Apparatus and method for detecting the presence of nitric oxide

Abstract

Provided herein is a sterilization indicator for detecting the presence and quantifying the amount of nitric oxide. The sterilization indicator comprises a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The sterilization indicator further comprises a support layer comprising the chromophore-containing compound. In some embodiments, the sterilization indicator further comprises a polymeric layer over at least a portion of the support layer for reducing diffusion of fluid through the polymeric layer to the chromophore-containing compound.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application is an international application claiming priority to U.S. Provisional Patent Application No. 63 / 141,711, filed January 26, 2021, U.S. Provisional Patent Application No. 63 / 141,676, filed January 26, 2021, and U.S. Provisional Patent Application No. 63 / 156,917, filed March 4, 2021, the contents of which are incorporated by reference in their entirety. [Technical field]

[0002] The present disclosure relates generally to sterilization indicators for detecting the presence and quantifying the amount of nitric oxide. The disclosure also relates to methods of forming sterilization indicators and methods of detecting the presence of nitric oxide. [Background technology]

[0003] Various products and articles, such as medical instruments, devices, and equipment, must be sterilized before use to prevent biological contamination of wound sites, samples, organisms, etc. Many sterilization processes are used in which the product or article is contacted with a sterilant. Examples of such sterilants include steam, nitric oxide, ethylene oxide, hydrogen peroxide, dry heat, etc.

[0004] Traditional visual indicators are available for steam, hydrogen peroxide, and dry heat. However, adequate visual indicators for nitric oxide are not available. One inadequate indicator of nitric oxide is the Griess assay, which detects nitrite rather than nitric oxide. The Griess assay does not detect NO in the gas phase, so multiple reagents must be used in combination to produce a reaction. Another inadequate indicator of nitric oxide relies on colorimetric assays that detect nitric oxide by either visible spectroscopy or fluorometry, which are completed in the solution phase. These reactions require the establishment of a complex gas / solution phase equilibrium and a device (spectrometer) to measure the level of NO present. This conflicts with the clinical need for sterilization, which requires a rapid indication of sterilization success or failure.

[0005] It would therefore be desirable to provide a sterilization indicator that detects the presence of and quantifies the amount of nitric oxide, and methods of making and using the sterilization indicator. Furthermore, other desirable features and characteristics will become apparent from the following summary and detailed description, and the appended claims, considered in conjunction with the foregoing technical field and background. Summary of the Invention

[0006] Provided herein are sterilization indicators for detecting the presence of nitric oxide. The sterilization indicators include a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The sterilization indicators further include a support layer that includes the chromophore-containing compound. In some embodiments, the sterilization indicators further include a polymer layer over at least a portion of the support layer to reduce diffusion of fluid through the polymer layer to the chromophore-containing compound.

[0007] Also provided herein is a sterilization indicator for quantifying the amount of nitric oxide. The sterilization indicator comprises a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The sterilization indicator further comprises a support layer comprising the chromophore-containing compound. In some embodiments, the sterilization indicator further comprises a polymer layer over at least a portion of the support layer to reduce diffusion of fluid through the polymer layer to the chromophore-containing compound.

[0008] Also provided herein is a method for detecting the presence of nitric oxide in a space. The method includes providing a nitric oxide source to expose the space to nitric oxide. The method further includes providing a sterilization indicator in the space. The method further includes exposing the sterilization indicator to nitric oxide. The method further includes observing a color change in the sterilization indicator after exposing the sterilization indicator to nitric oxide for a predetermined period of time to detect the presence of nitric oxide in the space.

[0009] Also provided herein is a method for quantifying the amount of nitric oxide in a space. The method includes providing a nitric oxide source to expose the space to nitric oxide. The method further includes providing a sterilization indicator in the space. The method further includes exposing the sterilization indicator to nitric oxide. The method further includes observing a color change in the sterilization indicator after exposing the sterilization indicator to nitric oxide for a predetermined period of time to quantify the amount of nitric oxide in the space.

[0010] Also provided herein is a method for forming a sterilization indicator for detecting the presence and amount of nitric oxide. The method includes providing a support layer. The method further includes providing a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The method further includes combining the support layer with the chromophore-containing compound. In some embodiments, the method further includes applying a polymer layer to at least a portion of the support layer to form the sterilization indicator.

[0011] Also provided herein is a method for forming a sterilization indicator for quantifying the amount of nitric oxide. The method includes providing a support layer. The method further includes providing a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The method further includes combining the support layer with the chromophore-containing compound. In some embodiments, the method further includes applying a polymer layer to at least a portion of the support layer to form the sterilization indicator.

[0012] In a non-limiting embodiment, a solid sterilization indicator is provided in which a visible dye or chromophore changes color from clear to bright green upon exposure to gas-phase nitric oxide. However, it will be understood that other dyes can be used to produce different color transitions (e.g., yellow to red). The diffusion of oxygen and nitric oxide to the dye or chromophore can be controlled by injecting the chromophore into a solid matrix such as cellulose and overcoating it with a polymer such as polyvinyl chloride (PVC). Cellulose-based tape (e.g., cellophane) or polypropylene tape can also be used as a diffusion barrier to control contact between nitric oxide and the dye or chromophore. The sensitivity of the sterilization indicator to nitric oxide and the timing of its response can be adjusted by adjusting the amount of dye or chromophore and the identity and thickness of the overcoat / diffusion layer. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a cross-sectional perspective view of a non-limiting embodiment of a sterilization indicator.

[0014] [Figure 2] FIG. 10 is a cross-sectional perspective view of another non-limiting embodiment of a sterilization indicator.

[0015] [Figure 3] FIG. 10 is a cross-sectional perspective view of another non-limiting embodiment of a sterilization indicator.

[0016] [Figure 4] 10 is a photograph of a comparative sterilization indicator at various time points.

[0017] [Figure 5] 10A-10C are photographs of non-limiting embodiments of exemplary sterilization indicators at various time points.

[0018] [Figure 6] 1 is a graph showing the color change over time of a non-limiting embodiment of an exemplary sterilization indicator.

[0019] [Figure 7] 1 is a photograph of various non-limiting embodiments of an exemplary sterilization indicator.

[0020] [Figure 8] 1 is a perspective view showing a non-limiting embodiment of an article to be sterilized or disinfected. FIG.

[0021] [Figure 9] FIG. 4 is a perspective view of a non-limiting embodiment of a device including the sterilization indicator of FIGS. 1-3.

[0022] [Figure 10] 10 is a cross-sectional perspective view of a non-limiting embodiment of a support for the device of FIG. 9.

[0023] [Figure 11] 11 is a cross-sectional perspective view of a non-limiting embodiment of a case for the support of FIG. 10. FIG.

[0024] [Figure 12] 4 is a photograph showing a non-limiting embodiment of a barrier including the sterilization indicator of FIGS. 1-3. Detailed Description of the Invention

[0025] Except in the examples or where otherwise expressly indicated, all numerical quantities herein expressing amounts of substances or conditions of reaction and / or use are understood to be modified by the word "about" in describing the broadest scope of the present disclosure. In various embodiments, the terms "about" and "approximately," when referring to a specified measurable value (parameter, amount, temporal duration, etc.), are meant to encompass the specified value and variations from the specified value, e.g., variations of no more than ±10%, or no more than ±5%, or no more than ±1%, or no more than ±0.1%, of the specified value, to the extent appropriate for practice in the disclosed embodiments. Accordingly, the value to which the modifier "about" or "approximately" refers is itself specifically disclosed.

[0026] Generally, it is preferable to work within the stated numerical ranges. Furthermore, unless expressly stated to the contrary, percent, "parts," and ratio values are weight percent, parts by weight, and weight ratios, respectively. In the context of this invention, when a group or class of substances is described as suitable or preferred for a given purpose, it means that mixtures of any two or more members of that group or class are also suitable or preferred. Descriptions of components in chemical terms refer to the components at the time of addition in any combination specified herein and do not necessarily exclude chemical interactions between the components of a mixture once mixed. The initial definition of an acronym or other abbreviation applies to all subsequent uses of the same abbreviation in this specification and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation. Furthermore, unless expressly stated to the contrary, measurements of physical properties are determined by the same techniques as those previously or subsequently referenced for the same physical property.

[0027] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a singular element is intended to include plural elements.

[0028] As used herein, "embodiment" means that a particular feature, structure, or characteristic is included in at least one manifestation, example, or implementation of the invention. Furthermore, particular features, structures, or characteristics can be combined in any suitable manner, as would be apparent to one of ordinary skill in the art. All combinations of features from different embodiments are intended to be within the scope of the invention, and it is not necessary for the examples to explicitly describe every possible permutation. Thus, any claimed embodiment may be used in any combination.

[0029] As used herein, the term "wt%" (and related abbreviation "wt%") refers to weight percent, typically expressed by weight of dry matter. As such, it should be understood that wt% can be calculated based on the total weight of the composition, or can be calculated from the ratio between two or more components / portions of a mixture (e.g., total weight of dry matter).

[0030] As used herein, the term "substantially" refers to the complete or nearly complete extent of an action, property, characteristic, state, structure, item, or result. As a given example, an object being "substantially" enclosed means that the object is either completely enclosed or nearly completely enclosed, and the overall result is the same as if the object were completely enclosed.

[0031] The drawings are semi-schematic and not to scale, and in particular, some dimensions are exaggerated in the drawings for clarity of presentation. Similarly, while the figures in the drawings generally have similar orientations for ease of explanation, this depiction in the drawings is arbitrary. In general, the sterilization indicator can be operated in any orientation. When a first element or layer is referred to herein as being "on," "over," "under," or "underlying" a second element or layer, it will be understood that the first element or layer may be directly on the second element or layer, or that there may be an intervening element or layer through which a straight line can be drawn between the features in an overlying relationship. When a first element or layer is referred to as being "on" a second element or layer, the first element or layer is directly on and in contact with the second element or layer. Furthermore, spatially relative terms such as "upper," "top," "lower," and "under" may be used herein to describe the relationship of one element or feature to another element or feature, as shown in the figures, for ease of explanation. It will be understood that spatially relative terms are intended to encompass different orientations of the sterilization indicator during use or operation in addition to the orientation depicted in the figures. For example, if the sterilization indicator in the figures were turned over, elements described as being "below" other elements or features would now be oriented "above" the other elements or features. Thus, the exemplary term "below" can encompass either an orientation of above or below. The sterilization indicator may be in other orientations (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein may likewise be interpreted accordingly.

[0032] Throughout this disclosure, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this disclosure in order to more fully describe the state of the art to which this disclosure pertains.

[0033] The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.

[0034] FIG. 1 is a cross-sectional perspective view of a non-limiting embodiment of a sterilization indicator 10 for detecting the presence of nitric oxide. The sterilization indicator 10 includes a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. In various embodiments, the chromophore-containing compound includes 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (“ABTS”), methyl organge (MeORG), thymol blue (ThBlu), or a combination thereof. It will be appreciated that any chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide can be utilized. In one exemplary embodiment, the chromophore-containing compound includes, consists essentially of, or is ABTS. Without being limited by theory, it is believed that ABTS oxidizes in the presence of nitric oxide to form its radical cation, as described below. [ka]

[0035] As a result of oxidation in the presence of nitric oxide, the clear ABTS undergoes a color change to form the bright green ABTS radical cation. Thus, in various embodiments, this oxidation in the presence of nitric oxide causes the sterilization indicator 10 to undergo a color change (e.g., from clear to bright green). However, it should be understood that the sterilization indicator 10 may undergo any combination of color changes depending on the components of the sterilization indicator 10.

[0036] The sterilization indicator 10 further comprises a support layer 12. The support layer 12 may have a first surface 14 and a second surface 16 opposite the first surface 14. However, it should be understood that the support layer 12 may have any number of surfaces, such as three, four, five, six, etc. In various embodiments, the support layer 12 has a rectangular configuration or an oval configuration. However, it should be understood that the support layer 12 may have any geometric configuration suitable for supporting the sterilization indicator 10. The thickness of the support layer 12 may be from about 0.1 micron to about 1000 microns, optionally from about 1 to about 100, or optionally from about 1 to about 10 mils.

[0037] The support layer 12 includes a chromophore-containing compound. In some embodiments, the support layer 12 has a porous or woven structure, and the chromophore-containing compound is disposed within the pores or interstices within the woven structure. In other embodiments, the chromophore-containing compound may be combined with a moldable material to form a support structure 12 containing the chromophore-containing compound. In certain embodiments, the support layer 12 includes, consists essentially of, consists of, or is a cellulose-containing material. Non-limiting examples of suitable cellulose-containing materials include cellulose filter paper, such as Whatman No. 1 quantitative filter paper.

[0038] The chromophore-containing compound may be dispersed within support structure 12, disposed on support structure 12, or both. The chromophore-containing compound may be uniformly dispersed within support structure 12, disposed on support structure 12, or the chromophore-containing compound may be present as a gradient relative to the configuration of support structure 12. In certain embodiments, the chromophore-containing compound is distributed throughout support structure 12. uniformly The chromophore-containing compound may be present in or disposed on support structure 12 in an amount of at least a trace amount, optionally at least 6.9 mg / mL, or optionally at least 25 mg / mL, based on the total surface area of support structure 12.

[0039] The sterilization indicator 10 further comprises a polymeric layer 18 on at least a portion of the support layer 12 to reduce the diffusion of a fluid through the polymeric layer to the chromophore-containing compound. In various embodiments, the fluid may be a liquid or a gas, such as oxygen, nitric oxide, or hydrogen peroxide. In certain embodiments, the polymeric layer 18 may be adapted to reduce the diffusion of hydrogen peroxide to a greater extent than the diffusion of nitric oxide to the chromophore-containing compound. In various embodiments, the polymeric layer 18 may be formed from a polymeric material having a diffusion rate for nitric oxide no greater than the diffusion rate of NO in air. In these and other embodiments, the polymeric layer 18 may be formed from a polymeric material having a diffusion rate for oxygen no greater than the diffusion rate in air. In these and other embodiments, the polymeric layer 18 may be formed from a polymeric material having a diffusion rate for hydrogen peroxide no greater than the diffusion rate in air.

[0040] Polymer layer 18 can be formed from polymeric materials including polyvinyl chloride, polyester, cellulose-containing materials, polypropylene, or combinations thereof. However, it should be understood that any other polymeric material can be utilized for polymeric layer 18, so long as the polymeric material exhibits the above-described diffusion properties and the polymeric material is inert to the chromophore-containing compounds. The thickness of polymeric layer 18 can be from about 0.1 micron to about 1000 microns, optionally from about 1 to about 100, or optionally from about 5 to about 10 mils.

[0041] The polymeric material may further include various additives such as, but not limited to, a solvent component, a plasticizer component, a surfactant component, a colorant component, a filler component, or combinations thereof.

[0042] The solvent component can include an organic solvent, however, it should be understood that the solvent component can also include other solvents, including water, that are known to solvate solutes, so long as the solvent is compatible with the components of the polymeric material and the chromophore-containing compound.

[0043] Examples of organic solvents suitable for the solvent component include, but are not limited to, toluene, xylene, butyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl amyl ketone, methanol, isopropanol, butanol, hexane, acetone, ethylene glycol, monoethyl ether, propylene glycol methyl ether, VM and P naphtha, mineral spirits, heptane, other aliphatic, alicyclic, aromatic hydrocarbons, aromatic petroleum distillates, esters, ethers, and ketones, or combinations thereof. In certain embodiments, the solvent component comprises methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), toluene, propylene glycol methyl ether, or combinations thereof.

[0044] The plasticizer component can include plasticizers that can be used to modify various properties, including, but not limited to, coating hardness, imparting hydrophobicity, and / or modifying fluid diffusivity. Plasticizers include, but are not limited to, phthalates, trimellitates, benzoates, adipates, sebacates, maleates, citrates, epoxidized vegetable oils, sulfonamides, organophosphates, glycols / polyethers, polymeric plasticizers, and polybutenes, or combinations thereof. However, it should be understood that the plasticizer component can include other plasticizers understood in the art, so long as the plasticizer is compatible with the polymeric material and the chromophore-containing compound components.

[0045] The plasticizer may be an ester-based plasticizer. Examples of suitable ester-based plasticizers include, but are not limited to, dioctyl phthalate (DOP), n-hexyl-n-decyl phthalate (NHDP), n-octyl-decyl phthalate (NODP), di(isononyl) phthalate (DINP), di(isodecyl) phthalate (DIDP), diundecyl phthalate (DUP), di(isotridecyl) phthalate (DTDP), di-2-ethylhexyl adipate (DOA), di-n-octyl-n-decyl adipate (DNODA), diisononyl adipate (DINA), di-2-ethylhexyl azelate (DOZ), di-2-ethylhexyl sebacate (DOS), trioctyl trimellitate (TOTM), trioctyl phosphate (TOP), tricresyl phosphate (TCP), aliphatic polyester plasticizers, aliphatic polyol plasticizers, or combinations thereof. It is understood that the plasticizer can include any phthalate ester known in the art, so long as it is compatible with the polymeric material and the components of the chromophore-containing compound. The plasticizer component can be present in the polymer in various amounts.

[0046] The surfactant component can include anionic surfactants, nonionic surfactants, cationic surfactants, zwitterionic surfactants, or combinations thereof. However, it should be understood that the surfactant component can include other surfactants understood in the art, so long as the surfactant is compatible with the polymer and chromophore-containing compound components. The surfactant component can be present in the polymer in various amounts.

[0047] The colorant component can include, but is not limited to, one or more colorants, such as pigments, dyes, or combinations thereof, to achieve the color of the coating. These colorants are used in addition to the chromophore-containing compound. Suitable colorants are generally soluble or dispersible in the solvent components of the polymer material and the chromophore-containing compound. The colorant component can be present in the polymer in various amounts.

[0048] The filler component includes, but is not limited to, fillers that can be used for various purposes, such as cost control, rheology control, lubricity improvement, and prevention of seizure and galling. The filler component may include an inorganic filler. Examples of suitable inorganic fillers include, but are not limited to, powdered nickel, copper, zinc, and aluminum. Suitable mineral fillers include, but are not limited to, talc, calcium carbonate, silicates such as mica, wollastonite, titanium dioxide, quartz, fumed silica, precipitated silica, graphite, boron nitride, or combinations thereof. The filler component can be present in the polymer in various amounts.

[0049] In addition to the aforementioned components of polymer layer 18, there are several other factors that can affect the diffusion of fluid to the chromophore-containing compound and the reactivity of nitric oxide with the chromophore-containing compound, including, but not limited to, the temperature of the space, the humidity level of the space, the acidity of polymer layer 18, the thickness of polymer layer 18, and the concentration of the chromophore-containing compound.

[0050] 2 is a cross-sectional perspective view illustrating a non-limiting embodiment of a sterilization indicator 10. In certain embodiments, the support layer 12 comprises a first portion 20 and a second portion 22 adjacent to the first portion 20. In these and other embodiments, the first portion 20 includes the polymer layer 18, and the second portion 22 is substantially free of the polymer layer 18. By directly exposing the second portion 22 of the support layer 12 to nitric oxide, the sterilization indicator 10 can be adapted to function as a linear timing dosimeter. This linear timing dosimeter provides a gradual transfer of nitric oxide from the second portion 22 to the first portion 20, with the distance transferred being linearly proportional to the duration of exposure to nitric oxide. In some embodiments, the linear timing dosimeter is linearly proportional for at least 2 hours, optionally at least 3 hours, or optionally at least 4 hours.

[0051] 3 is a cross-sectional perspective view showing a non-limiting embodiment of sterilization indicator 10. Polymer layer 18 is on at least a portion of first surface 14 of backing layer 12, while second surface 16 of backing layer 12 remains substantially free of polymer layer 18. However, as noted above, polymer layer 18 may be on at least a portion of second surface 16.

[0052] In various embodiments, the sterilization indicator 10 further includes a backing layer 24 overlying the first surface 14. The backing layer 24 can be in a variety of forms, including, for example, polymeric films, paper, cardboard, stock cards, woven and nonwoven webs, fiber-reinforced films, foams, composite film-foams, or combinations thereof. The backing layer 24 can include a variety of materials, such as, for example, fibers, lignocellulose, wood, foams, and thermoplastic polymers, such as polyolefins (e.g., polyethylenes such as high-density polyethylene, low-density polyethylene, linear low-density polyethylene, and linear very-low-density polyethylene), polypropylene, and polybutylene; vinyl copolymers (e.g., polyvinyl chloride, plasticized and unplasticized polyvinyl chloride, polyvinyl acetate); olefin-based copolymers, such as ethylene / methacrylate copolymers, ethylene / vinyl acetate copolymers, acrylonitrile-butadiene-styrene copolymers, and ethylene / propylene copolymers; acrylic polymers and copolymers; polyurethanes; and combinations thereof. Suitable blends also include blends of thermoplastic polymers, elastomeric polymers, and combinations thereof, such as, for example, polypropylene / polyethylene, polyurethane / polyolefin, polyurethane / polycarbonate, and polyurethane / polyester.

[0053] In these and other embodiments, the sterilization indicator 10 further comprises an adhesive layer 26 overlying the second surface 16. The adhesive layer 26 can be based on a variety of adhesives. Non-limiting examples of suitable adhesives include various pressure-sensitive adhesives, such as water-insoluble natural rubber adhesives, blends of natural and synthetic rubber adhesives, and combinations of styrene-isoprene-styrene block copolymers with tackifying resins, vinyl ethers, and high molecular weight acrylate copolymers. Various water-dispersible pressure-sensitive adhesives are also available. It will be understood that a separate backing layer 24 may be present over the adhesive layer 26.

[0054] A method of detecting the presence of nitric oxide in a space is also provided. The method includes providing a source of nitric oxide to expose the space to nitric oxide. The method further includes providing a sterilization indicator 10 to the space. The method further includes exposing the sterilization indicator 10 to nitric oxide. The method further includes observing a color change of the sterilization indicator 10 after exposing the sterilization indicator 10 to nitric oxide for a predetermined period of time to identify the presence of nitric oxide in the space.

[0055] In some embodiments, it is desired to disinfect or sterilize a space and objects within the space using nitric oxide. Non-limiting examples of suitable spaces include examination rooms, classrooms, restaurants, aircraft cabins, vehicle interiors, etc. In these embodiments, the method further includes discontinuing exposure of the space to nitric oxide after a color change in sterilization indicator 10 is observed.

[0056] In other embodiments, the space may be a container or receptacle containing an item desired to be sterilized and then removed from the space. Non-limiting examples of suitable items include medical equipment, educational materials, portable devices, food service equipment, etc. In these embodiments, the method further includes providing the item to be sterilized to the space, exposing the item to nitric oxide, and removing the item from the space.

[0057] In certain embodiments, the space is disposed within the environment and is substantially fluidly isolated from the environment. By "substantially fluidly isolated," it is meant that the transfer of fluid from the environment to the space and vice versa is minimized. However, it should be understood that the space need not be (but may be) hermetically isolated from the environment for the sterilization indicator 10 to be operable.

[0058] Use of the sterilization indicator 10 to confirm the presence of nitric oxide in a space is also provided in accordance with the above.

[0059] A method of forming a sterilization indicator 10 for detecting the presence of nitric oxide is also provided. The method includes providing a support layer 12. The method further includes providing a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide. The method further includes combining the support layer 12 with the chromophore-containing compound. The method further includes applying a polymer layer 18 to at least a portion of the support layer 12 to form the sterilization indicator 10.

[0060] In various embodiments, the method further includes drying the support layer 12 combined with the chromophore-containing compound in the presence of nitrogen before applying the polymer layer 18 .

[0061] In certain embodiments, as described above with respect to the linear timing dosimeter embodiment, the step of applying the polymer layer 18 to at least a portion of the support layer 12 is further defined as applying the polymer layer 18 to a first portion 20 of the support layer 12 such that a second portion 22 of the support layer 12 is substantially free of the polymer layer 18.

[0062] 8-12 show various views of components of a system including a sterilization indicator 10 for detecting the presence of nitric oxide proximate an article 28. Referring to FIGS. 8 and 9, a system can include an article 28 defining a cavity, such as a lumen of an endoscope. The system can further include a device 30, such as an optical fiber, for delivering nitric oxide to disinfect or sterilize the article 28. Non-limiting examples of suitable sterilization techniques are described in U.S. Provisional Patent Applications Nos. 63 / 141,676 and 63 / 156,917, which are incorporated by reference in their entireties. The device 30 can include a support 32 having a surface adapted to transmit electromagnetic radiation. The support 32 can have a first end 34 and a second end 36 spaced from the first end 34.

[0063] The apparatus 30 may further include an electromagnetic radiation source 38 in optical communication with the support 32 and adapted to generate electromagnetic radiation. In certain embodiments, the electromagnetic radiation source 38 includes an LED bulb coupled to the first end 34.

[0064] 9, the device 30 can further include a nitric oxide source 40 disposed on the surface of the support 32. Non-limiting examples of suitable nitric oxide sources are described in U.S. Provisional Patent Applications Nos. 63 / 141,676 and 63 / 156,917, which are incorporated by reference in their entireties. In certain embodiments, the nitric oxide source 40 comprises SNAP-PDMS or other nitric oxide sources. To this end, the nitric oxide source 40 is adapted to provide nitric acid in the presence of electromagnetic radiation generated by an electromagnetic radiation source 38 and transmitted through the support 32 from the first end 34 to the second end 36. The support 32 of the device 30 can be disposed within a lumen of an article 28 (e.g., an endoscope).

[0065] 10 and 11, the substrate 32 is an optical fiber including a PMMA core 42, a cladding layer 44, a nitric oxide source 46, and a PDMS protective layer 48. The substrate 32 may be wrapped within a case 50 formed from foam to allow insertion into the article 28 without contaminating the substrate 32. The case 50 may include a cap 52 for accessing the substrate 32.

[0066] 9 and 12, the device 30 may further include a sterilization indicator 10 proximate the second end 36 of the support 32. The sterilization indicator 10 may be disposed within a barrier 54 coupled to the second end 36 of the support 32. In one embodiment, the barrier 54 includes an indicator portion 56 and a locking portion 58, where the locking portion 58 couples the indicator portion 56 to the second end 36 of the support 32. The sterilization indicator 10 may be fluidly isolated from the exterior of the barrier 54. This isolation of the sterilization indicator 10 provides a direct indication of the presence of nitric oxide formed from the support 32 of the device 30 without interference from any source of nitric oxide outside the barrier 54, thereby providing user feedback regarding the production of nitric oxide by the device 30.

[0067] Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to these specific embodiments. While the foregoing detailed description of the present disclosure has presented at least one exemplary embodiment, it should be understood that numerous variations exist. It should also be understood that the exemplary embodiment is merely an example and is not intended to limit the scope, applicability, or configuration of the present invention in any way. Rather, the foregoing detailed description provides those skilled in the art with a convenient road map for implementing exemplary embodiments of the present invention. It should be understood that various changes can be made in the function and arrangement of elements described in the exemplary embodiments without departing from the scope of the present disclosure as set forth in the appended claims. [Industrial Applicability]

[0068] Although the present invention is not limited to a particular end application, use, or industry, employees of hospitals, schools, restaurants, airlines, and public transportation often rely on disinfection or sterilization, and the sterilization indicators described above are useful for detecting the presence of nitric oxide for disinfection or sterilization.

[0069] The following examples are illustrative of the sterilization indicators of the present disclosure and are intended to illustrate but not limit the invention. [Example]

[0070] The following examples are included to illustrate various embodiments contemplated herein. Those of skill in the art should understand that the techniques disclosed in the examples below are techniques discovered by the inventors to function well in the practice of the invention and, therefore, are believed to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments disclosed and still obtain like or similar results without departing from the spirit and scope of the invention. All percentages are by weight and, unless otherwise noted, all measurements are made at 23°C.

[0071] Example 1 (Comparative Example) Referring to Figure 4, Comparative Sterilization Indicator I was formed by immersing cellulose filter paper (Whatman No. 1 quantitative filter paper) in an aqueous solution of 8.4 mg / mL of 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and drying under nitrogen. When Comparative Sterilization Indicator I was then exposed to NO gas, it began to change color to dark green after approximately 15 minutes. The Comparative Sterilization Indicator I reached its final color change after approximately 3.5 hours.

[0072] Example 2 (Comparative Example) Comparative Sterilization Indicator II was formed by saturating cellulose filter paper (Whatman No. 1 quantitative filter paper) with a 6.9 mg / mL solution of 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) in methanol and drying under nitrogen. The comparative sterilization indicator II was then exposed to NO gas, which turned the indicator light green after approximately 3.5 minutes. The sterilization indicator II turned dark green after approximately 24 hours.

[0073] Example 3 (Illustrative) Cellulose filter paper (Whatman No. 1 quantitative filter paper) was soaked in an aqueous solution of 8.4 mg / mL 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and dried under nitrogen to form exemplary sterilization indicator I. The exemplary sterilization indicator I was then coated with 5 wt % PVC dissolved in THF. The exemplary sterilization indicator I was then exposed to NO gas and turned green after about 15 minutes, with the color intensity under the topcoat being less than that of the comparative sterilization indicators I and II.

[0074] Example 4 (Illustrative) Cellulose filter paper (Whatman No. 1 quantitative filter paper) was saturated with 6.9 mg / mL of 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) in methanol and dried under nitrogen. The paper was then coated with 5 wt % PVC dissolved in THF to form exemplary Sterilization Indicator II. Exemplary Sterilization Indicator II was then exposed to NO gas, turning dark green after approximately 15 minutes; however, the color intensity beneath the topcoat was weaker than that of the comparative Sterilization Indicators I and II.

[0075] Example 5 (Illustrative) Referring to Figure 5, a linear passive timer was created by soaking a strip of cellulose filter paper (Whatman No. 1 quantitative filter paper) in an 8.4 mg / mL aqueous solution of 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and drying under nitrogen. The paper was then wrapped in cellophane tape over all but the bottom 4 mm, creating an exemplary Sterilization Indicator III. The bottom strip of the exemplary Sterilization Indicator III was then exposed to NO gas. Rapid color development occurred at the bottom exposed edge, followed by a gradual increase in the tape-wrapped area. As shown in Figure 6, for NO, color development was linear with exposure time and distance traveled for approximately the first 4 hours of exposure.

[0076] Example 6 (Illustrative) Referring to Figure 7, dot timing dosimeters were also created using two different configurations. In the first configuration, the outer edge of the circle was exposed to allow sensing of NO, while the center of the circle was covered with a diffusion barrier, creating an "outward-in" dosimeter that indicated the progression of NO exposure as the dot developed color from the outer edge inward. In the second configuration, the center of the dot was exposed, and the outer edge contained a diffusion barrier. In this configuration, color developed first in the center of the dot and continued to develop "inward-outward." These symmetric dosimeters were insensitive to physical orientation relative to the NO source.

[0077] It is understood that the scope of the appended claims is not limited to the explicit and specific compounds, compositions, or methods described in the Detailed Description of the Invention, and that variations may occur among specific embodiments falling within the scope of the appended claims. With respect to any Markush group recited herein to describe particular features or aspects of various embodiments, different, special, and / or unexpected results may be obtained from each member of the respective Markush group, independent of all other Markush groups. Each member of a Markush group may be relied upon individually or in combination to provide sufficient support for specific embodiments within the scope of the appended claims.

[0078] Furthermore, the ranges and subranges relied upon in describing various embodiments of the present invention are understood to be individually and collectively encompassed by the appended claims and to describe and contemplate all ranges, including integers and / or fractional values therein, even if such values are not expressly recited herein. Those skilled in the art will readily recognize that the recited ranges and subranges fully describe and enable various embodiments of the present invention, and that such ranges and subranges can be further subdivided into related halves, thirds, quarters, fifths, etc. By way of example only, a "range of 0.1 to 0.9" can be further subdivided into a lower third, i.e., 0.1-0.3, a middle third, i.e., 0.4-0.6, and an upper third, i.e., 0.7-0.9, which, individually and collectively, are within the scope of the appended claims and can be relied upon individually and / or collectively to provide sufficient support for particular embodiments within the scope of the appended claims. Furthermore, with regard to terms defining or modifying a range, such as "at least," "greater than," "less than," or "at most," it is understood that such terms include subranges and / or upper or lower limits. As another example, a range of "at least 10" inherently includes subranges from at least 10 to 35, from at least 10 to 25, from 25 to 35, etc., each of which may be relied upon individually and / or collectively to provide sufficient support for particular embodiments within the appended claims. Finally, individual numerical values within a disclosed range may be relied upon to provide sufficient support for particular embodiments within the appended claims. For example, a "range of 1 to 9" includes various individual integers, such as 3, and individual numerical values containing decimal points (or fractions), such as 4.1, which may be relied upon to provide appropriate support for particular embodiments within the appended claims.

[0079] While the present invention has been described herein in an illustrative manner, it should be understood that the terminology used is intended to be in words of description, rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. The present invention may be practiced otherwise than as specifically described within the scope of the appended claims. The subject matter of all combinations of independent and dependent claims (both single and multiple dependent claims) is expressly contemplated herein.

Claims

1. 1. A sterilization indicator for detecting the presence of nitric oxide, comprising: a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide; a support layer containing the chromophore-containing compound; Contains the chromophore-containing compound comprises 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), methyl orange (MeORG), thymol blue (ThBlu), or a combination thereof; The sterilization indicator further comprises a polymer layer overlying at least a portion of the support layer for reducing diffusion of fluid through the polymer layer to the chromophore-containing compound, the polymer layer being formed from a polymeric material comprising polyvinyl chloride, polyester, a cellulose-containing material, polypropylene, or a combination thereof.

2. 10. The sterilization indicator of claim 1, wherein the support layer includes a nitric oxide source disposed on a surface of the support that releases nitric oxide.

3. The sterilization indicator of claim 1 , wherein the support layer comprises a cellulose-containing material.

4. The polymer layer comprises: (A) The diffusion rate of nitric oxide is not greater than the diffusion rate of nitric oxide in air; (B) The diffusion rate of oxygen is not greater than the diffusion rate of oxygen in air; (C) the diffusion rate of hydrogen peroxide is not greater than the diffusion rate of hydrogen peroxide in air, or Any combination of (A), (B), and (C) 10. The sterilization indicator of claim 1, formed from a polymeric material which is

5. 2. The sterilization indicator of claim 1, wherein the support layer comprises a first portion and a second portion adjacent to the first portion, the first portion comprising a polymer layer and the second portion being substantially free of the polymer layer.

6. 10. The sterilization indicator of claim 1, wherein the support layer has a first surface and a second surface opposite the first surface, and the polymer layer overlies at least a portion of the first surface.

7. 7. The sterilization indicator of claim 6, further comprising a backing layer overlying the first surface.

8. 7. The sterilization indicator of claim 6, further comprising an adhesive layer overlying the second surface.

9. 1. A method for detecting the presence of nitric oxide in a space, comprising: providing a nitric oxide source for exposing said space to nitric oxide; providing a sterilization indicator in the space, the sterilization indicator being as claimed in claim 1; exposing the sterilization indicator to the nitric oxide; and observing a color change of the sterilization indicator after exposing the sterilization indicator to the nitric oxide for a predetermined period of time to detect the presence of nitric oxide in the space.

10. 10. The method of claim 9, providing an item to be sterilized in the space; exposing the article to the nitric oxide; Removing the item from the space; and A method comprising:

11. 10. The method of claim 9, further comprising discontinuing exposure of the space to nitric oxide.

12. The method of claim 9 , wherein the space is disposed within an environment, the space being substantially fluidly isolated from the environment.

13. 10. Use of the sterilization indicator of claim 1 to identify the presence of nitric oxide in a space.

14. 1. A sterilization indicator for quantifying the amount of nitric oxide, comprising: a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide; a support layer comprising the chromophore-containing compound; a polymer layer overlying at least a portion of the support layer for reducing diffusion of fluid through the polymer layer to the chromophore-containing compound; Including, A sterilization indicator, wherein the chromophore-containing compound comprises 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), methyl orange (MeORG), thymol blue (ThBlu), or a combination thereof.

15. 15. The sterilization indicator of claim 14, wherein the support layer includes a nitric oxide source disposed on a surface of the support that releases nitric oxide.

16. 1. A method for quantifying the amount of nitric oxide in a space, comprising: providing a nitric oxide source for exposing said space to nitric oxide; providing a sterilization indicator in the space, the sterilization indicator being as claimed in claim 14; exposing the sterilization indicator to the nitric oxide; observing a color change of the sterilization indicator after exposing the sterilization indicator to nitric oxide for a predetermined period of time to quantify the amount of nitric oxide in the space; A method comprising:

17. 15. Use of the sterilization indicator of claim 14 for quantifying the amount of nitric oxide in a space.

18. 1. A method of forming a sterilization indicator for detecting the presence of nitric oxide, comprising: providing a support layer; providing a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide; combining the support layer and the chromophore-containing compound to form a sterilization indicator; Including, The method, wherein the chromophore-containing compound comprises 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), methyl orange (MeORG), thymol blue (ThBlu), or a combination thereof.

19. 20. The method of claim 18, further comprising applying a polymer layer to at least a portion of the backing layer to form the sterilization indicator.

20. 20. The method of claim 19, further comprising drying the support layer combined with the chromophore-containing compound in the presence of nitrogen before applying the polymer layer.

21. 20. The method of claim 19, wherein the support layer comprises a first portion and a second portion adjacent to the first portion, and wherein applying a polymer layer to at least a portion of the support layer is further defined as applying the polymer layer to the first portion such that the second portion is substantially free of the polymer layer.

22. 20. The method of claim 18, wherein the support layer comprises a nitric oxide source disposed on a surface of the support that releases nitric oxide.

23. 1. A method of forming a sterilization indicator for quantifying the amount of nitric oxide, comprising: providing a support layer; providing a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide; combining the support layer with the chromophore-containing compound; applying a polymer layer to at least a portion of the backing layer to form a sterilization indicator; Including, The method wherein the support layer comprises a nitric oxide source disposed on a surface of the support that releases nitric oxide.

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