated from an organic thiol compound 100 and a nitrite salt 140. For example, where the nitrosothiol compound is '-nitrosoglutathione or '-nitrosocysteine, the reactants may be glutathione orcysteine for the thiol compound and sodium nitrite for the nitrite sale. As will be readily appreciated, the appropriate molar ratios for the thiol and nitrite reagents can be easily ascertained by the skilled artisan (e.g., 1:1.1 ratio of thiol to nitrite) and suitable quantities can be added to achieve a desired final concentration. Of course, it should be appreciated that the addition of the reagents can be continuous or discontinuous (e.g., in response to a sensed quantity of the nitrosothiol compound). Most typically, the nitrosothiol compound will have a concentration of between 0.1 M and 1.0 M in the solution.

[0030] In further desirable aspects, and as also exemplarily illustrated in FIG.l, it should be appreciated that the concentration of formed nitrosothiol compound (RSNO) can be monitored with UV-VIS spectroscopy 125 (e.g., using a point of analysis method such as an Ocean Optics optical UV-VIS spectrometer). Likewise, it should be noted that the pH of the solution can also be monitored with UV-VIS spectroscopy using a ratiometric measurement that can be enabled by a pH indicator (such as thymol blue or methyl orange) in the solution. Such ratiometric system advantageously does not require calibration. Consequently, it should be appreciated that these two feedback parameters (quantity of the nitrosothiol compound and pH of the solution) allow for the maintenance of constant level of the nitrosothiol compound (via a control system that dispenses the thiol and the nitrite reagent in response to the determined quantity of the nitrosothiol compound) to be maintained.

[0031] Nitric oxide 130 can then be generated from the nitrosothiol compound in the solution by addition of energy, and it is generally preferred that energy source is a light source 150 and 160 (which may be tunable in frequency and / or intensity to adjust to different nitrosothiol compounds and / or rate of nitric oxide generation). As will be readily appreciated, the quantity / concentration of nitric oxide in the headspace of the reaction container can be monitored with an electrochemical NO sensor 110 (such as SGX-4NO-250 Nitric Oxide Gas sensor from Sensortech), which will allow for real-time measurement of nitric oxide concentrations / quantities when the solution is illuminated. In most typical embodiments, the entire flow path for the nitric oxide will be flushed and maintained with an inert gas (e.g., nitrogen) to reduce or even entire avoid presence of oxygen in the flow path. One or more flow meters can then be used to monitor the rate of gas flow into the sterilization chamber. Finally, it is preferred that the solution containing the nitrosothiol compound will be protected from ambient light, and that the solution may be sparged or purged with an inert gas. Thus, nitric oxide will only be generated in response to light from the illumination source.

[0032] With regard to the sterilization cycle it is contemplated that the objects in the sterilization chamber may be exposed to a static atmosphere containing the nitric oxide or a dynamic atmosphere containing the nitric oxide. To that end, the nitric oxide in the carrier gas may be delivered to a steady state concentration in the sterilization chamber and the carrier gas with the nitric oxide will be maintained in the chamber for a sufficient time. Alternatively, the nitric oxide in the carrier gas may be delivered in a continuous flow throughout the sterilization cycle with the nitric oxide being present in both cases at a sterilizing nitric oxide concentration. Of course, it should be noted that the articles for sterilization can be placed into the sterilization chamber directly, or the articles can be placed / sealed in a container that contains a microbial barrier that is permeable to nitric oxide as described in US provisional application with the serial number 63 / 438073, which was filed January 10, 2023, and which is incorporated by reference herein.

[0033] Therefore, and with further reference to FIG.l, it is contemplated that the sterilization chamber will include one or more sensors 190 to ascertain the presence and quantity of nitric oxide in the sterilization chamber, and to help ascertain absence of nitric oxide upon conclusion of the sterilization cycle before an operator opens the sterilization chamber. Most typically, upon conclusion of the sterilization cycle, the flow path for the nitric oxide will be purged with the inert gas and all residual nitric oxide will be moved from the system to an adsorber or catalyst that decomposes the nitric oxide. In addition, an activated charcoal filter may be included in the flow path to remove any odorous components form the gas exiting the sterilization chamber. Finally, to ascertain a desired degree (e.g., at least 95%) adsorption or catalytic destruction of the nitric oxide in the flow path, a further nitric oxide sensor 240 may be included at the terminal portion of the flow path.

[0034] In still further contemplated aspects, it should be appreciated that various modifications can be implemented into the exemplary system described above without departing form the inventive concept presented herein. For example, while it is generally preferred that the nitric oxide and carrier gas are being moved through the system at a pressure that is below 1 atm (e.g., with the vacuum pump creating a reduced pressure of about 5-10 Torr, or about 10-50 Torr, or about 50-100 Torr, or about 100-300 Torr, or about 300-700 Torr), moderate positive pressure levels to move the carrier are also deemed suitable for use herein and include pressures between 800 and 1,500 Torr, or between 1,500 and 2,500 Torr, or between 2,500 and 6,000 Torr, and in some cases even higher. Moderate positive pressure may be especially appropriatewhere the residence time of the nitric oxide in the flow path between the reaction container and the sterilization chamber is less than 48 hours, or less than 24 hours, or less than 12 hours, or even shorter.

[0035] With further regard to the nitric oxide generation, it is also noted that the nitric oxide generation from the precursor solution may be discontinuous (especially where the surge vessel has a relatively large volume relative to the sterilization chamber) or continuous to thereby generate a sterilizing nitric oxide concentration in the carrier gas. In most embodiments, the sterilizing nitric oxide concentration will be a steady-state concentration of nitric oxide of between 1 and 500 ppb, or between 1 and 10 ppb, or between 10-50 ppb, or between 50 and 250 ppb, or between 250 ppb and 500 ppb, or even more. Therefore, suitable sterilizing nitric oxide concentrations will be at 1 ppb, or at least 5 ppb, or at least 10 ppb, or at least 50 ppb, or at least 100 ppb, or at least 200 ppb, and even higher.

[0036] Moreover, it should be noted that the nature of the thiol and nitrite reagents may vary considerably, and it is indeed contemplated that all reagents are appropriate for use herein so long as such reagents allow for the formation of a nitric oxide donor in the solution in the reaction chamber, and so long as the nitric oxide donor can be decomposed to thereby generate nitric oxide. In addition, in still further contemplated aspects, it should also be appreciated that the solution containing the nitric oxide donor may be replaced with solid particles that comprise the nitric oxide donor and that upon energy exposure release nitric oxide. For example, solid particles may comprise a polymer that encloses or to which a nitric oxide donor is coupled. Suitable particles materials are described in WO 2022 / 164894, which incorporated by reference herein. In such embodiments, the particles may be fed to the reaction container (e.g, by a screw or auger drive), and spent particles can then be disposed of form the reaction container (in a batch or continuous fashion). Regardless of the particular nature of the nitric oxide donor it should be appreciated that the nitric oxide donor will represent an environmentally safe and chemically stable source of nitric oxide that can be replenished in simple manner. Moreover, generation of the nitric oxide is conceptually simple and does not require complex equipment. Finally, it should be appreciated that systems and methods presented herein may be integrated into or formed at least in part by already existing gas sterilization equipment. Viewed from another perspective, an existing gas sterilization system may be modified to include the nitric oxide generator, surge vessel, and vacuum pump in aretrofit to so add an alternate mode of gas sterilization or to replace an existing mode of gas sterilization (e.g., using ethylene oxide or hydrogen peroxide).

[0037] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” As used herein, the terms "about" and "approximately", when referring to a specified, measurable value (such as a parameter, an amount, a temporal duration, and the like), is meant to encompass the specified value and variations of and from the specified value, such as variations of + / -10% or less, alternatively + / -5% or less, alternatively + / -1% or less, alternatively + / -0.1% or less of and from the specified value, insofar as such variations are appropriate to perform in the disclosed embodiments. Thus, the value to which the modifier "about" or "approximately" refers is itself also specifically disclosed. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0038] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0039] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As also used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously.

[0040] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. Theinventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refer to at least one of something selected from the group consisting of A, B, C . . . . and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

CLAIMSWhat is claimed is:

1. A nitric oxide generator, comprising: a reaction container configured to maintain a solution containing a nitric oxide donor; a metering system configured to provide to the solution the nitric oxide donor or one or more reagents that generate the nitric oxide donor in the solution; and an energy source coupled to the reaction container and configured to provide energy to the solution in an amount sufficient to decompose the nitric oxide donor to thereby produce nitric oxide; a control circuit that is operationally coupled to the metering system and one or more sensors such that the control circuit controls operation of the sensors as a function of nitric oxide donor concentration in the solution, the one or more reagents, and / or a concentration or quantity of the produced nitric oxide.

2. The nitric oxide generator of claim 1, wherein the container is configured to protect the solution containing the nitric oxide donor from ambient light.

3. The nitric oxide generator of claim 1, wherein the container is configured to allow introduction and replacement of atmospheric oxygen from the container by an inert gas.

4. The nitric oxide generator of claim 1, wherein the solution is an aqueous solution, optionally containing a metal ion chelator.

5. The nitric oxide generator of claim 4, wherein the solution has a pH of equal or less than 4.0.

6. The nitric oxide generator of claim 1, wherein the nitric oxide donor comprises a nitrosothiol group.

7. The nitric oxide generator of claim 1, wherein the one or more reagents include an organic thiol compound and a nitrite, and wherein the nitric oxide donor is generated in the solution in situ by a reaction of the organic thiol compound with the nitrite.

8. The nitric oxide generator of claim 1, wherein the metering system comprises a liquid pump or a screw drive configured to dispense the nitric oxide donor or the one or more reagents into the solution.

9. The nitric oxide generator of claim 1, wherein the energy source is a light source, a heater, an ultrasonic emitter, or an impeller.

10. The nitric oxide generator of claim 1, wherein the sensor is a pH sensor, a UV-VIS sensor, a nitric oxide sensor, and / or a gas flow meter.

11. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a source of inert gas.

12. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a surge vessel.

13. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a sterilization chamber.

14. The nitric oxide generator of claim 1, wherein the generator is fluidly coupled to a vacuum pump.

15. A method of generating nitric oxide, comprising: reacting in a container an organic thiol compound and a nitrite to thereby generate a solution comprising a nitric oxide donor; providing energy to the solution in the reaction container to decompose at least some of the nitric oxide donor to thereby generate nitric oxide; moving the generated nitric oxide from the reaction container using a negative pressure gradient; and replenishing the nitric oxide donor by feeding additional organic thiol compound and nitrite to the solution.

16. The method of claim 15, wherein the solution comprises a metal ion chelator.

17. The method of claim 15, wherein the solution has a pH of equal or less than 4.0.

18. The method of claim 15, wherein a headspace over the solution is flushed with an inert gas, and / or wherein the solution is protected from ambient light.

19. The method of claim 15, wherein the energy is provided in form of light energy, heat energy, mechanical energy, and / or ultrasound energy.

20. The method of claim 15, further comprising a step of measuring nitric oxide concentration in the reaction container.

21. The method of claim 15, wherein the generated nitric oxide is moved from the reaction container into a surge vessel.

22. The method of claim 15, wherein the generated nitric oxide is moved from the reaction container into a sterilization chamber.

23. The method of claim 15, wherein the generated nitric oxide is moved using a vacuum pump.

24. The method of claim 15, further comprising a step of measuring a concentration of the nitric oxide, and wherein the nitric oxide donor is replenished in response to a measured nitric oxide concentration in the solution.

25. The method of claim 15, wherein residual nitric oxide is, after use as a sterilant, adsorbed or catalytically destroyed.

26. A sterilization system for sterilization of an object using gaseous nitric oxide, comprising: a reaction container that is fluidly coupled to a surge vessel and a sterilization chamber such that nitric oxide produced in the reaction chamber moves from the reaction container through the surge vessel to the sterilization chamber; an energy source coupled to the container and configured to provide energy to a solution in the container in an amount sufficient to decompose the nitric oxide donor in the solution to thereby produce nitric oxide; and a vacuum pump fluidly coupled to the sterilization chamber such that the vacuum pump draws the nitric oxide from the container, the surge vessel, and the sterilization chamber to a nitric oxide adsorbent or catalyst.

27. The sterilization system of claim 26, wherein the reaction container comprises one or more ports configured to receive a nitric oxide donor or one or more reagents that generate the nitric oxide donor.

28. The sterilization system of claim 26, wherein the energy source is a light source, a heater, an ultrasonic emitter, or an impeller.

29. The sterilization system of claim 26, further comprising a plurality of nitric oxide sensors that measure nitric oxide concentrations in one or more of the reaction container, the sterilization chamber, and an exhaust of the vacuum pump.

30. The sterilization system of claim 26, further comprising a sensor that measures concentration of the nitric oxide donor in the reaction container.

31. A method of sterilizing an object using nitric oxide, comprising: generating in a reaction container nitric oxide from a solution containing a nitric oxide donor; moving the generated nitric oxide from the reaction container to a sterilization chamber using a negative pressure gradient; and maintaining a sterilizing nitric oxide concentration in the sterilization chamber for a time sufficient to sterilize the object.

32. The method of claim 31, wherein the nitric oxide donor comprises a nitrosothiol group.

33. The method of claim 31, wherein the nitric oxide donor is generated in the solution from a reaction between an organic thiol compound and a nitrite.

34. The method of claim 31, wherein the nitric oxide is generated from the nitric oxide donor by photolytic decomposition of the nitric oxide donor.

35. The method of claim 31, wherein the nitric oxide is moved from the reaction container to the sterilization chamber via a surge vessel.

36. The method of claim 35, wherein the surge vessel has a volume that is greater than a volume of the sterilization chamber, and / or has an inner volume between 10 cm3and 1,000 cm3.

37. The method of claim 31, wherein the negative pressure gradient is generated using a vacuum pump that is downstream of the sterilization chamber.

38. The method of claim 31, wherein the sterilizing nitric oxide concentration is between 1-50 PPb.

39. The method of claim 31, wherein the sterilizing nitric oxide concentration is maintained for a time of between 10-120 min and / or at a temperature of between 0-50 °C.

40. The method of claim 31, wherein residual nitric oxide is, after use as a sterilant, adsorbed or catalytically destroyed.

Images