Patent Description:
The use of NO in inhalation therapy has also been explored. Inhaled nitric oxide has been used to treat lung failure, and has been shown to enhance pulmonary vasodilation and lower pulmonary vascular resistance. Inhaled nitric oxide has also been used to treat neonates with hypoxic respiratory failure, and has been shown to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation therapy. The use of inhaled nitric oxide may prove to be beneficial in other areas as well, such as during lung transplants, for treating pulmonary hypertension, as an inhaled antiseptic agent, etc. <CIT> discloses a system wherein nitric oxide gas is generated electrochemically from a solution reservoir containing a copper (II) ligand complex and a dissolved source of nitrite. <CIT> discloses polymeric films, which include a polymer matrix having at least one of a discrete or polymeric RSNO adduct, which are capable of releasing nitric oxide. <NPL>) discloses a comparative study, wherein tert-dodecane S-nitrosothiol (tDodSNO) showed to be superior photoactivated nitric oxide donor when compared to S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP).

According to the present invention, there is provided a gas delivery device, comprising:
a nitric oxide (NO) generating system, including:.

Preferred features of the invention are set out in the dependent claims.

Several examples of gas delivery devices are disclosed herein. In the example devices, nitric oxide (NO) gas is generated photolytically on demand from a solid phase nitric oxide donor that is sensitive to light of particular wavelength(s). The solid phase nitric oxide donor is capable of generating NO gas in-situ in response to light exposure to light. In-situ NO gas generation from these NO donor molecules eliminates the need for nitric oxide tanks (i.e., NO in compressed gas cylinders), which simplifies the device and reduces the cost of the device. Some examples of the gas delivery devices disclosed herein do not include any gas tanks, and thus can be configured as portable inhalation devices. Other examples of the gas delivery devices disclosed herein do include at least a nitrogen gas tank, making these examples less portable, but highly suitable, for example, in a hospital setting.

Moreover, with the example gas delivery devices disclosed herein, the amount of NO that is generated can be precisely controlled by varying the pulse length and/or intensity of the light applied to the solid phase nitric oxide donor. This enables a suitable amount of NO to be generated in order to obtain a desired effect in a particular application. As one example, a steady therapeutic dose (e.g., from about <NUM> ppbv (parts per billion by volume) to about <NUM> ppmv (parts per million by volume)) of NO may be generated for inhaled nitric oxide treatments. The concentration of the NO in the output gas stream also depends, at least in part, on the flow rate of the gas(es) utilized. Moreover, with the example gas delivery devices disclosed herein, the amount of NO<NUM> can also be controlled so that it is below a threshold level. In the present invention, an NO<NUM> level in the output gas may be less than <NUM> parts per million by volume (ppmv), and in some instances, may be less than <NUM> ppmv.

In the examples disclosed herein, a nitric oxide donor is used that is in solid form and that is light sensitive. By "solid form," it is meant that the NO donor is not a liquid or a fluid, and is firm and stable in shape. In some examples, the NO donor may be in crystalline or powder form. By "light sensitive," it is meant that the NO donor is photolyzable, i.e., is capable of undergoing photolysis when exposed to a particular wavelength or wavelengths of light. In particular, the NO donor is capable of releasing NO gas molecules when exposed to the particular wavelength or wavelengths of light. Examples of the solid, light sensitive NO donor may include light sensitive S-nitrosothiols. Some specific examples of light sensitive S-nitrosothiols may be selected from the group consisting of S-nitroso-N-acetyl-penicillamine (SNAP) crystals, S-nitrosoglutathione (GSNO) crystals, and combinations thereof.

In the examples disclosed herein, the particular wavelength or wavelengths of light used to generate the nitric oxide may depend, in part, upon the NO donor used and the desired rate of NO release. In the present invention, the light wavelengths range from about <NUM> to about <NUM>. If a particular wavelength results in a lower than desired rate of NO release, this deficiency may be compensated for by using a higher light power surface density.

Also in the examples disclosed herein, the solid phase, light sensitive nitric oxide donor may be immobilized on or in a substrate. By "immobilized," it is meant that the solid, light sensitive nitric oxide donor can be attached to the substrate using an adhesive, or can be doped in or covalently attached to a polymer or other thin film, or can be contained in a cavity formed on the substrate.

Several examples of gas delivery devices are disclosed herein. Each of the gas delivery devices includes a nitric oxide generating system, which itself includes an NO cartridge. <FIG> illustrate five different examples of the NO cartridge.

In <FIG>, the NO cartridge <NUM> includes a substrate <NUM>, the solid, light sensitive NO donor <NUM> immobilized on a surface S<NUM> of the substrate <NUM>, and an NO permeable and light transparent membrane <NUM> positioned on the solid, light sensitive NO donor <NUM>.

In this example, the substrate <NUM> acts as a physical carrier for the NO donor <NUM>. As such, any substrate <NUM> may be used, including polymers, papers, glasses, metals, etc. In some examples, the substrate <NUM> may be impermeable to nitric oxide, or may be selected so that nitric oxide has low solubility in the substrate <NUM>. This may be desirable to prevent the substrate <NUM> from acting as a microreactor for nitrogen dioxide (NO<NUM>) generation.

The solid, light sensitive NO donor <NUM> may be any of the examples set forth herein. While the NO donor <NUM> is shown as a continuous layer in <FIG>, it is to be understood that the NO donor <NUM> may be crystals or powder particles that are spread across the substrate surface S<NUM>.

In this example, the NO donor <NUM> may be immobilized on the substrate <NUM> using an adhesive <NUM>. Examples of suitable adhesives <NUM> include pressure sensitive adhesives, such as elastomers alone or compounded with a tackifier (e.g., a rosin ester). The elastomer can be an acrylic. In some examples, the adhesive <NUM> may be a liquid or gel that is spread on the substrate <NUM>. In other examples, the adhesive <NUM> may be a double-sided tape that is adhered on the substrate <NUM>.

The NO donor <NUM> may be applied to the adhesive <NUM> using any suitable technique. Upon application, pressure may be applied to the NO donor <NUM> to assist in adhering the NO donor <NUM> to the adhesive <NUM>. The adhesive <NUM> enables a relatively consistent distribution of the NO donor <NUM> over the surface area of the substrate <NUM>.

This example of the NO cartridge <NUM> also includes an NO permeable and light transparent membrane <NUM> positioned on the solid, light sensitive NO donor <NUM>. This example membrane <NUM> is permeable to nitric oxide. As such, NO that is released from the NO donor <NUM> can pass through nanopores or micropores of the membrane <NUM> into a recipient gas stream. This example membrane <NUM> is also transparent to the wavelength(s) of light used to release the nitric oxide from the NO donor <NUM>. As such, in this example, light of desirable wavelength(s) (shown as hv in <FIG>) may be transmitted to the NO donor <NUM> through the membrane <NUM>. As examples, the membrane <NUM> may be transparent to one or more wavelengths of light ranging from about <NUM> to about <NUM>.

An example of the NO permeable and light transparent membrane <NUM> includes polycarbonate, such as polycarbonate track etch membranes. Commercially available NO permeable and light transparent membranes <NUM> include WHATMAN® NUCLEPORE™ Track-Etched Membranes (from GE Healthcare) and TRAKETCH® (from Sabeu). These membranes <NUM> may be nanoporous (e.g., diameter ranging from about <NUM> to less than <NUM>) or microporous (e.g., diameter ranging from about <NUM> to less than <NUM>).

The NO permeable and light transparent membrane <NUM> may be positioned on the solid, light sensitive NO donor <NUM> and adhered to the substrate <NUM> using the adhesive <NUM>.

While not shown in <FIG>, the NO cartridge <NUM> may also include a second solid, light sensitive NO donor adhered to the opposed surface S<NUM>, and a second NO permeable and light transparent membrane positioned on the second solid, light sensitive NO donor. This example enables NO to be generated from both sides of the NO cartridge <NUM>. An example of this is shown in <FIG>.

Referring now to <FIG>, another example of the NO cartridge <NUM>' includes a light transparent substrate <NUM>', the solid, light sensitive NO donor <NUM> immobilized on a surface S<NUM> of the light transparent substrate <NUM>', and a porous membrane <NUM>' positioned on the solid, light sensitive NO donor <NUM>.

In this example, the substrate <NUM>' acts as a physical carrier for the NO donor <NUM> and also enabled light hv to be transmitted to the NO donor <NUM>. As such, in this example, any substrate <NUM>' that is transparent to one or more wavelengths of light ranging from about <NUM> to about <NUM> may be used. An example the light transparent substrate <NUM>' is a transparent polymer (e.g., poly(methylmethacrylate), polyethylene terephthalate, etc.) or a glass material. In some examples, the light transparent substrate <NUM>' may be impermeable to nitric oxide, or may be selected so that nitric oxide has low solubility in the substrate <NUM>'. This may be desirable to prevent the substrate <NUM>' from acting as a microreactor for nitrogen dioxide (NO<NUM>) generation.

In this example, the NO donor <NUM> may be immobilized on the substrate <NUM>' using a light transparent adhesive <NUM>'. The adhesive <NUM>' may be selected to be transparent to the wavelength of light being used in the application. In some examples, the adhesive <NUM>' is transparent to ultraviolet wavelengths. In other examples, the adhesive <NUM>' is transparent to wavelengths of light ranging from about <NUM> to <NUM>. The NO donor <NUM> may be applied to the adhesive <NUM>' using any suitable technique. Upon application, pressure may be applied to the NO donor <NUM> to assist in adhering the NO donor <NUM> to the adhesive <NUM>'. The adhesive <NUM>' enables a relatively consistent distribution of the NO donor <NUM> over the surface area of the substrate <NUM>'. The adhesive <NUM>' is also a very thin layer, and thus any absorbance that might otherwise take place is low.

This example of the NO cartridge <NUM>' also includes a porous membrane <NUM>' positioned on the solid, light sensitive NO donor <NUM>. This example membrane <NUM>' may or may not be transparent to the wavelength(s) of light used to release the nitric oxide from the NO donor <NUM>. This example membrane <NUM>' is also porous, and thus permeable to nitric oxide. As such, NO that is released from the NO donor <NUM> can pass through nanopores or micropores of the membrane <NUM>' into a recipient gas stream. Examples of non-transparent, porous membranes <NUM>' include porous polytetrafluoroethylene (PTFE), polypropylene, polyethylene, polyamide, polyvinylidene difluoride, etc. Examples of transparent, porous membranes <NUM>' include any of the examples provided for the membrane <NUM>. These membranes <NUM>' may be nanoporous or microporous.

The porous membrane <NUM>' may be positioned on the solid, light sensitive NO donor <NUM> and adhered to the substrate <NUM>' using the adhesive <NUM>' or <NUM>.

For either of the NO cartridges <NUM>, <NUM>', the dimensions of the substrate <NUM>, <NUM>' and the membrane <NUM>, <NUM>', and the amount of the NO donor <NUM> may depend, in part, upon the dimensions of the gas delivery device in which the cartridge <NUM>, <NUM>' is to be used as well as the desirable rate of NO release. As an example, <NUM> SNAP is enough for generating <NUM> ppm NO in <NUM>/min flow rate for <NUM> hours. For this example, <NUM> x <NUM> of SNAP can be distributed on a <NUM> x <NUM> diameter circular surface and covered with a <NUM> microporous membrane. For increasing the NO release duration, flow rate, or concentration, the amount of the NO donor <NUM> should also be increased. Sheet filter materials (e.g., for the membrane <NUM>, <NUM>') may be available in sizes up to <NUM> x <NUM>, and thus can be cut to any desirable size and/or shape.

Referring now to <FIG>, another example of the NO cartridge <NUM>" includes a substrate <NUM>" and the solid, light sensitive NO donor <NUM> immobilized in the substrate <NUM>".

In this example, the substrate <NUM>" may be transparent to the light hv that is to be transmitted to the NO donor <NUM>, and may also be permeable to the generated NO gas. Examples of the substrate <NUM>" include silicone rubber, poly(vinyl chloride), polyurethane, etc..

While not shown, it is to be understood that the substrate <NUM>" having the NO donor <NUM> therein may be positioned on another physical carrier. In these instances, the physical carrier is micro-structured or porous, or the substrate <NUM>" having the NO donor <NUM> therein is attached to the physical carrier with a limited surface area. These configurations facilitate easy gas transport from the side of the substrate <NUM>" having the NO donor <NUM> therein facing the physical carrier, and prevent gas build up between the substrate <NUM>" having the NO donor <NUM> and the physical carri er.

In an example, the NO donor <NUM> may be immobilized in the substrate <NUM>" using a solvent swelling method. With this method, the solid NO donor <NUM> is dissolved in a swelling solvent of the substrate <NUM>" at a concentration that exceeds its solubility threshold in the substrate <NUM>". A swelling solvent does not dissolve the substrate <NUM>", but rather, the substrate <NUM>" uptakes the swelling solvent (and the NO donor dissolved therein) and becomes swollen. When the solvent evaporates, the NO donor <NUM> remains in its crystal form within the bulk of the substrate <NUM>". In another example, the NO donor <NUM> may be immobilized in the substrate <NUM>" by blending the solid NO donor <NUM> with an uncured substrate material to form a mixture, casting a film of the mixture, and curing the substrate material. The solid NO donor <NUM> becomes embedded into the cured substrate <NUM>".

The solid, light sensitive NO donor <NUM> may be any of the examples set forth herein.

For the NO cartridges <NUM>", the dimensions of the substrate <NUM>", and the amount of the NO donor <NUM> may depend, in part, upon the dimensions of the gas delivery device in which the cartridge <NUM>" is to be used as well as the desirable rate of NO release. Moreover, the amount of the NO donor <NUM> may also depend upon the method used to introduce the NO donor <NUM> to the substrate <NUM>".

Referring now to <FIG>, still other examples of the NO cartridge 10A and 10B are depicted. In these examples, the NO donor <NUM> is introduced and immobilized in one or more cavities <NUM> that are formed on the substrate <NUM> or <NUM>'. It has been found that the NO<NUM> level from these NO cartridges 10A, 10B is very low (e.g., < <NUM> ppm), and thus these NO cartridges 10A, 10B may be used without an NO<NUM> scrubber.

These NO cartridges 10A and 10B may include the substrate <NUM> and the NO permeable and light transparent membrane <NUM> (as described in reference to <FIG>) or the light transparent substrate <NUM>' and the porous membrane <NUM>' (as described in reference to <FIG>).

In one example of <FIG>, the substrate <NUM> and the NO permeable and light transparent membrane <NUM> are adhered using an adhesive <NUM>". This example adhesive includes adhesive portions <NUM> on opposed sides of a core layer <NUM>. In this example, since the light hv is introduced through the light transparent membrane <NUM>, the adhesive <NUM> and the core layer <NUM> may not be transparent. Any example of the adhesive <NUM> disclosed herein may be used, and any non-transparent core layer <NUM> may be used.

In another example of <FIG>, the light transparent substrate <NUM>' and the porous membrane <NUM>' are adhered using an adhesive <NUM>". This example adhesive includes adhesive portions <NUM>' on opposed sides of a core layer <NUM>. In this example, since the light hv is introduced through the light transparent substrate <NUM>', the adhesive <NUM>' and the core layer <NUM> may be transparent. Some examples of the transparent adhesive <NUM>" include <NUM>™ Optically Clear Adhesive CEF08XX (821X/818X) Series and <NUM>™ Ultra-clean Laminating Adhesives 501FL and 502FL.

In <FIG>, one layer of the adhesive <NUM>" is included, where the single layer <NUM>" includes one core layer <NUM> and the adhesive <NUM> or <NUM>' on opposed sides of the one core layer <NUM>. In <FIG>, multiple layers of the adhesive <NUM>" are included, which include two or more core layers <NUM> and the adhesive <NUM> or <NUM>' on opposed sides of each of the two or more core layers <NUM>. As depicted, the multi-layered adhesive <NUM>" in <FIG> includes alternating layers of the adhesive <NUM> or <NUM>' and the core layers <NUM>, with the adhesive <NUM> or <NUM>' at the outermost sides to adhere the substrate <NUM> to the light transparent membrane <NUM> or to adhere the light transparent substrate <NUM>' to the porous membrane <NUM>'.

As shown in both <FIG>, a cavity <NUM> is formed in the adhesive <NUM>". While a single cavity <NUM> is shown, it is to be understood that any number of cavities may be included. In the top view of <FIG>, multiple cavities <NUM> are included.

In one example, the cavity/cavities <NUM> are formed into the single or multi-layered adhesive <NUM>" using a cutting plotter. The cavity/cavities <NUM> may be formed in the adhesive <NUM>" before the adhesive <NUM>" is secured to the substrate <NUM> or <NUM>'. Liners may be removably attached to the adhesive <NUM> or <NUM>' at the outermost sides when the cavity/cavities <NUM> are defined in the single or multi-layered adhesive <NUM>". The lateral dimension (e.g., diameter) of each cavity <NUM> may depend, in part upon the fabrication method, the NO donor <NUM> particle size, etc. In an example, the lateral dimension ranges from about <NUM> to about <NUM>. In another example, the lateral dimension of the cavity <NUM> is about <NUM>. The depth of each cavity <NUM> may depend upon the thickness of the adhesive <NUM>". In an example, the depth ranges from about <NUM> to about <NUM>.

One of the liners may be removed in order to attach the single or multi-layered adhesive <NUM>" (having the cavity/cavities <NUM> defined therein) to the substrate <NUM> or <NUM>'. The other of the liners may remain in place when the NO donor <NUM> is introduced into the cavity/cavities <NUM>.

The NO donor <NUM> may be deposited into the cavity/cavities <NUM> using any suitable technique, such as screen printing, electrostatic deposition, xerography, etc. The solid, light sensitive NO donor <NUM> may be any of the examples set forth herein.

Once the NO donor <NUM> is deposited, the other of the liners may be removed, and the light transparent membrane <NUM> or the porous membrane <NUM>' may be adhered to the adhesive <NUM>".

The NO cartridges <NUM>, <NUM>', <NUM>", 10A, 10B may be used in one or more gas delivery devices. <FIG> illustrate different examples of the gas delivery devices disclosed herein. Each of the gas delivery devices may be used to generate nitric oxide for inhalation therapy. With each device, the method generally involves generating nitric oxide gas by selectively applying light to a solid, light sensitive NO donor; mixing the nitric oxide gas with an oxygen-containing gas to form an output gas stream; and monitoring a nitric oxide level and a nitrogen dioxide level of the output gas stream at least prior to delivery to an inhalation unit. The methods may vary somewhat depending upon the device that is used. As such, each method will be described in more detail with the corresponding gas delivery device.

Referring now to <FIG>, one example of the gas delivery device 20A is depicted. The gas delivery device 20A is suitable for use with the NO cartridge <NUM> shown in <FIG> or the NO cartridges 10A or 10B shown in <FIG>. In this example, the gas delivery device 20A includes: i) a nitric oxide (NO) generating system 22A, which includes a chamber <NUM>, the NO cartridge <NUM>, 10A, or 10B contained within the chamber <NUM> (where the NO cartridge <NUM>, 10A, or 10B includes the substrate <NUM>, the solid, light sensitive NO donor <NUM> immobilized on the surface S<NUM> of the substrate <NUM>, and the NO permeable and light transparent membrane <NUM> positioned on the solid, light sensitive NO donor <NUM>), and a light source <NUM> operatively positioned to selectively expose the solid, light sensitive NO donor <NUM> to light hv to generate NO gas; ii) an inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> to introduce an oxygen-containing gas OC and form an output gas OG including the NO gas; and iii) an outlet conduit <NUM> to transport a stream of the output gas OG from the NO generating system 22A. While not specifically shown in <FIG>, it is to be understood that the solid, light sensitive NO donor <NUM> may be immobilized on the surface S<NUM> of the substrate <NUM> using an adhesive <NUM> (e.g., as described in reference to <FIG>) or using the cavity/cavities <NUM> (e.g., as described in reference to <FIG>).

With the gas delivery device 20A, the method includes: operating the light source <NUM> to emit light onto the NO donor <NUM>, which photolytically releases NO from the donor <NUM> within the chamber <NUM>; introducing an oxygen-containing gas OC into the chamber <NUM>, where the NO and the oxygen-containing gas OC mix to form an output gas OG; and transporting the output gas OG from the chamber <NUM> to a desired destination. Details of this method and the gas delivery device 20A will now be described.

The NO generating system 22A of the device 20A includes the chamber <NUM> where photolysis takes place (i.e., a photolysis chamber). The chamber <NUM> may be made of any suitable material that can contain the cartridge <NUM>, and that is not permeable to the oxygen-containing gas OC or to nitric oxide NO. If the light source <NUM> is positioned outside of the chamber <NUM> (as shown in <FIG>), the chamber <NUM> should be formed of a material that is transparent to the wavelength(s) of light hv emitted by the light source <NUM>. In this example, the chamber may be formed of glass, acrylonitrile butadiene styrene (ABS), low density polyethylene (LDPE), etc. If the light source <NUM> is positioned inside of the chamber <NUM>, the chamber <NUM> should be formed of a material that is non-transparent to the wavelength(s) of light hv emitted by the light source <NUM>. In this example, the chamber <NUM> may be formed of polytetrafluoroethylene (PTFE), high density polyethylene (HDPE), stainless steel, etc..

The chamber <NUM> may be sealed around an inlet <NUM> (connected to a conduit <NUM> used to introduce the oxygen-containing gas OC) and an outlet <NUM> (connected to a conduit <NUM> used to transport a stream of the output gas OG). The chamber <NUM> may also be disposable so that the entire NO generating system 22A can be discarded at the end of its useful life, or the chamber <NUM> can include an opening through which the NO cartridge <NUM>, 10A, or 10B can be replaced.

The NO generating system 22A also includes the cartridge <NUM>, 10A, or 10B. The NO cartridge <NUM> may be any of the examples described in reference to <FIG>, and the NO cartridge 10A, 10B may be any of the examples described in reference to <FIG> that includes the substrate <NUM> and the NO permeable and light transparent membrane <NUM>. In the example shown in <FIG>, the NO cartridge <NUM>, 10A, or 10B includes the NO donor <NUM> and the NO permeable and light transparent membrane <NUM> positioned on both surfaces S<NUM>, S<NUM> of the substrate <NUM>, and thus, NO can be generated from both sides of the NO cartridge <NUM> using separate light sources <NUM>. While not shown in detail in <FIG>, the NO donor <NUM> may be positioned on the substrate surfaces S<NUM>, S<NUM> with the adhesive <NUM> or within the cavity/cavities <NUM>.

The NO generating system 22A also includes the light source <NUM>. Any light source <NUM> may be used that is capable of emitting light that initiates photolysis of the solid, light sensitive NO donor <NUM>. In other words, any light source <NUM> may be used that is capable of emitting the particular wavelength or wavelengths of light that cause the nitric oxide to be released from the NO donor <NUM>. As such, the light source <NUM> may depend, in part, upon the NO donor <NUM> used and the desired rate of NO release. As examples, the light source <NUM> may be a high intensity light emitting diode (LED), a laser diode, a lamp, etc. Suitable LEDs may be those having a nominal wavelength ranging from about <NUM> to about <NUM>, such as <NUM>, or <NUM>, or <NUM>, or <NUM>.

One or more light sources <NUM> may be used to release NO from the NO donor <NUM> positioned on a single surface S<NUM> or S<NUM>. The use of multiple light sources may enable further control over the NO release. For example, if higher levels of NO are desirable, all of the light sources <NUM> facing the surface S<NUM> may be activated to emit light toward the NO donor <NUM> on the surface S<NUM>, and if lower levels of NO are desirable, less than all of the light sources <NUM> may be activated.

The light source <NUM> is positioned to selectively expose the NO donor <NUM> to light hv. The light source <NUM> may be positioned outside of a light transparent chamber <NUM> or may be positioned inside of a non-transparent chamber <NUM>. In some examples, the light source <NUM> may be attached to the chamber <NUM> (e.g., either inside or outside). In these examples and when the chamber <NUM> is disposable, the light source <NUM> may be disposed of with the chamber <NUM>. In these examples and when the chamber <NUM> is not disposable (but rather receives a disposable cartridge <NUM>), the light source <NUM> may be reused with several NO cartridges <NUM>. In these examples, the light source <NUM> may also be removable from the inside or outside of the chamber <NUM> so that it can be replaced at the end of its useful life. In some other examples, the light source <NUM> may be attached to a device housing (not shown) that also houses the chamber <NUM>. In these examples, the light source <NUM> may not be directly attached to the chamber <NUM>, but is positioned to direct the light hv to the NO donor <NUM> when operated. In these examples, the light source <NUM> may be removable from the device housing so that it can be replaced at the end of its useful life.

When the light source <NUM> is attached to the inside of the chamber <NUM>, any adhesive or other suitable securing mechanism may be used to attach the light source <NUM> to an interior chamber wall. When the light source <NUM> is attached to the outside of the chamber <NUM> (as shown in <FIG>), any light transparent adhesive <NUM> or other suitable securing mechanism that will not block the light from the light source <NUM> may be used to attach the light source <NUM> to an exterior chamber wall. The light source <NUM> may also be operatively positioned outside of, but not attached to the chamber <NUM>.

Electronic circuitry may be operatively connected to the light source <NUM> to control when the source(s) <NUM> is/are turned ON and OFF, the duration of an ON cycle, the intensity, the power surface density, etc. The electronic circuitry may be part of a sensing and feedback system, which will be described in further detail below.

The light source <NUM> may be turned ON for any time interval up to, for example, <NUM> hours per cartridge <NUM>, and thus may photolytically release NO during this time interval. Longer time intervals may be possible, depending upon the amount of NO donor <NUM> in the cartridge <NUM>. When it is desired to stop generating NO, the light source <NUM> is turned OFF so that light hv is no longer emitted on the NO donor <NUM>. The NO release lifetime may be longer when larger substrates <NUM> are used and/or when higher amounts of the NO donor <NUM> are used.

In this example, the NO gas released from the NO donor <NUM> permeates through the membrane <NUM> and into the chamber <NUM>. The photolysis of the NO donor <NUM> may generate aerosol droplets as well as the NO gas. Aerosol droplets are undesirable for various medical applications. It is to be understood that the membrane <NUM> prevents any aerosol droplets from entering the chamber <NUM> with the NO gas.

The gas delivery device 20A shown in <FIG> also includes the inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> (e.g., at inlet <NUM>) to introduce the oxygen-containing gas OC to the chamber <NUM>. The oxygen-containing gas OC may be at least substantially pure oxygen gas O<NUM>, or air, or a hypoxic gas that includes oxygen. In this example, the oxygen-containing gas OC may be delivered from any suitable gas source (e.g., compressed gas cylinder (not shown), gas pump <NUM> that delivers ambient air, etc.), which can regulate the flow of the oxygen-containing gas OC, or can be coupled to a flow controller to regulate the flow of the oxygen-containing gas OC into the inlet <NUM>. Any suitable gas flow rate may be used. As an example, the flow rate of the oxygen-containing gas OC may range from about <NUM>/min to about <NUM>/min. In another example, the source or flow controller may regulate the flow of the oxygen-containing gas OC so that the output gas stream OG contains from about <NUM>% oxygen to about <NUM>% oxygen. In an example, <NUM>% air saturation may be used as the oxygen-containing gas OC, which corresponds to about <NUM>/L (ppm) of O<NUM> in the output gas stream OG.

The inspiratory gas conduit <NUM> may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide. Examples of suitable tubing material include poly(vinyl chloride) (PVC), polyurethane (PU), polyethylene (PE), fluorinated polymers, etc..

In the chamber <NUM>, the oxygen-containing gas OC mixes with the photolytically released NO gas to form an output gas stream OG. A stream of the output gas OG may exit the NO generating system 22A through an outlet <NUM> into the outlet conduit <NUM>. The outlet conduit <NUM> may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide in the output gas OG. The length of the outlet conduit <NUM> may also be relatively short in order to avoid nitrogen dioxide (NO<NUM>) formation before the stream is delivered to a desirable destination (e.g., a recipient <NUM>). Since the oxygen-containing gas OC is introduced just prior to delivery to the recipient <NUM>, the impact on the NO concentration is minimal or nil due to the short contact time between the NO and the oxygen-containing gas OC.

In some examples, the output gas OG stream may be transported as a result of pressure from the gas source, which may include a regulator to control the flow rate. In other examples, the output gas OG stream may be transported as a result of pressure from a vacuum positioned downstream.

The outlet conduit <NUM> may be, or may be operatively connected to, a delivery conduit <NUM>. The delivery conduit <NUM> is operatively connected to an inhalation unit <NUM>, which is capable of transporting the output gas stream OG to a recipient/patient <NUM>. The delivery conduit <NUM> may be any suitable polymeric or other tubing that is impermeable to the output gas stream OG. In an example, the delivery conduit <NUM> may also have a one-way valve so that the output gas stream OG does not flow back into the NO generating system 22A. The inhalation unit <NUM> may be a ventilator, a face mask, a nasal cannula, or some other suitable apparatus for delivering the output gas stream OG to the airways of the patient <NUM>.

The gas delivery device 20A may further include a sensing and feedback system. In an example, the sensing and feedback system includes a sensor <NUM> in contact with the output gas stream OG to monitor the nitric oxide level (i.e., NO concentration) of the output gas OG, and a controller <NUM> that is operatively connected to the sensor <NUM> and the light source <NUM>, where the controller <NUM> can adjust a parameter of the light source <NUM> in response to the nitric oxide level from the sensor <NUM>. While not shown, it is to be understood that the sensing and feedback system may also include a separate sensor for monitoring the NO<NUM> concentration.

The sensor(s) <NUM> may be positioned in contact with the output gas stream OG. The sensor(s) <NUM> may be positioned in the output conduit <NUM> or in the delivery conduit <NUM>, or in another conduit that is split or branched off of the output or delivery conduit <NUM>, <NUM>. When the other conduit is used, it receives at some of the output gas stream OG and transports it to the sensor <NUM>. The sensor(s) <NUM> may be used to monitor the NO levels and the NO<NUM> levels in the output gas stream OG. It may be desirable to monitor the NO level and the NO<NUM> level for feedback control. In particular, feedback control helps to avoid forming NO<NUM> (nitrogen dioxide), which can be generated by the reaction of O<NUM> with NO and can be toxic to the recipient/patient <NUM>.

It may be desirable to position the sensor(s) <NUM> close to the photolysis chamber (e.g., <NUM>, <NUM>', <NUM>) in order to better feedback control the NO release. It may also be desirable to position the sensor(s) <NUM> close to the inhalation unit <NUM> (e.g., within about <NUM> feet of the inhalation unit <NUM>). This positioning may be desirable to ensure that the gas stream entering the patient <NUM> has higher levels of NO and lower levels of NO<NUM>, although this positioning could also delay the feedback control.

Any suitable NO sensor <NUM> may be used. In an example, the sensor <NUM> is an amperometric NO sensor. One type of amperometric sensor is a Shibuki-style sensor (not shown), which is based on the oxidation of NO to nitrate (NO<NUM>-) at an inner platinum (Pt) electrode position behind a gas permeable membrane. In another example, the sensor <NUM> is a chemiluminescence sensor.

Another example amperometric NO sensor includes working electrode(s) (e.g., platinum, gold, etc.) directly deposited (e.g., by chemical reduction) on the surface of a polymer electrolyte (i.e., an ionomer film). This example of the sensor <NUM> also includes a reference electrode and a counter electrode, which are immersed in an inner electrolyte solution that also wets the ionomer phase. In this sensor, the portion of the output gas stream OG flows over the surface of the working electrode(s). A positive potential is applied (e.g., about 1V versus Ag/AgCl), and electrochemical reactions occur at the interface of the working electrode(s) and the ionomer film. In an example, the positive potential applied to the working electrode(s) ranges from about <NUM> V to about <NUM> V. The NO in the output gas stream OG electrochemically oxidizes to nitrite/nitrate to output current signals proportional to NO(g) levels.

In other examples, the amperometric NO sensor can include another working electrode on the same surface of the ionomer film as the working electrode(s), and a less positive potential may be applied to that other working electrode so that only NO<NUM> is oxidized (and not NO) and sensed (via current measured). The NO sensor signal can be corrected for any NO<NUM> present using a bipotentiostat. These amperometric NO sensors exhibit relatively rapid response times, and a high surface area of the working electrode(s) yields larger currents than the Shibuki configuration.

As mentioned herein, it is to be understood that another sensor may also be included to monitor the NO<NUM> levels in the output gas stream OG.

The sensor data (i.e., the concentration of NO in the output gas stream OG and/or the concentration of NO<NUM> in the output gas stream OG) is transmitted to the controller <NUM>. In an example, the controller <NUM> is a PID controller (a proportional-integral-derivative controller). <FIG> illustrates a schematic diagram of the electronic circuitry in the sensing and feedback system, including, along the other listed components, the sensor(s) <NUM>, the controller <NUM>, and the light source(s) <NUM>. The ISB is an individual sensor board, which is a potentiostat that keeps the working electrode versus the reference electrode at a constant potential and measures the current. The ISB also converts the measured current to an analog (e.g., 0V - 3V or 0V - 5V voltage signal or <NUM> mA - <NUM> mA current) signal which can be easily converted to a digital signal (with the analog digital (A/D) converter) and processed within the controller unit <NUM>. The feedback from the sensor <NUM> may be used to servo-regulate one or more parameters of the light source(s) <NUM> to achieve an at least substantially constant concentration of NO at the delivery end. The data may also be used to regulate the flow of the output gas stream OG.

When the sensor data indicates that the NO level is too high or too low, the light source <NUM> may be turned ON or OFF, the light intensity and/or power surface density may be adjusted, and/or the flow rate of one or more of the gases may be adjusted. In an example, the sensor <NUM> monitors a nitric oxide level of the output gas stream OG, and based on the nitric oxide level of the output gas stream OG, the controller <NUM> one of: maintains the current status of the light source(s)<NUM> (e.g., when the NO is at a desired level); or adjusts the light source(s) <NUM> to increase NO production (e.g., when the nitric oxide level of the output gas stream OG is below a target level); or adjusts the light source(s) <NUM> to decrease NO production (e.g., when the nitric oxide level of the output gas stream OG is above the target level). When the sensed NO level is too low, one or more of the light source(s) <NUM> may be turned ON or turned up. For example, if multiple light sources <NUM> are included and one is ON when the low level is sensed, an additional light source <NUM> may be turned ON to increase the NO release rate. When the sensed NO level is too high, one or more of the light source(s) <NUM> may be turned OFF or turned down. As an example, the light intensity and/or power surface density may be modulated to be increased or decreased in order to increase or decrease, respectively, the rate of NO release, and thus the flux of NO swept from the NO generating device 22A and present in the output gas stream OG.

The target NO level may be based upon the given application in which the NO is being used. The target level may be very low or very high, depending upon the patient <NUM> and the application. As examples, the target level of NO for a newborn on inhalation therapy may range from about <NUM> ppm to about <NUM> ppm, and the target level of NO to be generated in an oxygenator to prevent activation of platelets and other cells during bypass surgery may range from about <NUM> ppm to about <NUM> ppm. Further, for antimicrobial applications, such as for lung infections, lower levels of NO may be useful for inhalation therapy, in the range of, for example, from about <NUM> ppb to about <NUM> ppm.

The sensor data may also be used to determine whether an undesirable amount of NO<NUM> is present in the output gas stream OG. If an undesirable amount of NO<NUM> is present, an alarm on the device 20A may be initiated and/or the flow rate may be adjusted to reduce the output gas OG delivery from the system 20A and/or the NO level may be adjusted accordingly.

The gas delivery device 20A may also include a nitrogen dioxide (NO<NUM>) filter <NUM>. The NO<NUM> filter <NUM> may be positioned in the delivery conduit <NUM> to receive the output gas stream OG before it is delivered to the inhalation unit <NUM>. Some examples of the NO<NUM> filter <NUM> remove at least some of the nitrogen dioxide from the output gas stream OG. As examples, a silica gel filter (with pre-conditioned silica particles) or a soda lime scrubber. These filters <NUM> may reduce the NO<NUM> to a level that is not physiologically relevant. Other examples of the NO<NUM> filter <NUM> convert the nitrogen dioxide back into nitric oxide. This conversion is desirable because no NO payload is lost in the form of scavenged (absorbed) NO<NUM>, but rather is reduced back into NO. An example of this type of NO<NUM> filter <NUM> includes ascorbic acid impregnated silica particles.

Referring now to <FIG>, another example of the gas delivery device 20B is depicted. The gas delivery device 20B is suitable for use with the NO cartridge <NUM> shown in <FIG> or with the NO cartridge <NUM>" shown in <FIG> or with the NO cartridge 10A, 10B shown in <FIG>. In this example, the gas delivery device 20B includes: i) a nitric oxide (NO) generating system 22B, which includes a vacuum environment <NUM>, the NO cartridge <NUM>, <NUM>", 10A, or 10B contained within the vacuum environment <NUM> (where the NO cartridge <NUM>, <NUM>" includes at least the substrate <NUM> or <NUM>" and the solid, light sensitive NO donor <NUM> immobilized on the substrate <NUM> or in the substrate <NUM>"), and a light source <NUM> operatively positioned to selectively expose the solid, light sensitive NO donor <NUM> to light hv to generate NO gas; ii) an outlet conduit <NUM>' to transport a stream of the NO gas from the NO generating system 22B; and iii) an inspiratory gas conduit <NUM>' operatively connected to the outlet conduit <NUM>' to introduce an oxygen-containing gas OC and form an output gas OG stream.

With the gas delivery device 20B, the method includes operating the light source <NUM> to emit light onto the NO donor <NUM>, which photolytically releases NO gas from the donor <NUM> within the vacuum environment <NUM>; transporting the NO gas from the vacuum environment <NUM> through an outlet conduit <NUM>'; introducing an oxygen-containing gas OC to the NO gas to form an output gas OG; and transporting the output gas OG to a desired destination.

In the vacuum environment <NUM>, the NO gas is generated in the absence of oxygen, which prevents NO<NUM> from forming. As such, the vacuum environment <NUM> may be particularly desirable for the NO cartridge <NUM>", which may include a substrate <NUM>" (e.g., silicone rubber) that is permeable to both NO and O<NUM>, and thus can act as a microreactor for NO<NUM> generation. Because the vacuum environment <NUM> is devoid of oxygen, the NO cartridge <NUM>" used in the vacuum environment can effectively photolytically release NO without also generating NO<NUM>. It is to be understood that the cartridge <NUM> (which does not act as a microreactor for NO<NUM> generation) may also be used in the vacuum environment <NUM>.

Details of this method and the gas delivery device 20B will now be described.

The NO generating system 22B of the device 20B includes the vacuum environment <NUM> where photolysis takes place (i.e., a photolysis chamber). The vacuum environment <NUM> may be a vacuum chamber may be made of any suitable material that can contain the cartridge <NUM> or <NUM>" and that can have air and other gases removed by a vacuum pump. Example materials for the vacuum environment <NUM> include stainless steel, aluminum, brass, high density ceramics, glass or acrylics. When a non-transparent material is used for the vacuum environment <NUM>, the vacuum environment <NUM> may include a window <NUM> formed of a material that is transparent to the wavelength(s) of light hv emitted by the light source <NUM>.

The vacuum environment <NUM> may include an opening through which the NO cartridge <NUM>, <NUM>", 10A, or 10B can be replaced at the end of its useful life.

The vacuum environment <NUM> also has outlet <NUM> operatively connected to a vacuum pump <NUM>, which can pump the NO gas out of the vacuum environment <NUM> into an outlet conduit <NUM>'.

The NO generating system 22B also includes the cartridge <NUM>, <NUM>", 10A, or 10B. The NO cartridge <NUM> may be any of the examples described in reference to <FIG>, or the NO cartridge <NUM>" may be any of the examples described in reference to <FIG>, or the NO cartridge 10A, 10B may be any of the examples described in reference to <FIG>, and the NO cartridge 10A, 10B may be any of the examples described in reference to <FIG> that includes the substrate <NUM> and the NO permeable and light transparent membrane <NUM>. It is to be understood that the cartridge <NUM>, <NUM>", 10A, or 10B may be positioned within the vacuum environment so that the NO donor <NUM> directly faces the light source <NUM>.

The NO generating system 22B also includes the light source <NUM>. The light source <NUM> may be any of the examples described in reference to <FIG>. The light source <NUM> may be positioned to selectively expose the NO donor <NUM> to light hv. In the device 22B, it may be desirable to position the light source <NUM> outside of a vacuum environment <NUM>. In some of these examples, the light source <NUM> may be directly attached to the outside of the vacuum environment <NUM> via any light transparent adhesive or other suitable securing mechanism that will not block the light from the light source <NUM>. In some other of these examples, the light source <NUM> may not be attached to the outside of the vacuum environment <NUM>, but rather may be operatively positioned to emit light hv through the window <NUM> (as shown in <FIG>).

Electronic circuitry may be operatively connected to the light source <NUM> to control when the source(s) <NUM> is/are turned ON and OFF, the duration of an ON cycle, the intensity, the power surface density, etc. In this example device 20B, the light source <NUM> may be turned ON for any time interval up to, for example, <NUM> hours per cartridge <NUM>, <NUM>", 10A, or 10B and thus may photolytically release NO during this time interval. Longer time intervals may be possible, depending upon the amount of NO donor <NUM> in the cartridge <NUM>, <NUM>", 10A, or 10B. When it is desired to stop generating NO, the light source <NUM> is turned OFF so that light hv is no longer emitted on the NO donor <NUM>. The NO release lifetime may be longer when larger substrates <NUM> or <NUM>" are used and/or when higher concentrations of the NO donor <NUM> are used.

In this example, the photolysis of the NO donor <NUM> generates pure NO gas (i.e., no other gases). Any aerosol droplets that are formed may be i) prevented from entering the vacuum environment <NUM> by the membrane <NUM> of the NO cartridge <NUM>, 10A, or 10B or ii) remain trapped within the substrate <NUM>" of the NO cartridge <NUM>", 10A, or 10B.

As such, the NO gas released from the NO donor <NUM> is the only gas present in the vacuum environment <NUM>. The pure NO gas may be transported out of the vacuum environment <NUM> as a result of pressure from a vacuum pump <NUM>. The NO gas may be transported through an outlet conduit <NUM>' (which may be formed of the same materials as outlet conduit <NUM> described in reference to <FIG>).

The gas delivery device 20B shown in <FIG> also includes the inspiratory gas conduit <NUM>' operatively connected to the outlet conduit <NUM>' to introduce the oxygen-containing gas OC to the NO gas within the conduit <NUM>'. The inspiratory gas conduit <NUM>' may be any of the materials described for the inspiratory gas conduit <NUM>. Moreover, the oxygen-containing gas OC may be any of the examples mentioned in reference to <FIG> (e.g., pure oxygen gas O<NUM>, or air, or a hypoxic gas that includes oxygen) and may be delivered from any of the gas sources mentioned in reference to <FIG>. The oxygen-containing gas source can include, or be coupled to, a flow controller to regulate the flow of the oxygen-containing gas OC into the inspiratory gas conduit <NUM>'. Any suitable gas flow rate may be used as described herein.

In the inspiratory gas conduit <NUM>', the oxygen-containing gas OC mixes with the photolytically released NO gas to form an output gas stream OG of the device 20B.

In the gas delivery device 20B, the outlet conduit <NUM>' and the inspiratory gas conduit <NUM>' may be operatively connected to, or may be integrally formed with, the delivery conduit <NUM>. The delivery conduit <NUM> is operatively connected to an inhalation unit <NUM>, which is capable of transporting the output gas stream OG to a recipient/patient <NUM>. The delivery conduit <NUM> and the inhalation unit <NUM> may be any of the examples described herein in reference to <FIG>.

In this example, the length of the inspiratory gas conduit <NUM>' and the delivery conduit <NUM> may be relatively short in order to avoid NO<NUM> formation before the stream is delivered to a desirable destination (e.g., a recipient <NUM>). Since the oxygen-containing gas OC is introduced just prior to delivery to the recipient <NUM>, the impact on the NO concentration is minimal or nil due to the short contact time between the NO and the oxygen-containing gas OC.

The gas delivery device 20B may further include a sensing and feedback system. In an example, the sensing and feedback system includes the sensor <NUM> in contact with the output gas stream OG to monitor the nitric oxide level (i.e., NO concentration) of the output gas OG, and a controller <NUM> that is operatively connected to the sensor <NUM> and the light source <NUM>, where the controller <NUM> can adjust a parameter of the light source <NUM> in response to the nitric oxide level from the sensor <NUM>. The sensor(s) in this example may also be used to monitor the nitrogen dioxide level of the output gas OG. The sensing and feedback system (including the sensor <NUM>, controller <NUM>, and electronic circuitry) may be any of the examples described herein in reference to <FIG>. The sensor data (i.e., the concentration of NO in the output gas stream OG and/or the concentration of NO<NUM> in the output gas stream OG) may be used as described in reference to <FIG>, e.g., to increase or decrease NO release from the NO generating system 22B.

The gas delivery device 20B may also include a nitrogen dioxide (NO<NUM>) filter <NUM>. The NO<NUM> filter may be positioned in the delivery conduit <NUM> to receive the output gas stream OG before it is delivered to the inhalation unit <NUM>. Any examples of the NO<NUM> filter <NUM> described herein may be used in the gas delivery device 20B.

Referring now to <FIG>, still another example of the gas delivery device 20C is depicted. The gas delivery device 20C is suitable for use with the NO cartridge <NUM> shown in <FIG> or with the NO cartridge <NUM>" shown in <FIG>, or with the NO cartridge 10A or 10B shown in <FIG>. In this example, the gas delivery device 20C includes: i) a nitric oxide (NO) generating system 22C, which includes a chamber <NUM>, the NO cartridge <NUM> or <NUM>" contained within the chamber <NUM>' (where the NO cartridge <NUM>, <NUM>", 10A, or 10B includes at least the substrate <NUM> or <NUM>" and the solid, light sensitive NO donor <NUM> immobilized on the substrate <NUM> or in the substrate <NUM>"), and a light source <NUM> operatively positioned to selectively expose the solid, light sensitive NO donor <NUM> to light hv to generate NO gas; ii) an inlet conduit <NUM> to deliver nitrogen gas N<NUM> to the chamber <NUM>'; iii) an outlet conduit <NUM>" to transport a stream of nitrogen gas and NO gas from the chamber <NUM>'; and iv) an inspiratory gas conduit <NUM>" operatively connected to the outlet conduit <NUM>" to introduce an oxygen-containing gas OC and form an output gas OG stream of the device 20C.

With the gas delivery device 20C, the method includes operating the light source <NUM> to emit light onto the NO donor <NUM>, which photolytically releases NO gas from the donor <NUM> within the chamber <NUM>'; introducing nitrogen gas into the chamber <NUM> to sweep the NO gas from the chamber <NUM>'; transporting the N<NUM>/NO gas mixture from the chamber <NUM> through an outlet conduit <NUM>"; introducing an oxygen-containing gas OC to the N<NUM>/NO gas mixture to form an output gas OG; and transporting the output gas OG to a desired destination.

In this example, N<NUM> is used as the sweep gas, and thus little or no oxygen is present in the chamber <NUM>'. This renders the device 20C suitable for use with the NO cartridge <NUM>", which may include a substrate <NUM>" (e.g., silicone rubber) that is permeable to both NO and O<NUM>, and thus can act as a microreactor for NO<NUM> generation. The N<NUM> sweep gas minimizes the presence of oxygen, and thus the NO cartridge <NUM>" can be used to effectively photolytically release NO without also generating too much (if any) NO<NUM> in the chamber <NUM>'. The N<NUM> sweep gas can be blended into an oxygen-containing gas prior to delivery to a patient. It is to be understood that the cartridge <NUM> (which does not act as a microreactor for NO<NUM> generation) may also be used in this example.

Details of this method and the gas delivery device 20C will now be described.

The NO generating system 22C of the device 20C includes the chamber <NUM>'. In this example, the chamber <NUM>' may be any examples set forth for the chamber <NUM> or may be a vacuum environment <NUM>.

The NO generating system 22C also includes the cartridge <NUM>, <NUM>", 10A, or 10B. The NO cartridge <NUM> may be any of the examples described in reference to <FIG>, and the NO cartridge <NUM>" may be any of the examples described in reference to <FIG>, and the NO cartridge 10A or 10B may be any of the examples described in reference to <FIG> that include the substrate <NUM> and the NO permeable and light transparent membrane <NUM>. It is to be understood that the cartridge <NUM>, <NUM>", 10A, or 10B may be positioned within the chamber <NUM>' so that the NO donor <NUM> directly faces the light source <NUM>.

In this example, the light source <NUM> is shown within the chamber <NUM>'. It is to be understood that the light source <NUM> may alternatively be positioned outside of the chamber <NUM>' in accordance with any of the examples described in reference to <FIG>. The light source <NUM> may also be any of the examples described in reference to <FIG> and may be in electrical communication with the electronic circuitry disclosed herein, as long as the light source <NUM> is positioned to illuminate the NO donor <NUM> within the chamber <NUM>'.

The chamber <NUM>' includes an inlet <NUM>, which is attached to an inlet conduit <NUM> that delivers nitrogen gas to the chamber <NUM>'. The nitrogen gas N<NUM> may be supplied to the inlet conduit <NUM> from a gas source, such as the compressed gas tank <NUM> or an oxygen scrubber. The compressed gas tank <NUM> may include compressed nitrogen gas N<NUM>, with a regulator to control the flow rate of the nitrogen gas N<NUM> to the inlet conduit <NUM>. The oxygen scrubber (not shown) may be operatively connected to a pump that introduces ambient air into the oxygen scrubber. The ambient air is directed to a solution or particle bed of the oxygen scrubber, which is capable of removing the oxygen from the ambient air to generate the nitrogen gas N<NUM> that is delivered to the inlet conduit <NUM>. The nitrogen gas N<NUM> may be a mixed gas derived from ambient air, where the mixed gas contains nitrogen gas, argon gas, carbon dioxide, and potentially small amounts of other non-oxygen gases. In an example, the oxygen scrubber removes at least <NUM>% of the oxygen from the air, and thus the mixed gas may include less than <NUM>% of oxygen gas. In another example, the oxygen scrubber removes enough oxygen from the air so that the mixed gas includes <NUM>% or less of oxygen gas.

In this example of the device 20C, the inlet conduit <NUM> delivers the nitrogen gas N<NUM> to the nitric oxide generating system 22C, where NO has been photolytically generated or will be photolytically generated in the manner described herein using the light source <NUM>. The nitrogen purge gas N<NUM> may be introduced directly into the chamber <NUM>', or it may first pass through a flowmeter <NUM>, which measures and controls the linear, nonlinear, mass or volumetric flow rate of the nitrogen purge gas N<NUM>.

The nitrogen purge gas (N<NUM>) that is introduced into the system 22C picks up the nitric oxide that is generated. The resulting stream of nitrogen gas N<NUM> and nitric oxide N<NUM>/NO is then transported out of the system 22C through the outlet <NUM>. Any aerosol droplets that are formed may be i) prevented from entering the chamber <NUM>' by the membrane <NUM> of the NO cartridge <NUM>, 10A, or 10B or ii) remain trapped within the substrate <NUM>" of the NO cartridge <NUM>", 10A, or 10B. The N<NUM>/NO gas stream is transported through the outlet conduit <NUM>".

The gas delivery device 20C shown in <FIG> also includes the inspiratory gas conduit <NUM>' operatively connected to the outlet conduit <NUM>" to introduce the oxygen-containing gas OC to the N<NUM>/NO gas stream to form the output gas OG of this device 20C. The inspiratory gas conduit <NUM>' may be any of the materials described for the inspiratory gas conduit <NUM>. Moreover, the oxygen-containing gas OC may be any of the examples mentioned in reference to <FIG> (e.g., pure oxygen gas O<NUM>, or air, or a hypoxic gas that includes oxygen) and may be delivered from any of the gas sources mentioned in reference to <FIG>. An example of the gas source is an oxygen tank <NUM>, as shown in <FIG>. The oxygen-containing gas source, e.g., tank <NUM>, can include, or be coupled to, a flow controller to regulate the flow of the oxygen-containing gas OC into the inspiratory gas conduit <NUM>'. Any suitable gas flow rate may be used as described herein. The flow rate of the oxygen-containing gas OC may be continuous or intermittent, and may also depend upon the composition of the oxygen-containing gas OC and the desired fraction of inspired oxygen (i.e., FiO<NUM>).

In the gas delivery device 20C, the outlet conduit <NUM>" and the inspiratory gas conduit <NUM>' may be operatively connected to, or may be integrally formed with, a delivery conduit <NUM>. In the delivery conduit <NUM>, the oxygen-containing gas OC mixes with the N<NUM>/NO gas stream to form an output gas stream OG of the device 20C.

The delivery conduit <NUM> is operatively connected to an inhalation unit <NUM>, which is capable of transporting the output gas stream OG to a recipient/patient <NUM>. The delivery conduit <NUM> and the inhalation unit <NUM> may be any of the examples described herein in reference to <FIG>.

In this example, the length of the delivery conduit <NUM> may be relatively short in order to avoid loss of gas before the stream is delivered to a desirable destination (e.g., a recipient <NUM>). Since the oxygen-containing gas OC is introduced just prior to delivery to the recipient <NUM>, the impact on the NO concentration is minimal or nil due to the short contact time between the NO and the oxygen-containing gas OC.

The gas delivery device 20C may further include a sensing and feedback system. In an example, the sensing and feedback system includes the sensor <NUM> in contact with the output gas stream OG to monitor the nitric oxide level (i.e., NO concentration) of the output gas OG, and a controller <NUM> that is operatively connected to the sensor <NUM> and the light source <NUM>, where the controller <NUM> can adjust a parameter of the light source <NUM> in response to the nitric oxide level from the sensor <NUM>. The sensor(s) in this example may also be used to monitor the nitrogen dioxide level of the output gas OG. The sensing and feedback system (including the sensor <NUM>, controller <NUM>, and electronic circuitry) may be any of the examples described herein in reference to <FIG>. The sensor data (i.e., the concentration of NO in the output gas stream OG and/or the concentration of NO<NUM> in the output gas stream OG) may be used as described in reference to <FIG>, e.g., to increase or decrease NO release from the NO generating system 22C.

The gas delivery device 20C may also include a nitrogen dioxide (NO<NUM>) filter <NUM>. The NO<NUM> filter may be positioned in the delivery conduit <NUM> to receive the output gas stream OG before it is delivered to the inhalation unit <NUM>. Any examples of the NO<NUM> filter <NUM> described herein may be used in the gas delivery device 20C.

Referring now to <FIG>, another example of the gas delivery device 20D is depicted. The gas delivery device 20D is suitable for use with the NO cartridge <NUM>' shown in <FIG> or with some examples of the NO cartridge 10A or 10B. In this example, the gas delivery device 20D includes: i) a nitric oxide (NO) generating system 22C, which includes a chamber <NUM>, the NO cartridge <NUM>', 10A, or 10B contained within the chamber <NUM> (where the NO cartridge <NUM>', 10A, or 10B includes the light transparent substrate <NUM>', the solid, light sensitive NO donor <NUM> immobilized on the surface S<NUM> of the light transparent substrate <NUM>', and the porous membrane <NUM>' positioned on the solid, light sensitive NO donor <NUM>), and a light source <NUM> operatively positioned to selectively expose the solid, light sensitive NO donor <NUM> to light hv through the light transparent substrate <NUM>' to generate NO gas; ii) an inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> to introduce an oxygen-containing gas OC and form an output gas OG including the NO gas; and iii) an outlet conduit <NUM> to transport a stream of the output gas OG from the NO generating system 22D. While not specifically shown in <FIG>, it is to be understood that the solid, light sensitive NO donor <NUM> may be immobilized on the surface S<NUM> of the substrate <NUM>' using an adhesive <NUM> (e.g., as described in reference to <FIG>) or using the cavity/cavities <NUM> (e.g., as described in reference to <FIG>).

With the gas delivery device 20D, the method includes: operating the light source <NUM> to emit light through the light transparent substrate <NUM>' and onto the NO donor <NUM>, which photolytically releases NO from the donor <NUM> within the chamber <NUM>; introducing an oxygen-containing gas OC into the chamber <NUM>, where the NO and the oxygen-containing gas OC mix to form an output gas OG; and transporting the output gas OG from the chamber <NUM> to a desired destination. Details of this method and the gas delivery device 20D will now be described.

The NO generating system 22D of the device 20D includes the chamber <NUM> where photolysis takes place (i.e., a photolysis chamber). The chamber <NUM> may be any example of the chamber described in reference to <FIG>.

The NO generating system 22D also includes the cartridge <NUM>', 10A, or 10B. The NO cartridge <NUM>' may be any of the examples described in reference to <FIG>, and the NO cartridge 10A, 10B may any of the examples described in reference to <FIG> that include the light transparent substrate <NUM>' and the porous membrane <NUM>'.

The NO generating system 22D also includes the light source <NUM>. Any light source <NUM> may be used that is capable of emitting light that can be transmitted through the substrate <NUM>' of the cartridge <NUM>' and that initiates photolysis of the solid, light sensitive NO donor <NUM>. Any of the light sources <NUM> described herein may be used.

In the example shown in <FIG>, the light source <NUM> is positioned to selectively expose the NO donor <NUM> to light hv through the light transparent substrate <NUM>'. In this example of the NO cartridge <NUM>', 10A, or 10B, the membrane <NUM>' is transparent or non-transparent. As such, when a non-transparent membrane <NUM>' is used, unlike the example shown in <FIG>, the light source <NUM> in the device 22D is not positioned to direct light toward the membrane <NUM>', but rather is positioned to direct light toward the light transparent substrate <NUM>'. The light source <NUM> in the device 22D may be attached or otherwise operatively positioned inside or outside of the chamber <NUM> using any of the examples disclosed herein, as long as the emitted light can reach the NO donor <NUM> through the light transparent substrate <NUM>. In the example shown in <FIG>, the light source <NUM> is attached to the chamber <NUM> with the light transparent adhesive <NUM>. In other examples, the chamber <NUM> may include a window (similar to window <NUM> in <FIG>) between the light source <NUM> and the light transparent substrate <NUM>'.

Electronic circuitry may be operatively connected to the light source <NUM> to control when the source(s) <NUM> is/are turned ON and OFF, the duration of an ON cycle, the intensity, the power surface density, etc. The electronic circuitry may be part of a sensing and feedback system as described herein.

The light source <NUM> may be turned ON for any time interval up to, for example, up to <NUM> hours per cartridge <NUM>', and thus may photolytically release NO during this time interval. Longer time intervals may be possible, depending upon the amount of NO donor <NUM> in the cartridge <NUM>'. When it is desired to stop generating NO, the light source <NUM> is turned OFF so that light hv is no longer emitted on the NO donor <NUM> through the light transparent substrate <NUM>'. The NO release lifetime may be longer when larger substrates <NUM>' are used and/or when higher amounts of the NO donor <NUM> are used.

In this example, the NO gas released from the NO donor <NUM> permeates through the membrane <NUM>' and into the chamber <NUM>. The membrane <NUM>' prevents any aerosol droplets from being generated.

The gas delivery device 20D shown in <FIG> also includes the inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> (e.g., at inlet <NUM>) to introduce the oxygen-containing gas OC to the chamber <NUM>. The inspiratory gas conduit <NUM>, the oxygen-containing gas OC, and the gas source may be any of the examples mentioned in reference to <FIG>. The oxygen-containing gas source can also include, or be coupled to, a flow controller to regulate the flow of the oxygen-containing gas OC into the inspiratory gas conduit <NUM>. Any suitable gas flow rate may be used as described herein.

In the chamber <NUM>, the oxygen-containing gas OC mixes with the photolytically released NO gas to form an output gas stream OG. A stream of the output gas OG may exit the NO generating system 22D through an outlet <NUM> into the outlet conduit <NUM>. The outlet conduit <NUM> may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide in the output gas OG. The length of the outlet conduit <NUM> may also be relatively short in order to avoid NO<NUM> formation before the stream is delivered to a desirable destination (e.g., a recipient <NUM>). Since the oxygen-containing gas OC is introduced just prior to delivery to the recipient <NUM>, the impact on the NO concentration is minimal or nil due to the short contact time between the NO and the oxygen-containing gas OC.

In the gas delivery device 20D, the outlet conduit <NUM> may be, or may be operatively connected to, a delivery conduit <NUM>. The delivery conduit <NUM> is operatively connected to an inhalation unit <NUM>, which is capable of transporting the output gas stream OG to a recipient/patient <NUM>. The delivery conduit <NUM> and the inhalation unit <NUM> may be any of the examples described herein in reference to <FIG>.

The gas delivery device 20D may further include a sensing and feedback system. In an example, the sensing and feedback system includes the sensor <NUM> in contact with the output gas stream OG to monitor the nitric oxide level (i.e., NO concentration) of the output gas OG, and a controller <NUM> that is operatively connected to the sensor <NUM> and the light source <NUM>, where the controller <NUM> can adjust a parameter of the light source <NUM> in response to the nitric oxide level from the sensor <NUM>. The sensor(s) in this example may also be used to monitor the nitrogen dioxide level of the output gas OG. The sensing and feedback system (including the sensor <NUM>, controller <NUM>, and electronic circuitry) may be any of the examples described herein in reference to <FIG>. The sensor data (i.e., the concentration of NO in the output gas stream OG and/or the concentration of NO<NUM> in the output gas stream OG) may be used as described in reference to <FIG>, e.g., to increase or decrease NO release from the NO generating system 22B.

The gas delivery device 20D may also include a nitrogen dioxide (NO<NUM>) filter <NUM>. The NO<NUM> filter may be positioned in the delivery conduit <NUM> to receive the output gas stream OG before it is delivered to the inhalation unit <NUM>. Any examples of the NO<NUM> filter <NUM> described herein may be used in the gas delivery device 20D.

Referring now to <FIG>, still another example of the gas delivery device 20E is depicted. The gas delivery device 20E is suitable for use with the NO cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B shown respectively in <FIG>, <FIG>. In this example, the gas delivery device 20E includes: i) a nitric oxide (NO) generating system 22E, which includes a chamber <NUM>, the NO cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B contained within the chamber <NUM>, and a light source <NUM> operatively positioned to selectively expose the solid, light sensitive NO donor <NUM> to light hv (e.g., directly or through the light transparent substrate <NUM>') to generate NO gas; ii) an inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> to introduce an oxygen-containing gas OC to the chamber <NUM>; iii) an outlet conduit <NUM> to transport a stream of at least the oxygen-containing gas OC and the NO gas from the chamber <NUM> to a delivery conduit <NUM>; and iv) a nitrogen dioxide filter <NUM> positioned to receive the stream OG before it is delivered to the delivery conduit <NUM>.

With the gas delivery device 20E, the method includes: operating the light source <NUM> to emit light onto the NO donor <NUM>, which photolytically releases NO from the donor <NUM> within the chamber <NUM>; introducing an oxygen-containing gas OC into the chamber <NUM>, where the NO and the oxygen-containing gas OC form a gas mixture; transporting the gas mixture from the chamber <NUM> to the nitrogen dioxide filter, where NO<NUM> may be reduced or removed to form the output gas OG; and transporting the output gas OG to the delivery conduit <NUM>.

The gas delivery device 20E may be used with any of the cartridges <NUM>, <NUM>', <NUM>", 10A, or 10B, although the cartridges <NUM>, <NUM>', 10A, 10B may generate little to no NO<NUM>. The device 20E may be particularly suitable for use with the cartridge <NUM>". As mentioned herein, the NO cartridge <NUM>" may include a substrate <NUM>" (e.g., silicone rubber) that is permeable to both NO and O<NUM>, and thus can act as a microreactor for NO<NUM> generation. Because the chamber <NUM> in this example may include oxygen and has the oxygen-containing gas OC introduced thereto, the NO cartridge <NUM>" may generate NO<NUM> in addition to photolytically releasing the NO gas. The nitrogen dioxide filter <NUM> may be used to remove the NO<NUM> before delivery of the gas stream to the recipient <NUM>.

Details of this method and the gas delivery device 20E will now be described.

The NO generating system 22E of the device 20E includes the chamber <NUM> where photolysis takes place (i.e., a photolysis chamber). The chamber <NUM> may be any example of the chamber described in reference to <FIG>.

The NO generating system 22E also includes the cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B. The NO cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B may be any of the examples described in reference to <FIG>, <FIG>.

The NO generating system 22E also includes the light source <NUM>. Any light source <NUM> may be used that is capable of emitting light that initiates photolysis of the solid, light sensitive NO donor <NUM>. Any of the light sources <NUM> described herein may be used. The positioning of the light source <NUM> in this example will depend upon the NO cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B that is used. For example, the light source <NUM> may be positioned to emit light toward the NO permeable and light transparent membrane <NUM> of the NO cartridge <NUM>, 10A, or 10B, or toward the light transparent substrate <NUM>' of the NO cartridge <NUM>', 10A, or 10B, or toward the NO donor immobilized in the substrate <NUM>" of the NO cartridge <NUM>".

The light source <NUM> may be turned ON for any time interval up to, for example, <NUM> hours per cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B and thus may photolytically release NO during this time interval. Longer time intervals may be possible, depending upon the amount of NO donor <NUM> in the cartridge <NUM>, <NUM>', <NUM>", 10A, or 10B. When it is desired to stop generating NO, the light source <NUM> is turned OFF so that light hv is no longer emitted on the NO donor <NUM> through the light transparent substrate <NUM>'. The NO release lifetime may be longer when larger substrates <NUM>, <NUM>', <NUM>" are used and/or when higher amounts of the NO donor <NUM> are used.

In this example when the NO cartridge <NUM> or some examples of 10A or 10B is used, the NO gas released from the NO donor <NUM> permeates through the membrane <NUM> and into the chamber <NUM>. In this example when the NO cartridge <NUM>' or some examples of 10A or 10B is used, the NO gas released from the NO donor <NUM> permeates through the membrane <NUM>' and into the chamber <NUM>. In this example when the NO cartridge <NUM>" is used, the NO gas released from the NO donor <NUM> permeates through the substrate <NUM>" and into the chamber <NUM>.

The gas delivery device 20E shown in <FIG> also includes the inspiratory gas conduit <NUM> operatively connected to the chamber <NUM> (e.g., at inlet <NUM>) to introduce the oxygen-containing gas OC to the chamber <NUM>. The inspiratory gas conduit <NUM>, the oxygen-containing gas OC, and the gas source may be any of the examples mentioned in reference to <FIG>. The oxygen-containing gas source can also include, or be coupled to, a flow controller to regulate the flow of the oxygen-containing gas OC into the inspiratory gas conduit <NUM>. Any suitable gas flow rate may be used as described herein.

In the chamber <NUM>, the oxygen-containing gas OC mixes with the photolytically released NO gas. When the NO cartridge <NUM>" is used, the substrate <NUM>" may act as a microreactor for the NO and the oxygen gas, and thus some nitrogen dioxide may be formed in the chamber <NUM>. As such, in some examples of the NO generating system 22E, the gas mixture in the chamber <NUM> includes NO gas, the oxygen-containing gas OC, and NO<NUM>.

In this device 20E, the gas mixture in the chamber <NUM> is transported through an outlet <NUM> into the outlet conduit <NUM>. The outlet conduit <NUM> may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide in the output gas OG.

In some examples, gas mixture may be transported as a result of pressure from the gas source, which may include a regulator to control the flow rate. In other examples, the gas mixture may be transported as a result of pressure from a vacuum positioned downstream.

In the gas delivery device 20E, the outlet conduit <NUM> may be, or may be operatively connected to, a delivery conduit <NUM>. However, in this example device 20E, the nitrogen dioxide (NO<NUM>) filter <NUM> is positioned between the two conduits <NUM>, <NUM>. The NO<NUM> filter <NUM> receives the gas mixture to remove any NO<NUM> or to reduce the amount of NO<NUM> and to form the output gas stream OG of this device 20E. Any examples of the NO<NUM> filter <NUM> described herein may be used in the gas delivery device 20E.

In this example, the output gas stream OG may then be transported from the NO<NUM> filter <NUM>, through the delivery conduit <NUM>, and to the inhalation unit <NUM>, which is capable of delivering the output gas stream OG to a recipient/patient <NUM>. The delivery conduit <NUM> and the inhalation unit <NUM> may be any of the examples described herein in reference to <FIG>.

The gas delivery device 20E may further include a sensing and feedback system. In an example, the sensing and feedback system includes the sensor <NUM> in contact with the output gas stream OG to monitor the nitric oxide level (i.e., NO concentration) and the nitrogen dioxide level (i.e., NO<NUM> concentration) of the output gas OG after it has passed through the NO<NUM> filter <NUM>. The sensing and feedback system may further include the controller <NUM> that is operatively connected to the sensor(s) <NUM> and the light source <NUM>, where the controller <NUM> can adjust a parameter of the light source <NUM> in response to the nitric oxide level and/or the nitrogen dioxide from the sensor(s) <NUM>.

The sensing and feedback system (including the sensor <NUM>, controller <NUM>, and electronic circuitry) may be any of the examples described herein in reference to <FIG>. The sensor data (i.e., the concentration of NO in the output gas stream OG and/or the concentration of NO<NUM> in the output gas stream OG) may be used as described in reference to <FIG>, e.g., to increase or decrease NO release from the NO generating system 22E.

It is to be understood that any of the example NO cartridges <NUM>, <NUM>', <NUM>", 10A, or 10B may be organized in a parallel arrangement in order to increase the NO release from any of the gas delivery devices 20A through 20E.

While not shown in <FIG>, it is to be understood that the gas generating devices 20A through 20E may be incorporated into portable or stationary housings that may also include electronic circuitry, user interface panels, sensors, filters, gas pumps, etc. Two example portable device configurations are shown in <FIG>.

To further illustrate the present disclosure, examples are given herein.

In this example, two different NO donors, namely S-nitroso-N-acetylpenicillamine (SNAP) crystals or solid S-nitrosoglutathione (GSNO), were respectively doped into polydimethylsiloxane (PDMS) films. These examples were representative of the NO cartridge <NUM>" shown in <FIG>.

The respective crystals or solid powders were blended with uncured silicone rubber, and the blends were cast into films and then cured. The SNAP crystal concentration or the solid GSNO concentration in the films was <NUM> wt% and the films had <NUM> diameters.

LED light sources with nominal wavelengths of <NUM>, <NUM>, and <NUM> were used to expose the films to light in order to initiate photolysis and generate NO gas. The light power surface density was set to <NUM> mW/cm<NUM> for each light source. An amperometric sensor was used to detect the NO levels.

<FIG> shows the kinetics of gas phase NO levels and <FIG> shows the cumulative NO release for the PDMS-SNAP film when exposed to a) <NUM>, b) <NUM>, and c) <NUM>. <FIG> shows the kinetics of gas phase NO levels and <FIG> shows the cumulative NO release for the PDMS-GSNO film when exposed to a) <NUM>, b) <NUM>, and c) <NUM>.

The curves in <FIG>, <FIG> show the mean values and the error bars correspond to the standard error of the mean of the three parallel measurements. The results in <FIG> show that photolysis of SNAP and GSNO to generate NO gas may be accomplished with several different light sources. The results also indicate that the LED with the <NUM> nominal wavelength may be the most effective for both NO donors.

The results in <FIG> illustrate that when the PDMS-SNAP films and the PDMS-GSNO films are illuminated with a constant light power surface density, the NO emission from such films is not steady. As such, additional films were prepared and tested with a feedback system similar to that shown in <FIG>.

In this example, S-nitroso-N-acetylpenicillamine (SNAP) was doped into polydimethylsiloxane (PDMS) films. These examples were representative of the NO cartridge <NUM>" shown in <FIG>.

The SNAP crystals were blended with uncured silicone rubber, and the blends were cast into films and then cured. The SNAP crystal concentration in the films was <NUM> wt% and the films had <NUM> diameters.

LED light sources with nominal wavelengths of <NUM>, <NUM>, and <NUM> were used to expose the films to light in order to initiate photolysis and generate NO gas. The light power surface density was set to <NUM> mW/cm<NUM> for each light source. The sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate. In this example, an amperometric NO sensor was used to continuously monitor the NO level in the delivered gas. The target NO level was <NUM> ppb, and the light power surface density was adjusted if necessary based on the sensor feedback.

<FIG> shows the NO level in the delivered gas stream (thicker lines) and the cumulative NO release (skinny lines) for the PDMS-SNAP films exposed to <NUM>, <NUM>, and <NUM>. <FIG> shows the duty cycles for the pulse width modulation (PWM) of the <NUM> LED light source, the <NUM> LED light source, and the <NUM> LED light source.

Additional PDMS-SNAP films were tested with the target NO levels set to <NUM> ppb, <NUM> ppb, and <NUM> ppb. For this test, the light source with the nominal wavelength of <NUM> was used, and the sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate. The amperometric NO sensor was used to continuously monitor the NO level in the delivered gas, and the light power surface density was adjusted if necessary based on the sensor feedback.

<FIG> shows the NO level in the delivered gas stream (thicker lines) and the cumulative NO release (skinny lines) for the PDMS-SNAP films exposed to <NUM>. <FIG> shows the duty cycles for the pulse width modulation of the <NUM> LED light source at the various target NO levels.

These results show that relatively consistent and steady NO emission may be achieved using the feedback system disclosed herein.

Still other PDMS-SNAP films were tested with the target NO levels changed stepwise to <NUM> ppb, <NUM> ppb, <NUM> ppb, <NUM> ppb, <NUM> ppb, and <NUM> ppb and then back in the reverse direction. For this test, the light source with the nominal wavelength of <NUM> was used, and the sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate. The amperometric NO sensor was used to continuously monitor the NO level in the delivered gas, and the light power surface density was adjusted if necessary based on the sensor feedback.

<FIG> shows the NO setpoint and the actual NO level measured for the PDMS-SNAP films exposed to <NUM>. <FIG> shows the duty cycles for the pulse width modulation of the <NUM> LED light source at the various target NO levels.

Still other PDMS-SNAP films were tested with the target NO level set to <NUM> ppb. For this test, the light source with the nominal wavelength of <NUM> was used, and the sweep gas (recipient gas) was nitrogen at varying flow rates. The amperometric NO sensor was used to continuously monitor the NO level in the delivered gas, and the light power surface density was adjusted if necessary based on the sensor feedback.

<FIG> shows the system response to the perturbation of the flow rate of the nitrogen gas. The nitrogen gas flow rate changes are shown in the center, the effect on NO release is shown at the top, and the effect on the duty cycles for the pulse width modulation of the <NUM> LED light source is shown at the bottom.

PDMS-SNAP films were tested with nitrogen gas and air to determine when nitrogen dioxide was generated.

The LED light source with a nominal wavelength of <NUM> was used to expose the films to light in order to initiate photolysis and generate NO gas. The light power surface density was set to <NUM> mW/cm<NUM>. For some tests, the sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate. For other tests, the sweep gas (recipient gas) was air at <NUM> SCCM flow rate. In this example, amperometric NO sensors were used to continuously monitor the NO level in the delivered gases. The target NO level was <NUM> ppb, and the light power surface density was adjusted if necessary based on the sensor feedback.

<FIG> shows the NO level in the delivered N<NUM> or air gas streams (thicker lines) and the cumulative NO release (skinny lines) for the PDMS-SNAP films exposed to <NUM>. <FIG> shows the duty cycles for the pulse width modulation of the <NUM> LED light source when used with the N<NUM> gas stream or the air gas stream.

The results in <FIG> indicate that nitrogen dioxide is forming when the air gas stream is used. The NO<NUM> formation may take place in the PDMS film, as it is highly soluble of both oxygen and NO. As such, an NO<NUM> filter or a vacuum chamber may be used with the NO donor doped films disclosed herein.

Based on the results in Example <NUM>, the following test was performed. In this example, S-nitroso-N-acetylpenicillamine (SNAP) was doped into polydimethylsiloxane (PDMS) films. These examples were representative of the NO cartridge <NUM>" shown in <FIG>.

The SNAP crystals were blended with uncured silicone rubber, and the blends were cast into films and then cured. The SNAP crystal concentration in the films was <NUM> and the films had <NUM> diameters.

The LED light source with a nominal wavelength of <NUM> was used to expose the films to light in order to initiate photolysis and generate NO gas. The light power surface density was set to <NUM> mW/cm<NUM>. For this test, the sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate. Once mixed with the NO, the sweep gas was mixed with oxygen gas (<NUM> SCCM flow rate) in order to deliver <NUM> ppb NO gas in <NUM>% O<NUM> stream. The NO concentration was measured after mixing the two gas streams.

<FIG> shows the NO level in the combined stream (solid line) and the cumulative NO release (dashed lines) for the PDMS-SNAP films exposed to <NUM>. <FIG> shows the duty cycles for the pulse width modulation of the <NUM> LED light source when used with the combined stream.

The results in <FIG> indicate that nitrogen is a suitable sweep gas and that the addition of oxygen subsequently helps to reduce the NO<NUM> formation.

Based on the results in Example <NUM>, the following test was performed. In this example, solid S-nitrosoglutathione (GSNO) was doped into polydimethylsiloxane (PDMS) films. These examples were representative of the NO cartridge <NUM>" shown in <FIG>.

The solid GSNO was blended with uncured silicone rubber, and the blends were cast into films and then cured. The solid GSNO concentration in the films was <NUM> wt% and the films had <NUM> diameters.

The LED light source with a nominal wavelength of <NUM> was used to expose the films to light in order to initiate photolysis and generate NO gas. The light power surface density was set to <NUM> mW/cm<NUM>. For this test, the sweep gas (recipient gas) was nitrogen at <NUM> SCCM flow rate or air at <NUM> SCCM flow rate. One nitrogen stream was tested as is, another nitrogen stream was tested after being passed through a conditioned silica gel NO<NUM> scrubber, and the air stream was tested after being passed through a conditioned silica gel NO<NUM> scrubber.

<FIG> shows the NO and NO<NUM> levels in the nitrogen stream, <FIG> shows the NO and NO<NUM> levels in the nitrogen stream after being passed through a conditioned silica gel NO<NUM> scrubber, and <FIG> shows the NO and NO<NUM> levels in the air stream after being passed through a conditioned silica gel NO<NUM> scrubber. The NO<NUM> scrubber did not change the available NO yield from the film, but it did remove the NO<NUM> generated in the presence of oxygen. The released loadings were close to zero in all of these tests, and thus are not visible in <FIG>.

An adhesive (crystal clear GORILLA® tape) was applied on opposed surfaces of a substrate, and S-nitrosoglutathione (GSNO) solids were spread onto the adhesive on both surfaces. Track etch polycarbonate films were placed over the solids and adhered to the substrate surfaces. This example was representative of the NO cartridge <NUM> shown in <FIG> and <FIG>.

LED light sources with a nominal wavelength of <NUM> was used to expose the NO donors to light in order to initiate photolysis and generate NO gas that permeated through the polycarbonate membranes. The light power surface density was set to <NUM> mW/cm<NUM> for each light source. For this test, the sweep gas (recipient gas) was air at <NUM>/min flow rate. Both NO and NO<NUM> levels were measured in the delivered gas. The tests were performed at target NO levels of <NUM> ppb, <NUM> ppb, <NUM> ppb and <NUM> ppb, and the light intensity was controlled based on the sensor feedback.

<FIG> show the NO and NO<NUM> levels in the air stream at the various target levels. The NO levels are on track with the target levels, and the NO<NUM> levels were minimal (<FIG>) if present at all.

A system including four NO cartridges was generated.

For each NO cartridge, a different patterned adhesive was generated to include cavities. For each patterned adhesive, <NUM><NUM> area hexagon shaped cavities were cut into a <NUM> thick and <NUM> diameter circular piece of <NUM>™ Optically Clear Adhesive using a cutting plotter. The geometry of the patterned adhesive and the individual cavities was similar to that shown in <FIG>. One of the liners was removed from each of the patterned adhesives, and two of the patterned adhesives were adhered to one glass substrate and the other two of the patterned adhesives were adhered to another glass substrate. <NUM> of SNAP was screen printed into the cavities of each of the patterned adhesives. The other of the liners was removed from each of the patterned adhesives, and a track etch polycarbonate film/membrane was placed over and adhered to each of the patterned adhesives.

To form the system, the glass substrates (each of which included two of the NO cartridges) were sealed together at the top and bottom so that the membranes (<NUM> or <NUM>') of each cartridge were facing each other and so that air could flow between the membranes. The top view of the system is schematically shown in <FIG> (illustrating two of the NO cartridges), and a cross-sectional view of the system taken along a line from the top of the system (as shown in <FIG>) to the bottom of the system is shown in <FIG>. In <FIG>, it is to be understood that the portion of the cross-section labeled with the cavities <NUM> and NO donor <NUM> is shown schematically and that the view may actually include several individual cavities and the NO donor positioned therein.

While not used in this particular example, <FIG> illustrates another example of the system including several NO cartridges. In this example, one glass substrate (<NUM> or <NUM>') is used, and the patterned adhesives are adhered to opposed sides of the glass substrate. The cavities of each patterned adhesive is filled with the NO donor and the membrane (<NUM> or <NUM>') is positioned over the patterned adhesive having the NO donor located within its cavities).

For this example, an LED light source with a nominal wavelength of <NUM> was used to expose the NO donor in the cavities to light in order to initiate photolysis and generate NO gas that permeated through the polycarbonate membranes. For this test, the sweep gas (recipient gas) was air at <NUM>/min flow rate. Both NO and NO<NUM> levels were measured in the delivered gas using amperometric gas sensors (data labeled iNO in <FIG>). The light power was feedback controlled based on the signal amperometric NO gas sensor and the target NO level as a reference signal. The NO and NO<NUM> levels of the output gas stream were validated with ozone chemiluminescent NO and NOx analyzers (data labeled NOA in <FIG>).

<FIG> shows the NO and NO<NUM> levels in the air streams. The NO levels are on track with the target levels, and the NO<NUM> levels were minimal, if present at all. These results show that for low-dose NO (<NUM> ppm) delivery, the nitric oxide cartridge shown in <FIG> can be used without an NO<NUM> scrubber.

It is to be understood that the ranges provided herein include the stated range and any value or sub-range within the stated range, as if the value(s) or sub-range(s) within the stated range were explicitly recited. For example, a range from about <NUM> to about <NUM> should be interpreted to include not only the explicitly recited limits of from about <NUM> to about <NUM>, but also to include individual values, such as about <NUM>, about <NUM>, <NUM>, <NUM>, etc., and sub-ranges, such as from about <NUM> to about <NUM>, etc. Furthermore, when "about" is utilized to describe a value, this is meant to encompass minor variations (up to +/-<NUM>%) from the stated value.

Reference throughout the specification to "one example", "another example", "an example", and so forth, means that a particular element (e.g., feature, structure, and/or characteristic) described in connection with the example is included in at least one example described herein, and may or may not be present in other examples. In addition, it is to be understood that the described elements for any example may be combined in any suitable manner in the various examples unless the context clearly dictates otherwise.

Claim 1:
A gas delivery device, comprising:
a nitric oxide (NO) generating system, including:
a chamber;
an NO cartridge contained within the chamber, the NO cartridge including:
a light transparent substrate that is transparent to one or more wavelengths of light ranging from about <NUM> to about <NUM>;
a solid, light sensitive NO donor immobilized on a surface of the light transparent substrate via an adhesive that is transparent to wavelengths of light ranging from about <NUM> to about <NUM>; and
a porous membrane positioned on the solid, light sensitive NO donor and adhered to the light transparent substrate;
a light source operatively positioned to selectively expose the solid, light sensitive NO donor to light through the light transparent substrate to generate NO gas;
an inspiratory gas conduit operatively connected to the chamber to introduce an oxygen-containing gas and form an output gas including the NO gas; and
an outlet conduit to transport a stream of the output gas from the NO generating system.