Trauma Covering Material

Abstract

The disclosed embodiments relate to wound dressings capable of generating nitric oxide. The wound dressing may comprise a cover layer, an activating layer such as an acid-providing layer, and a nitrite-providing layer. The activating layer may comprise acidic groups and may be a hydrogel, xerogel, or other suitable material. The nitrite-providing layer may comprise mesh components embedded with antioxidants / reducing agents such as nitrite and sodium isoascorbate. Nitrite ions in the nitrite-providing layer may react with acidic groups in the activating layer to generate nitric oxide. Furthermore, the wound dressing may be manufactured and stored to reduce the degradation of antioxidants / reducing agents, thereby enabling stable nitric oxide production.

Description

[Technical Field]

[0001] Background technology

[0002] Materials, devices, methods, and systems, including therapeutic compositions, wound care materials, their uses, and methods of treatment using them, are disclosed herein. In some examples, the materials, devices, and systems described herein include wound dressings configured for nitric oxide (NO) delivery and / or delivery of other active substances.

[0003] Explanation of related technologies Nitric oxide (NO) is a well-known molecule with multiple biological functions. For example, nitric oxide affects vasodilation, stimulates angiogenesis, influences host immune responses, and exhibits potent broad-spectrum antibacterial and antibiofilm activity. Due to these multiple roles, NO has a potent effect on tissues, and increased levels of NO may support accelerated wound healing, especially in chronic wounds.

[0004] In addition, diabetic patients often have lower levels of nitric oxide compared to healthy individuals, and reduced nitric oxide supply in diabetic patients is an aggravating factor in healing chronic ulcers. Reduced nitric oxide supply can lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can also lead to reduced blood flow to the extremities, thereby potentially increasing the likelihood of diabetic patients developing neuropathy and non-healing ulcers, and raising the risk of lower limb amputation.

[0005] Therefore, there is a need for an improved mechanism for delivering an effective dose of nitric oxide to the wound. Under normal conditions, nitric oxide (NO), as a free radical, is short-lived and is converted to a more stable chemical species within seconds of its generation. Therefore, for example, when gaseous nitric oxide comes into contact with air, it is rapidly oxidized to produce nitric oxide (NO2). Consequently, maintaining high concentrations of nitric oxide over long periods within wound dressings or other similar structures can be difficult. Therefore, devices or wound dressings having one or more layers containing a more stable composition can effectively generate nitric oxide over time upon activation for stable and sustained delivery of nitric oxide to biological tissue. Of particular note is the mechanism for delivering nitric oxide in combination with the use of wound dressings, especially negative pressure wound dressings, and / or during negative pressure wound therapy and / or other appropriate therapies. [Overview of the Initiative]

[0006] Embodiments of this disclosure relate to materials, devices, methods, and systems for wound treatment. Some disclosed embodiments relate to materials, devices, methods, and systems for delivering nitric oxide to a wound. Those skilled in the art will understand that the applications of the materials, devices, methods, and systems described herein are not limited to specific tissues or specific injuries.

[0007] In some embodiments, a wound dressing for treating a wound may comprise a cover layer configured to form a seal around the wound, an activator layer, a dry nitrite supply layer, a dry nitrite supply layer that is liquid-free or relatively liquid-free, and a water-absorbing dispersion layer.

[0008] In certain embodiments, the wound dressing further comprises a masking layer configured to at least partially limit the visibility of the wound. The dry nitrite supplying layer may contain a nitrite. The nitrite may contain sodium nitrite. The dry nitrite supplying layer may further contain an antioxidant / reducing agent. The reducing agent may be sodium isoascorbate. The nitrite and antioxidant / reducing agent in the dry nitrite supplying layer may be colocalized on the mesh component. The nitrite and antioxidant / reducing agent can be colocalized on the mesh component by embedding a mixture of the nitrite and reducing agent within the mesh component. An activator layer may be positioned above the nitrite supplying layer. In some embodiments, the nitrite supplying layer may be positioned above the activator layer. A water-absorbing dispersion layer may be positioned between the activator layer and the dry nitrite supplying layer. The activator layer may contain a hydrogel or xerogel. The wound dressing may comprise a second dry nitrite supplying layer. Wound dressings may be configured to generate nitric oxide when placed on a wound. In some embodiments, wound dressings may be configured not to generate nitric oxide before being placed on the wound.

[0009] In some embodiments, wound treatment devices are provided for treating wounds. In some embodiments, the wound treatment device may comprise a nitrite-providing layer containing a mesh component. In some embodiments, the mesh component may comprise a colocalized nitrite and an antioxidant / reducing agent. In some embodiments, the wound treatment device may comprise an activator layer containing a hydrogel. In some embodiments, the activator layer may be configured to donate protons to the nitrite-providing layer to produce nitric oxide. In some embodiments, the nitrite and antioxidant / reducing agent may be embedded within the mesh component. In some embodiments, the nitrite and antioxidant / reducing agent may be solubilized and / or suspended in an anhydrous carrier before being embedded within the mesh component. In some embodiments, the anhydrous carrier is water-soluble or miscible. In some embodiments, the water-miscible anhydrous carrier may be selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, blends of PEG having different molecular weights, glycerol, triacetin, acetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylamine, ethylene glycol, formic acid, furfuryl alcohol, methanol, methyldiethanolamine, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propanoic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol. In some embodiments, the water-miscible anhydrous carrier may further contain a surfactant. In some embodiments, the mesh components of the nitrite supply layer may be stored in a dry state. In some embodiments, antioxidants / reducing agents co-localized with nitrite in the mesh components of the nitrite supply layer may have higher stability than antioxidants / reducing agents that are not stored in a dry state.In some embodiments, the antioxidant / reducing agent may exhibit higher stability after sterilization compared to the stability of the antioxidant / reducing agent in a sterilized wound dressing when the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the wound treatment device may be configured to produce less discoloration than a wound treatment device in which the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the mesh may include a coated polypropylene mesh. In some embodiments, the activator layer may include a composite material comprising a gelled fiber substrate loaded with an acidic hydrogel. In some embodiments, the hydrogel may further include an aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate and 2-acrylamido-2-methyl-1-propanesulfonic acid. In some embodiments, the wound treatment device may further include a water-absorbing dispersion layer. In some embodiments, the wound treatment device may further include a cover layer configured to form a seal around the wound. In some embodiments, the cover layer may be breathable. In some embodiments, the wound treatment device may further include a masking layer, which may be configured to at least partially limit the visibility of the wound. In some embodiments, the nitrite may be sodium nitrite. In some embodiments, the antioxidant / reducing agent may be sodium isoascorbate, ferrous sulfate, or a derivative of vitamin C. The vitamin C derivative may include L-ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glucoside, tetrahexyldecyl ascorbate, ethylated L-asorbic acid, or any suitable vitamin C derivative. In some embodiments, the mesh component comprises a 2.5 × 2.5 cm mesh loaded with any amount of nitrite and antioxidant / reducing agent, each from 1 to 5 mg, and the nitrite and antioxidant / reducing agent are suspended in a suitable carrier.

[0010] In some embodiments, methods for treating wounds are provided. In some embodiments, the method may further include applying a wound dressing to the wound. In some embodiments, the wound dressing may include a nitrite-providing layer containing mesh components. In some embodiments, the wound dressing may include a nitrite-providing layer containing mesh components. In some embodiments, the mesh components may include colocalized nitrite and antioxidant / reducing agents. In some embodiments, the wound dressing may include an activator layer containing a hydrogel. In some embodiments, the activator layer may be configured to donate protons to the nitrite-providing layer to produce nitric oxide. In some embodiments, the nitrite and antioxidant / reducing agents may be embedded within the mesh components. In some embodiments, the nitrite and antioxidant / reducing agents may be solubilized and / or suspended in an anhydrous carrier before being embedded within the mesh components. In some embodiments, the anhydrous carrier is water-soluble or miscible. In some embodiments, the water-miscible anhydrous carrier may be selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, blends of PEG having different molecular weights, glycerol, triacetin, acetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylamine, ethylene glycol, formic acid, furfuryl alcohol, methanol, methyldiethanolamine, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propanoic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol. In some embodiments, the water-miscible anhydrous carrier may further contain a surfactant. In some embodiments, the mesh components of the nitrite supply layer may be stored in a dry state.In some embodiments, antioxidants / reducing agents co-localized with nitrites in the mesh components of the nitrite-supplying layer may have higher stability than antioxidants / reducing agents not stored in a dry state. In some embodiments, antioxidants / reducing agents may exhibit higher stability after sterilization compared to the stability of antioxidants / reducing agents in sterilized wound dressings when the antioxidants / reducing agents are not stored in a dry state. In some embodiments, the wound dressing may be configured to produce less discoloration than wound treatment devices in which the antioxidants / reducing agents are not stored in a dry state. In some embodiments, the mesh may include a coated polypropylene mesh. In some embodiments, the activator layer may include a composite material comprising a gelled fiber substrate loaded with an acidic hydrogel. In some embodiments, the hydrogel may further include an aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate and 2-acrylamido-2-methyl-1-propanesulfonic acid. In some embodiments, the wound dressing may further comprise a water-supplying dispersion layer. In some embodiments, the wound dressing may further comprise a cover layer configured to form a seal around the wound. In some embodiments, the cover layer may be breathable. In some embodiments, the wound dressing may further comprise a masking layer configured to at least partially limit the visibility of the wound. In some embodiments, the nitrite may be sodium nitrite. In some embodiments, the antioxidant / reducing agent may be sodium isoascorbate, ferrous sulfate, or a derivative of vitamin C. In some embodiments, the mesh component comprises a 2.5 × 2.5 cm mesh loaded with any amount of nitrite and antioxidant / reducing agent, each from 1 to 5 mg, and the nitrite and antioxidant / reducing agent are suspended in a suitable carrier.

[0011] The alternative or additional embodiments described herein provide compositions comprising one or more features of the above description or any other description herein.

[0012] Alternative or additional embodiments described herein provide a wound contact layer that includes one or more of the features of the above description or any description elsewhere in this specification.

[0013] Alternative or additional embodiments described herein provide a wound dressing that includes one or more of the features of the above description or any description elsewhere in this specification.

[0014] Alternative or additional embodiments described herein provide a wound treatment system that includes one or more of the features of the above description or any description elsewhere in this specification.

[0015] Alternative or additional embodiments described herein provide a method of treating a wound that includes one or more of the features of the above description or any description elsewhere in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] [Figure 1] FIG. 1 is a schematic diagram of an example of a negative pressure wound therapy system. [Figure 2A] FIG. 2 illustrates one embodiment of a negative pressure wound treatment system using a pump, a flexible fluid connector, and a wound dressing capable of absorbing and storing wound exudate. [Figure 2B] FIG. 3 illustrates one embodiment of a negative pressure wound treatment system using a flexible fluid connector and a wound dressing capable of absorbing and storing wound exudate. [Figure 2C] FIG. 4 illustrates a cross-section of one embodiment of a fluid connector connected to a wound dressing. [Figure 2D] FIG. 5 illustrates a cross-section of one embodiment of a wound dressing. [Figure 3A] FIG. 6 illustrates embodiments of a wound dressing capable of absorbing and storing wound exudate for use without negative pressure. [Figure 3B] FIG. 7 illustrates embodiments of a wound dressing capable of absorbing and storing wound exudate for use without negative pressure. [Figure 3C]Examples of wound dressings that can absorb and store wound exudate and are used without negative pressure are provided. [Figure 3D] Examples of wound dressings that can absorb and store wound exudate and are used without negative pressure are provided. [Figure 3E] A cross-section of one embodiment of a wound dressing that can absorb and store wound exudate, and is used without negative pressure, is illustrated. [Figure 4] This is an exploded view of one embodiment of a wound dressing capable of generating nitric oxide. [Figure 5] Figure 4 is a cross-sectional view of the wound dressing. [Figure 6] An example of a chemiluminescence experiment protocol and equipment configuration is provided. [Figure 7] Examples of negative pressure and nitric oxide delivery experiments are provided. [Figure 8A] An example of chemiluminescence experimental results for sodium nitrate mesh is illustrated. [Figure 8B] An example of chemiluminescence experimental results for a complete coating design with pull-out tabs and self-sealing boundaries is illustrated. [Figure 8C] An example of chemiluminescence experimental results for a coating material containing a biodegradable film is illustrated. [Figure 9] An example of a graph showing peak NO and NO2 outputs for an acrylic adhesive containing hydrogel is illustrated. [Figure 10A] An example of chemiluminescence experimental results for a nitric oxide coating material is illustrated. [Figure 10B] An example of chemiluminescence experimental results for a nitric oxide coating material is illustrated. [Figure 10C] An example of chemiluminescence experimental results for a nitric oxide coating material is illustrated. [Figure 10D] An example of chemiluminescence experimental results for a nitric oxide coating material is illustrated. [Figure 11A] An embodiment of a wound dressing configured to generate nitric oxide is shown. [Figure 11B]An embodiment of a wound dressing configured to generate nitric oxide is shown. [Figure 11C] An embodiment of a wound dressing configured to generate nitric oxide is shown. [Figure 11D] An embodiment of a wound dressing configured to generate nitric oxide is shown. [Figure 11E] An embodiment of a wound dressing configured to generate nitric oxide is shown. [Figure 12] An example of a hydrogel-based wound dressing system is provided. [Figure 13] An example of a hydrogel-based wound dressing system is provided. [Figure 14] An illustrative process for hydrogel formation is shown. [Figure 15] An example of chemiluminescence experimental results for a typical acidic AMPS-based hydrogel without sodium isoascorbate, when in contact with a polypropylene mesh immersed in a sodium nitrite aqueous solution, is illustrated. [Figure 16] An example of chemiluminescence results for an acidic hydrogel having 1.0 SA, brought into contact with a suspension prepared by dispersing 0.1 g of sodium nitrite and 0.1 g of sodium isoascorbate in 2 g of PEG400, is illustrated. The 1.0 SA gel can be prepared with the following components (parts by weight per 100 g batch): 63.32 g of sodium AMPS, 0.0323 g of piperazine diacrylamide, 5.436 g of AMPS(H+), 31.19 g of glycerol, and 0.01629 g of 2-hydroxy-2-methylpropiophenone. The upper line plotted is NO2 and the lower line is NO. [Figure 17A]An example experimental setup for evaluating the antimicrobial activity of a coating consisting of a hydrogel / DuraFiber composite with a top layer of IV3000, 1.0SA or 0.7SA, and a polypropylene (PP) mesh embedded with a PEG400 / sodium nitrite / sodium isoascorbate suspension is illustrated. The 0.7SA gel can be prepared with the following components (parts by weight per 100g batch): 65.28g sodium AMPS, 0.0317g piperazine diacrylamide, 3.923g AMPS(H+), 30.74g glycerol, and 0.01756g 2-hydroxy-2-methylpropiophenone. The top plotted line is NOX, the middle plotted line is NO, and the bottom line is NO2. [Figure 17B] Figure 17A shows an overview of the experimental setup for the evaluation. [Figure 17C] Figures 17A and 17B illustrate the results regarding the reduction from the vaccinated control group used for evaluation. [Figure 18A] The chemiluminescence results for a 3x3cm composite of DuraFiber are shown, where approximately 6g of 1.0SA acidic hydrogel was loaded and a 50uL suspension, prepared by dispersing 0.1g of sodium nitrite and 0.1g of sodium isoascorbate in various water-miscible anhydrous carriers, was brought into contact with a 2.5x2.5 PP mesh embedded with the suspension. The generation of nitric oxide using PEG400 as the water-miscible anhydrous carrier is shown. The top plotted line is NOX, the middle line is NO, and the bottom line is NO2. [Figure 18B] The chemiluminescence results for a 3x3cm composite of DuraFiber are shown, where approximately 6g of 1.0SA acidic hydrogel was loaded and a 50uL suspension, prepared by dispersing 0.1g of sodium nitrite and 0.1g of sodium isoascorbate in various water-miscible anhydrous carriers, was brought into contact with a 2.5x2.5 PP mesh embedded with the suspension. The results when PEG600 was used as a water-miscible anhydrous carrier are shown. The top plotted line represents NOX, the middle line represents NO, and the bottom line represents NO2. [Figure 18C]The chemiluminescence results for a 3x3cm composite of DuraFiber are shown, where approximately 6g of 1.0SA acidic hydrogel was loaded and a 50uL suspension, prepared by dispersing 0.1g of sodium nitrite and 0.1g of sodium isoascorbate in various water-miscible anhydrous carriers, was brought into contact with a 2.5x2.5 PP mesh embedded with this suspension. The results for using 50 / 50w / w blends of PEG300 and PEG1500(FLEX) as water-miscible anhydrous carriers are also shown. The top plotted line represents NOx, the middle line represents NO, and the bottom line represents NO2. [Figure 18D] The chemiluminescence results for a 3x3cm composite of DuraFiber are shown, where approximately 6g of 1.0SA acidic hydrogel was loaded and a 50uL suspension, prepared by dispersing 0.1g of sodium nitrite and 0.1g of sodium isoascorbate in various water-miscible anhydrous carriers, was brought into contact with a 2.5x2.5 PP mesh embedded with the suspension. The results for using a 41 / 1 w / w blend of PEG400 and PEG4000 (SORB) as an anhydrous water-miscible carrier are also shown. The top plotted line represents NOX, the middle line represents NO, and the bottom line represents NO2. [Figure 18E] The results from Figures 18A to 18D are combined onto a single graph. [Modes for carrying out the invention]

[0017] overview Embodiments described herein relate to materials, apparatus, methods, and systems that incorporate, include, or utilize one or more compositions and / or materials that effectively generate a gas (e.g., nitric oxide) over time upon activation. Embodiments herein may relate to devices and / or wound dressings having one or more layers containing compositions and / or materials that effectively generate nitric oxide over time upon activation. For example, one or more nitric oxide generating layers may include a nitrite-delivering layer containing nitrites and capable of releasing nitrite ions, thereby enabling the nitrite ions to generate nitric oxide upon reaction with an acid.

[0018] In some embodiments, one or more nitric oxide generating layers may further include an acid group providing layer in addition to a nitrite delivery layer. One or more nitric oxide generating layers may be used as standalone components for separate positioning at the wound site, or they may be incorporated into any number of multilayer wound dressings and wound treatment devices, as described below with reference to Figures 1 to 18E. Embodiments of this disclosure are generally applicable for use in negative pressure or decompression therapy systems or compression therapy systems under ambient conditions.

[0019] Some of the preferred embodiments described herein incorporate, include, or utilize one or more nitric oxide generating layers. Such one or more nitric oxide generating layers may possess one or more of the following functional characteristics: inflammation-related activity, blood flow-related activity, antimicrobial, antiplankton and antibiofilm activity, ease of application and / or removal as a single component, cleavability / tearability, conformity to the three-dimensional contour of the wound surface, abrasion resistance, suitability for negative pressure wound therapy and / or pressure wound therapy, exudate management, ability to facilitate autolytic debridement of the wound, ability to promote wound healing, and self-expression of compositional or functional changes. Antimicrobial activity may include one or more of broad-spectrum antimicrobial activity, antibiofilm activity, rapid killing of microorganisms, and sustained killing of microorganisms, such as antimicrobial activity in vitro, and the microorganisms may include one or more of the following: Gram-negative bacteria, Gram-positive bacteria, fungi, yeasts, viruses, algae, archaea, and protozoa.

[0020] Certain preferred embodiments described herein provide a wound healing system. Such a wound healing system may comprise a nitric oxide generating layer configured to be sized to position over a wound and / or the peri-wound area. Those skilled in the art will understand that when the device / covering / layer is described to be positioned over or over a wound, such device / covering / layer may extend over the peri-wound area and treat it. In some examples, stimulation of the peri-wound area and / or wound margin may play a role in initiating the wound healing process, and the wound healing process may be activated through the delivery of nitric oxide to the peri-wound area and / or wound margin. The delivery of nitric oxide to the peri-wound area and / or wound margin may target, for example, epithelial cell activity to promote epithelial tongue migration, vasodilation of the microcirculation of the peri-wound skin to promote abundance by providing oxygen and nutrients, and angiogenesis to promote granulation tissue formation. The wound treatment systems described herein may further comprise a secondary wound dressing configured to be positioned separately on top of the nitric oxide generating layer. The nitric oxide generating layer may have an adhesive bonded to its underside, the adhesive may be configured such that the nitric oxide generating layer can be positioned in close proximity to the wound. The secondary wound dressing, when used, may bond to the skin surrounding the wound and may be the same size as the nitric oxide generating layer or larger, so that the nitric oxide generating layer is in contact with or positioned in close proximity to the wound and / or the area surrounding the wound. The secondary wound dressing may, alternatively or additionally, be configured to form a seal to the skin surrounding the wound so that the nitric oxide generating layer is in contact with or positioned in close proximity to the wound. The wound treatment system may further comprise a negative pressure source configured to supply negative pressure to the wound through the secondary wound dressing and through the wound contact layer.

[0021] Certain other preferred embodiments described herein provide multilayer wound dressings, such as those described herein with respect to Figures 1 to 13. Such multilayer wound dressings may incorporate one or more nitric oxide generating layers as constituent layers, or alternatively, may comprise a composite or laminate containing one or more nitric oxide generating layers as part of one of its constituent layers. A multilayer wound dressing may comprise a nitric oxide generating layer as described above or elsewhere herein, a permeable and / or absorbent layer above / below one or more nitric oxide generating layers, a wound contact layer below one or more nitric oxide generating layers, and a cover layer on the permeable and / or absorbent layers. The wound dressing may further comprise a negative pressure port located above or above the cover layer. One or more nitric oxide generating layers may have substantially the same outer periphery as the outer periphery of the cover layer. Alternatively, one or more nitric oxide generating layers may have a smaller outer periphery than the outer periphery of the cover layer.

[0022] Those skilled in the art will understand that nitric oxide generating compositions, such as those disclosed in any disclosed section of this Spec. or elsewhere in this Spec., can be loaded into one or more nitric oxide generating layers in any preferred form, such as by adsorption, absorption, chemical and / or physical adhesion entanglement, and / or in powder form. Those skilled in the art will further understand that reaction compositions, such as those disclosed in any section of this Spec. or elsewhere in this Spec., can be incorporated by any preferred means into any preferred absorbent layer disclosed in this section or elsewhere in this Spec., and / or any preferred permeable layer disclosed in this section or elsewhere in this Spec., and / or any foam layer disclosed in this section or elsewhere in this Spec.

[0023] In certain embodiments, wound treatment systems and multilayer wound dressings disclosed above or elsewhere in this specification may incorporate or include a nitric oxide generating layer. As described in this section or elsewhere in this specification, in particular below, the nitric oxide generating layer may be configured to be activated to release nitric oxide. At least a portion of the released nitric oxide may be released, for example, by diffusion. To facilitate the release and diffusion of nitric oxide, the nitric oxide generating layer may be positioned in close proximity to the wound.

[0024] Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other preferred sites. Such methods may include placing a nitric oxide generating layer on a wound, either separately or by arranging a multilayer wound dressing having a nitric oxide generating layer. The methods may include adhering a separate nitric oxide generating layer and / or a multilayer wound dressing having a nitric oxide generating layer to healthy skin surrounding the wound. Such methods may further include one or more of the following steps: A further wound dressing may be placed on a separate nitric oxide generating layer or on a multilayer wound dressing having a nitric oxide generating layer placed on a wound. Wound exudate, or any other moist or aqueous medium, may be provided to reach and / or come into contact with the nitric oxide generating layer. The wound exudate, or any other moist or aqueous medium, may be diffused or absorbed into a wound dressing incorporating the nitric oxide generating layer or into a wound dressing provided on top of the nitric oxide generating layer. Negative pressure may be applied to a separate nitric oxide generating layer or a multilayer wound dressing having a nitric oxide generating layer, thereby drawing wound exudate directly into the nitric oxide generating layer, into a wound dressing incorporating a nitric oxide generating layer, or into a wound dressing provided on top of a nitric oxide generating layer.

[0025] Those skilled in the art will understand that wound dressings, devices, and systems disclosed in this "Summary" section or elsewhere in this specification may include, in addition to, or instead of, nitric oxide generating layers, compositions, or materials, one or more layers, compositions, materials, or components that generate gases other than nitric oxide. For example, a wound dressing or device may include one or more layers that, upon activation, effectively generate vasodilators such as carbon monoxide or hydrogen sulfide over time.

[0026] Those skilled in the art will further understand that carbon monoxide and / or hydrogen sulfide may be used, where appropriate, instead of or in combination with nitric oxide delivery elements (such as layers). Further details regarding the generation and delivery of carbon monoxide and / or hydrogen sulfide can be found in Chapter 6 of the text of Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells, ISBN 978-0-12-803814-7, which is incorporated herein by reference. For example, hydrogen sulfide may be generated from elements / layers containing cleavable / releasing hydrogen sulfide, diallylthiosulfinate, GYY4137, S-mesalamine ATB-429, S-naproxen ATB-346, S-diclofenac ATB-337 / ACS-15. For example, carbon monoxide can be generated from elements / layers that provide a complex of carbon monoxide bound to a suitable metal such as chromium, molybdenum, tungsten, manganese, rhenium, iron, ruthenium, cobalt, rhodium, and iridium. Such a complex can be enzymatically triggered to release carbon monoxide, be photocleavable, and / or induce carbon monoxide release in response to interaction with a suitable ligand.

[0027] Methods for treating wounds Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other preferred sites. Such methods may include placing one or more nitric oxide generating layers on a wound, either separately or by arranging a multilayer wound dressing having one or more nitric oxide generating layers. The methods may include adhering one or more separate nitric oxide generating layers and / or a multilayer wound dressing having one or more nitric oxide generating layers to healthy skin surrounding the wound, such as the peri-wound area. The methods may further include one or more of the following steps: Further wound dressings may be placed on one or more separate nitric oxide generating layers, or on a multilayer wound dressing having one or more nitric oxide generating layers placed on a wound. Wound exudate, or any other moist or aqueous medium, may be provided to reach and / or come into contact with one or more nitric oxide generating layers. Wound exudate, or any other moist or aqueous medium, may be diffused or drawn up into a wound dressing incorporating one or more nitric oxide generating layers, or into a wound dressing provided on top of one or more nitric oxide generating layers. Negative pressure may be applied to one or more separate nitric oxide generating layers, or to a multilayer wound dressing having one or more nitric oxide generating layers, as described in the following “Negative Pressure Wound Therapy (NPWT) Systems” section or elsewhere in this specification, thereby drawing wound exudate directly into one or more nitric oxide generating layers, or into a wound dressing incorporating one or more nitric oxide generating layers, or into a wound dressing provided on top of one or more nitric oxide generating layers.

[0028] Methods for treating wounds, intact tissue, or other preferred sites, as described above or elsewhere in this specification, may further include delivering negative pressure to the wound through a wound contact layer, as described in the following “Negative Pressure Wound Therapy (NPWT)” section or elsewhere in this specification. The wound contact layer may substantially maintain the delivered negative pressure for at least about 24 hours, or at least about 48 hours, or at least about 72 hours. Alternatively, methods for treating wounds, intact tissue, or other preferred sites may include applying pressure (positive) to the wound through a wound contact layer. Alternatively, methods may include modifying atmospheric pressure, negative pressure, and pressure to the wound through a wound contact layer in a programmable manner.

[0029] In some embodiments, a method for treating a wound, intact tissue, or other preferred site may involve using a wound contact layer, or a wound treatment system or wound dressing comprising a wound contact layer, under ambient conditions unrelated to a negative pressure wound therapy system, as described above or elsewhere in this specification.

[0030] In some embodiments, methods for treating wounds, intact tissue, or other preferred sites can reduce wound bioburden by, for example, reducing the number of viable microorganisms (CFU / sample) within the first four hours after application of the wound dressing, at least in vitro. In some examples, the number of viable microorganisms can be reduced by 4 log or more 48–72 hours after the wound dressing is placed in contact with the microorganisms.

[0031] Negative Pressure Wound Therapy (NPWT) System Embodiments of this disclosure will be understood to be applicable, in general and without limitation, to use in topical negative pressure ("TNP") therapy systems. Briefly, negative pressure wound therapy can help close and heal many forms of “difficult-to-heal” wounds by reducing tissue edema, promoting blood flow and granular tissue formation, and removing excess exudate, thereby reducing bacterial load (and therefore risk of infection). In addition, the therapy can reduce wound anxiety, leading to earlier healing. TNP therapy systems can also assist in the healing of surgically closed wounds by helping to remove fluid and stabilize tissue in a parallel position of closure. Further beneficial uses of TNP therapy can be found in grafts and flaps where removing excess fluid is important and it is required that the graft be in close proximity to the tissue to ensure tissue viability.

[0032] As used herein, a reduced pressure or negative pressure level such as -X mmHg represents a pressure level relative to normal ambient pressure, which may correspond to 760 mmHg (or 1 atm, 29.93 inHg, 101.325 kPa, 14.696 psi, etc.). Thus, a negative pressure value of -X mmHg reflects an absolute pressure that is X mmHg lower than 760 mmHg, or in other words, an absolute pressure of (760-X) mmHg. Furthermore, negative pressures "lower" or "smaller" than X mmHg correspond to pressures closer to atmospheric pressure (e.g., -40 mmHg is lower than -60 mmHg). Negative pressures "higher" or "larger" than -X mmHg correspond to pressures further away from atmospheric pressure (e.g., -80 mmHg is higher than -60 mmHg). In some embodiments, a local ambient atmospheric pressure is used as a reference point, and such a local pressure does not necessarily have to be, for example, 760 mmHg.

[0033] The negative pressure range in some embodiments of this disclosure may be about -80 mmHg, or between about -20 mmHg and about -200 mmHg. It should be noted that these pressures are relative to normal ambient pressure, which may be 760 mmHg. Therefore, -200 mmHg would substantially be about 560 mmHg. In some embodiments, the pressure range may be between about -40 mmHg and about -150 mmHg. Alternatively, pressure ranges of -75 mmHg or less, -80 mmHg or less, or above -80 mmHg can be used. In other embodiments, pressure ranges below -75 mmHg may be used. Alternatively, pressure ranges of approximately -100 mmHg or even above -150 mmHg can be supplied by the negative pressure device.

[0034] In some embodiments of the wound closure devices described herein, increased wound reduction may lead to increased tissue expansion in the surrounding wound tissue. This effect may be amplified, in some cases, by changing the force applied to the tissue, for example, by changing the negative pressure applied to the wound over time, in conjunction with an increase in the tensile force applied to the wound by the embodiment of the wound closure device. In some embodiments, the negative pressure may be changed over time, for example, using a sine wave, a square wave, or in synchronization with one or more physiological indicators of the patient (e.g., heart rate). Examples of such applications, where further disclosures relating to the foregoing may be found, include U.S. Patent No. 8,235,955, titled "Wound treatment apparatus and method," issued on 7 August 2012, and U.S. Patent No. 7,753,894, titled "Wound cleansing apparatus with stress," issued on 13 July 2010. The disclosures of both of these patents are incorporated herein by reference in their entirety.

[0035] Embodiments of wound dressings, wound dressing components, wound treatment apparatuses and methods described herein may also be used in combination with, or in addition to, those described in "APPARATUSES AND METHODS FOR NEGATIVE PRESSURE WOUND THERAPY," filed on 22 May 2013 under International Application No. PCT / IB2013 / 001469 and published on 28 November 2013 under International Publication No. 2013 / 175306(A2), and "WOUND DRESSING," filed on 31 July 2013 under International Application No. PCT / IB2013 / 002060 and published on 31 July 2013 under International Publication No. WO2014 / 020440, the disclosures thereof being incorporated herein in their entirety by reference. Embodiments of wound dressings, wound treatment devices, and methods described herein may also be used in combination with, or in addition to, those described herein, including further details relating to wound dressings, components and principles of wound dressings, and embodiments of materials used in wound dressings. These embodiments are incorporated herein by reference.

[0036] In addition, several embodiments relating to TNP wound treatment, including wound dressings, in combination with the pumps or associated electronic devices described herein may also be used in combination with, or in addition to, those described in International Publication No. 2016 / 174048(A1) on November 3, 2016, titled "REDUCED PRESSURE APPARATUSES," which is incorporated herein by reference in its entirety. In some of these embodiments, the pumps or associated electronic devices may be integrated within the wound dressing to provide a single article to be applied to the wound.

[0037] Multilayer wound dressings for NPWT Figure 1 illustrates an example of a negative pressure wound therapy system 700. The system includes a wound cavity 710 covered with a wound dressing 720, which may be a dressing according to one of the examples described herein. The dressing 720 is positioned on, inside, all over, or around the wound cavity 710 and may further seal the wound cavity, thereby allowing negative pressure to be maintained within the wound cavity. For example, a film layer of the wound dressing 720 may provide a substantially fluid-impermeable seal over the wound cavity 710. In some embodiments, a wound filler, such as a layer of foam or gauze, may be used to fill the wound. The wound filler may include one or more nitric oxide generating layers (e.g., a nitrite delivery layer, an acid group providing layer), as described in this section or elsewhere in this specification. For example, in conventional negative pressure wound therapy systems that utilize foam (RENASYS-F) or gauze (RENASYS-G), such as the Smith & Nephew RENASYS negative pressure wound therapy system, the foam or gauze may be supplemented with a nitric oxide generating layer as described above. When supplementing a foam or gauze layer or other wound packing material, one or more nitric oxide generating layers may be inserted separately into the wound or pre-attached to the wound packing material for insertion into the wound.

[0038] One or more luminal tubes or conduits 740 connect the wound dressing 720 to a negative pressure device 750 configured to supply decompression. The negative pressure device 750 includes a negative pressure source. The negative pressure device 750 may be a canister-less device (meaning that exudate is collected into the wound dressing and / or moved through the tube 740 for collection to another location). In some embodiments, the negative pressure device 750 may include or be configured to support a canister. In addition, in any of the embodiments disclosed herein, the negative pressure device 750 may be fully or partially embedded in, attached to, or supported by the wound dressing 720.

[0039] The conduit 740 may be any suitable article configured to provide at least substantially sealed fluid passages or paths between the negative pressure device 750 and the wound cavity 710 to supply reduced pressure to the wound cavity. The conduit 740 may be formed from polyurethane, PVC, nylon, polyethylene, silicone, or any other suitable rigid or flexible material. In some embodiments, the wound dressing 720 may have ports configured to receive the ends of the conduit 740. For example, the ports may include holes in the film layer. In some embodiments, the conduit 740 may pass through and / or separately beneath the film layer of the wound dressing 720 to supply reduced pressure to the wound cavity 710 to maintain a desired level of reduced pressure within the wound cavity. In some embodiments, at least a portion of the conduit 740 is integral with or attached to the wound dressing 720.

[0040] Figure 2A illustrates one embodiment of a negative pressure wound treatment system 10 using a wound dressing 100 together with a fluid connector 110. Additional examples of negative pressure wound treatment including wound dressings combined with the pump described herein may also be used in combination with, or in addition to, those described in U.S. Patent No. 9,061,095, which is incorporated by reference in whole. In the figure, the fluid connector 110 may comprise an elongated conduit, more preferably a bridge 120 having a proximal end 130 and a distal end 140, and an applicator 180 at the distal end 140 of the bridge 120. The system 10 may include a negative pressure source, such as a pump or a negative pressure unit 150 capable of supplying negative pressure. The pump may include a canister or other container for storing wound exudate and other fluids that may be removed from the wound. The canister or container may also be provided separately from the pump. In some embodiments, the pump 150 may be a canisterless pump, such as a PICO® pump sold by Smith & Nephew. The pump 150 may be connected to the bridge 120 via a tube, or the pump 150 may be connected directly to the bridge 120. During use, the dressing 100 is placed over a suitably prepared wound, which in some cases may be filled with wound packing material such as foam or gauze, as described above. The applicator 180 of the fluid connector 110 has a sealing surface that is placed over the gap in the dressing 100 and seals to the uppermost surface of the dressing 100. Either before, during, or after the connection of the fluid connector 110 to the dressing 100, the pump 150 is connected to a tube connector via a tube, or directly to the bridge 120. The pump is then started, thereby supplying negative pressure to the wound. The application of negative pressure may be continued until the desired level of wound healing is achieved.

[0041] As shown in Figure 2B, the fluid connector 110 preferably comprises an enlarged distal end or head 140 that fluidly communicates with the covering material 100, as will be described in more detail below. In one embodiment, the enlarged distal end has a round or circular shape. The head 140 is illustrated in the figure to be located near the edge of the covering material 100, but may be located anywhere on the covering material. For example, in some embodiments, it may be provided in the center or off-center, not on or near the edge or corner of the covering material 100. In some embodiments, the covering material 10 may comprise two or more fluid connectors 110, each comprising one or more heads 140 that fluidly communicate with it. In a preferred embodiment, the head 140 may be 30 mm in dimension along the widest edge. The head 140 at least partially forms an applicator 180 configured to seal to the uppermost surface of the wound dressing as described above.

[0042] Figure 2C illustrates a cross-section through a wound dressing 100 similar to the wound dressing 10 described in International Patent Application Publication No. 2013 / 175306(A2), which is incorporated in whole by reference, together with a fluid connector 110. Alternatively, the wound dressing 100, which may be any embodiment of the wound dressings disclosed herein, or any combination of any number of features of the embodiments of the wound dressings disclosed herein, may be placed over a wound site to be treated. The dressing 100 may be positioned to form a sealed cavity over the wound site. In a preferred embodiment, the dressing 100 includes a backing layer 220 attached to an uppermost or cover layer, or an optional wound contact layer 222, both of which are described in more detail below. These two layers 220, 222 are preferably joined or sealed together to define an internal space or chamber. This internal space or chamber may include additional structures that can be adapted to disperse or transmit negative pressure and to store wound exudate and other fluids removed from the wound, and other functions which will be described in more detail below. Examples of such structures described below include a permeable layer 226 and an absorbent layer 221.

[0043] As used herein, the upper layer, top layer, or upper layer refers to the layer furthest from the surface of the skin or wound while the dressing is in use and positioned over the wound. Conversely, the lower layer, bottom layer, bottom layer, or lower layer refers to the layer closest to the surface of the skin or wound while the dressing is in use and positioned over the wound.

[0044] As illustrated in Figure 2C, the wound contact layer 222 may be a polyurethane layer, a polyethylene layer, or another flexible layer perforated or otherwise permeable to liquids and gases, for example, via a hot-pinning process, a laser ablation process, or an ultrasonic process, or in several other ways. The wound contact layer 222 has a lower surface 224 and an upper surface 223. Perforations 225 preferably include through holes in the wound contact layer 222, thereby allowing fluid to flow through the layer 222. The wound contact layer 222 helps prevent tissue infiltration into other materials of the wound dressing. Preferably, the perforations are small enough to satisfy this requirement while allowing fluid to flow through them. For example, perforations formed as slits or holes having dimensions in the range of 0.025 mm to 1.2 mm are considered small enough to help prevent tissue infiltration into the wound dressing while allowing wound exudate to flow into the dressing. In some configurations, the wound contact layer 222 may help maintain the overall integrity of the dressing 100 while also creating an airtight seal around the absorbent pad to maintain negative pressure at the wound.

[0045] Some embodiments of the wound contact layer 222 may also act as carriers for optional lower and upper adhesive layers (not shown). For example, a lower pressure-sensitive adhesive may be provided on the lower surface 224 of the wound dressing 100, while an upper pressure-sensitive adhesive layer may be provided on the upper surface 223 of the wound contact layer. The pressure-sensitive adhesive, which may be a silicone, hot-melt, hydrophilic colloid, or acrylic-based adhesive, or other such adhesives, may be formed on both sides of the wound contact layer, on one side of which is optionally selected, or not formed on either side of the wound contact layer. When a lower pressure-sensitive adhesive layer is used, it may help to adhere the wound dressing 100 to the skin around the wound site. In some embodiments, the wound contact layer may comprise a perforated polyurethane film. The lower surface of the film may comprise a silicone pressure-sensitive adhesive, and the upper surface may comprise an acrylic pressure-sensitive adhesive, thereby helping the dressing maintain its integrity. In some embodiments, the polyurethane film layer may have adhesive layers on both its upper and lower surfaces, and all three layers may be perforated together.

[0046] The permeable layer 226 may be located above the wound contact layer 222. In some embodiments, the permeable layer may be made of a porous material. As used herein, the permeable layer may be referred to as a spacer layer, and this term may be used interchangeably to refer to the same components described herein. The permeable layer 226 allows fluids, including liquids and gases, to permeate away from the wound site into the upper layers of the wound dressing. In particular, the permeable layer 226 preferably ensures that an open air channel can be maintained so that negative pressure is transmitted over the wound area even if the absorbent layer absorbs a considerable amount of exudate. The layer 226 should preferably remain open under the normal pressure that will be applied during negative pressure wound therapy, as described above, so that the entire wound site is subjected to equal negative pressure. The layer 226 may be formed from a material having a three-dimensional structure. For example, a knitted or woven spacer cloth (e.g., Baltex 7970 weft-knit polyester) or a nonwoven fabric may be used. The three-dimensional materials may include 3D spacer fabric materials similar to those described in International Publication No. WO2013 / 175306(A2) and International Publication No. WO2014 / 020440, the disclosures of which are incorporated in their entirety by reference.

[0047] In certain embodiments, the wound dressing 100 may incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layers, acid group providing layers) as described in this section or elsewhere in this specification. Those skilled in the art will understand that the wound dressing 100 may incorporate any of the one or more nitric oxide generating layers disclosed in this section or elsewhere in this specification. Those skilled in the art will also understand that one or more nitric oxide generating layers may be incorporated as part of all constituent layers or as part of constituent layers. In some embodiments, one or more nitric oxide generating layers may be provided below the permeable layer 226. In some embodiments, one or more nitric oxide generating layers may be provided above the wound contact layer 222. In certain embodiments, one or more nitric oxide generating layers may replace the permeable layer 226 so that one or more nitric oxide generating layers are provided between the absorbent layer 221 (further described below) and the wound contact layer 222. In some embodiments, one or more nitric oxide generating layers may supplement or replace the absorbent layer 221. In some embodiments, the wound dressing 100 does not have a wound contact layer 222, and one or more nitric oxide generating layers may be the bottom layer of the wound dressing 100. One or more nitric oxide generating layers may have the same or substantially similar size and shape as the permeable layer 226 and / or absorbent layer 221. In some embodiments, one or more nitric oxide generating layers or their components (e.g., the nitrite-providing layers described herein) may be separate from the wound dressing 100. For example, one or more nitric oxide generating layers or their components may be provided as separate layers that can be placed on a wound, and the wound dressing 100 may be placed on top of them.

[0048] One or more nitric oxide generating layers may be constructed to be flexible but rigid enough to withstand negative pressure, so that they do not collapse excessively and thereby adequately transmit negative pressure to the wound when negative pressure is supplied to the wound dressing 100. One or more nitric oxide generating layers may be constructed to include a sufficient number or size of pores to allow for the transmission of negative pressure. One or more nitric oxide generating layers may include gaps or holes below the ports, for example, to transmit negative pressure and / or wound fluid. Furthermore, one or more nitric oxide generating layers may have a thickness suitable for transmitting a suitable negative pressure to the wound. For example, one or more nitric oxide generating layers may have a thickness of about 1 mm to about 10 mm, or about 1 mm to about 7 mm, or about 1.5 mm to about 7 mm, or about 1.5 mm to about 4 mm, or about 2 mm to about 3 mm. In some embodiments, one or more nitric oxide generating layers may have a thickness of about 2 mm.

[0049] In some embodiments, the absorbent layer 221 is provided above the permeable layer 226. The absorbent, which may include a foam or nonwoven natural or synthetic material and optionally a superabsorbent material, forms a reservoir for fluid, specifically liquid to be removed from the wound site. In some embodiments, the layer 221 may also help draw the fluid toward the backing layer 220.

[0050] The material of the absorbent layer 221 can also prevent the fluid collected within the wound dressing 100 from flowing freely within the dressing, and preferably acts to contain any collected fluid within the dressing. The absorbent layer 221 also helps to disperse the fluid throughout the layer by an suction action, drawing the fluid away from the wound site and storing it throughout the absorbent layer. This helps to prevent aggregation in areas of the absorbent layer. The volume of the absorbent material must be sufficient to control the rate at which wound exudate flows when negative pressure is applied. Since the absorbent layer experiences negative pressure during use, the material of the absorbent layer is selected to absorb fluid under such conditions. There are several materials that can absorb fluid under negative pressure, such as superabsorbent materials. The absorbent layer 221 may typically be manufactured from ALLEVYN® foam, Freudenberg 114-224-4, or Chem-Posite® 11C-450. In some embodiments, the absorbent layer 221 may include a composite material comprising superabsorbent powder, fibrous material such as cellulose, and binding fibers. In preferred embodiments, the composite material is an air-laid, heat-bonded composite material.

[0051] In some embodiments, the absorbent layer 221 is a layer of nonwoven cellulose fibers having a superabsorbent material in the form of dry particles dispersed throughout the layer. The use of cellulose fibers introduces a high-speed suction element that helps to quickly and evenly disperse the liquid absorbed by the coating material. The parallel arrangement of numerous twisted fibers leads to a strong capillary action of the fiber pad that helps to disperse the liquid. In this way, the liquid is efficiently supplied to the superabsorbent material. The suction action also helps to bring the liquid into contact with the upper cover layer in order to help increase the evaporation rate of the coating material.

[0052] It is preferable that gaps, holes, or orifices 227 are provided in the backing layer 220 to allow negative pressure to be applied to the dressing 100. The fluid connector 110 is preferably mounted or sealed to the top of the backing layer 220 over the orifice 227 fabricated in the dressing 100 to transmit negative pressure through the orifice 227. A long tube may be connected to the fluid connector 110 at a first end and to a pump unit (not shown) at a second end so that fluid can be drawn up from the dressing. If the fluid connector is bonded to the top layer of the wound dressing, the long tube may be connected to the first end of the fluid connector so that the tube or conduit extends away from the fluid connector parallel to or substantially parallel to the top surface of the dressing. The fluid connector 110 may be bonded and sealed to the backing layer 220 using an adhesive such as acrylic, cyanoacrylate, epoxy, UV-curable, or hot-melt adhesive. The fluid connector 110 may be formed from a soft polymer having a hardness of 30 to 90 on the Shore A scale, such as polyethylene, polyvinyl chloride, silicone, or polyurethane. In some embodiments, the fluid connector 110 may be made from a soft material or a suitable material.

[0053] Optionally, the absorbent layer 221 includes at least one through-hole 228 positioned beneath the fluid connector 110. In some embodiments, the through-hole 228 may be the same size as, or larger than, the opening 227 in the backing layer. As illustrated in Figure 2C, a single through-hole may be used to provide an opening beneath the fluid connector 110. It will be understood that multiple openings may be used as alternatives. In addition, if multiple ports are to be utilized according to a particular embodiment of the present disclosure, one or more openings may be fabricated in the absorbent layer to align with each fluid connector. Although not essential to the particular embodiment of the present disclosure, using through-holes in the superabsorbent layer may provide unobstructed fluid channels, particularly when the absorbent layer is near saturation.

[0054] As illustrated in Figure 2C, the gap or through-hole 228 is preferably provided in the absorbent layer 221 below the orifice 227 so that the orifice is directly connected to the permeable layer 226. This allows the negative pressure applied to the fluid connector 110 to be transmitted to the permeable layer 226 without passing through the absorbent layer 221. This ensures that even if the absorbent layer absorbs wound exudate, the negative pressure applied to the wound site is not obstructed by the absorbent layer. In other embodiments, the gap may not be provided in the absorbent layer 221, or alternatively, multiple gaps may be provided below the orifice 227. In further alternative embodiments, an additional layer, such as another permeable layer, or a concealing layer, as described in International Patent Application Publication WO2014 / 020440, which is incorporated entirely by reference, may be provided above the absorbent layer 221 and below the backing layer 220.

[0055] The backing layer 220 is preferably gas-impermeable but water vapor-permeable and may extend across the width of the wound dressing 100. For example, the backing layer 220 may be a polyurethane film (e.g., Elastollan SP9109) having a pressure-sensitive adhesive on one side. The backing layer 220 is gas-impermeable and therefore acts to cover the wound and seal the wound cavity on which the wound dressing is placed. In this way, an effective chamber is created between the backing layer 220 and the wound site, on which negative pressure can be established. Preferably, the backing layer 220 is sealed to the wound contact layer 222 within the boundary region around the dressing, for example, by adhesive or welding techniques, so that air is not drawn into the boundary region. The backing layer 220 protects the wound from external bacterial contamination (bacterial barrier) and allows fluid from wound exudate to move through the layer and evaporate from the outer surface of the film. The backing layer 220 preferably comprises two layers: a polyurethane film and an adhesive pattern spread on this film. The polyurethane film is preferably permeable to moisture and may be made from a material whose water permeability increases when wet. In some embodiments, the permeability of the backing layer increases when the backing layer is wet. The permeability of the wet backing layer may be up to about 10 times that of the dry backing layer.

[0056] The absorbent layer 221 may have a larger area than the permeable layer 226 so that the absorbent layer overlaps with the edge of the permeable layer 226, thereby ensuring that the permeable layer does not come into contact with the backing layer 220. This provides an outer channel of the absorbent layer 221 that comes into direct contact with the wound contact layer 222, facilitating more rapid absorption of exudate into the absorbent layer. Furthermore, this outer channel ensures that fluid does not accumulate around the periphery of the wound cavity, which would otherwise seep out from the sealing around the dressing and lead to leakage. As illustrated in Figure 2C, the absorbent layer 221 may have a smaller perimeter than the perimeter of the backing layer 220 so that the boundary or boundary region is defined between the edge of the absorbent layer 221 and the edge of the backing layer 220.

[0057] As shown in Figure 2C, one embodiment of the wound dressing 100 includes a gap 228 in the absorbent layer 221 located below the fluid connector 110. During use, for example, when negative pressure is applied to the dressing 100, the portion of the fluid connector facing the wound may come into contact with the permeable layer 226, and thus can help transmit negative pressure to the wound site even when the absorbent layer 221 is filled with wound fluid. Some embodiments may have a backing layer 220 that is at least partially adhered to the permeable layer 226. In some embodiments, the gap 228 is at least 1 to 2 mm larger than the diameter of the portion of the fluid connector 11 facing the wound or the orifice 227.

[0058] In particular, in embodiments involving a single fluid connector 110 and a through-hole, it may be preferable for the fluid connector 110 and the through-hole to be located off-center, as illustrated in Figure 2B. Such a location may allow the dressing 100 to be positioned on the patient such that the fluid connector 110 is elevated relative to the rest of the dressing 100. When positioned in this manner, the fluid connector 110 and the filter 214 may be less likely to come into contact with wound fluid that could prematurely occlude the filter 214 in order to prevent the transmission of negative pressure to the wound site.

[0059] Similar to the embodiments of wound dressings described above, some wound dressings include a perforated wound contact layer having a silicone adhesive on the skin contact surface and an acrylic adhesive on the back surface. In some embodiments, the wound contact layer may be constructed from polyurethane, polyethylene, or polyester. Above this bounded layer is a permeable layer. Above the permeable layer is an absorbent layer. The absorbent layer may include a superabsorbent nonwoven (NW) pad. The absorbent layer may be in contact with the permeable layer for approximately 5 mm beyond its periphery. The absorbent layer may have gaps or through-holes directed toward one end. The gaps may be approximately 10 mm in diameter. Above the permeable and absorbent layers is a backing layer. The backing layer may be a high water vapor permeability (MVTR) film, which is a pattern coated with acrylic adhesive. The high MVTR film and wound contact layer encapsulate the permeable and absorbent layers, creating a periphery boundary of approximately 20 mm. The backing layer may have a 10 mm gap that overlaps the gaps in the absorbent layer. Above the hole, a fluid connector may be connected, comprising a liquid-impermeable, gas-permeable semi-permeable membrane (SPM) or filter that overlaps the aforementioned gap.

[0060] Figure 2D illustrates an embodiment of a wound dressing similar to the wound dressings of Figures 2A-2C. Referring to Figure 2D, the masking or concealing layer 2107 may be positioned beneath at least a portion of the backing layer 2140. In some embodiments, the concealing layer 2107 may have any of the same features, materials, or other details as any other embodiment of the concealing layer disclosed herein, including, but not limited to, having any viewing windows or holes. An example of a wound dressing having a concealing layer and viewing windows is described in International Patent Publication WO2014 / 020440, which is incorporated in its entirety by reference. In addition, the concealing layer 2107 may be positioned adjacent to the backing layer or adjacent to any other dressing layer as desired. In some embodiments, the concealing layer 2107 may be bonded to the backing layer or formed integrally with the backing layer. Preferably, the concealing layer 2107 has substantially the same size and shape as the absorption layer 2110 and is configured to overlay it. Thus, in these embodiments, the concealing layer 2107 has a smaller area than the backing layer 2140.

[0061] Preferably, the absorption layer 2110 and the concealment layer 2107 include at least one through-hole 2145 positioned below the port 2150. Naturally, each of these various holes through the layers 2107, 2140, and 2110 may be of different sizes relative to one another. As illustrated in Figure 2D, a single through-hole may be used to create an opening below the port 2150. In certain embodiments, the port may be replaced by or used in combination with a fluid connector, such as the one illustrated in Figure 2C. It will be understood that multiple openings may be available as alternatives. In addition, if multiple ports are to be utilized according to a particular embodiment of the present disclosure, one or more openings may be fabricated in the absorption layer and concealment layer, aligned with each respective port. Although not essential to the particular embodiment of the present disclosure, using through-holes in the superabsorbent layer may provide an unobstructed fluid flow path, particularly when the absorption layer 2110 is near saturation.

[0062] A gap or through-hole 2144 may be provided in the absorbent layer 2110 and the concealing layer 2107 below the orifice 2144 so that the orifice is directly connected to the permeable layer 2105. This allows the negative pressure applied to the port 2150 to be transmitted to the permeable layer 2105 without passing through the absorbent layer 2110. This ensures that even if the absorbent layer absorbs wound exudate, the negative pressure applied to the wound site is not obstructed by the absorbent layer. In other embodiments, the gap may not be provided in the absorbent layer 2110 and / or the concealing layer 2107, or alternatively, multiple gaps may be provided below the orifice 2144.

[0063] In some embodiments, the concealing layer 2107 may help reduce the unsightly appearance of the dressing during use by using a material that provides partial concealment or masking of the dressing surface. In one embodiment, the concealing layer 2107 only partially conceals the dressing to allow the clinician to access necessary information by observing the spread of exudate across the dressing surface. The partial masking properties of this embodiment of the concealing layer allow the clinician to perceive different colors caused by exudate, blood, by-products, etc., on the dressing, enabling visual assessment and monitoring of the extent of the spread across the dressing. However, because the change in the color of the dressing from its clean state to its exudated state is slight, it is unlikely that the patient will notice the aesthetic difference. Reducing or eliminating visual indicators of wound exudate from a patient's wound is likely to have a positive impact on the patient's health, for example, by reducing stress.

[0064] In some embodiments, the concealment layer may be formed from a nonwoven fabric (e.g., polypropylene) and can be heat-bonded using a diamond pattern with a 19% bonding area. In various embodiments, the concealment layer may be hydrophobic or hydrophilic. Depending on the application, in some embodiments, a hydrophilic concealment layer may provide additional moisture permeability. However, in some embodiments, a hydrophobic concealment layer can still provide sufficient moisture permeability (i.e., through appropriate material selection and thickness of the concealment layer), while also allowing for better retention of dyes or colors in the concealment layer. Thus, dyes or colors can be trapped beneath the concealment layer. In some embodiments, this may allow the concealment layer to be colored in a light color or white. In preferred embodiments, the concealment layer is hydrophobic. In some embodiments, the concealment layer material may be sterilizable using ethylene oxide. In other embodiments, sterilization may be performed using gamma irradiation, electron beam, steam or other alternative sterilization methods. In addition, in various embodiments, the concealment layer may be colored or tinted, for example, with medical blue. The concealing layer may also be constructed from multiple layers, including a colored layer laminated or fused to a stronger uncolored layer. Preferably, the concealing layer is odorless and exhibits minimal fiber shedding.

[0065] Multilayer covering material for use without negative pressure Figures 3A to 3D illustrate various embodiments of wound dressings 500 that can be used to heal wounds without negative pressure. Figure 3E illustrates a cross-section of the wound dressings of Figures 3A to 3D. As shown in the dressings of Figures 3A to 3E, wound dressings may have multiple layers similar to those described with reference to Figures 2A to 2D, except that the dressings of Figures 3A to 3E do not include ports or fluid connectors. The wound dressings of Figures 3A to 3E may include a cover layer 501 and an optional wound contact layer 505, as described herein. In some embodiments, the cover layer 501 may be permeable to moisture and / or air. The wound dressing may include various layers positioned between the wound contact layer 505 and the cover layer 501. For example, the dressing may include one or more absorbent layers or one or more permeable layers, as described herein with reference to Figures 2A to 2D.

[0066] As shown in Figures 3A to 3E, the dressing 500 may include a perforated wound contact layer 505 and an upper film 501. Further components of the wound dressing 500 include a foam layer 504, such as a layer of polyurethane hydrocellular foam, of a size suitable for covering the recommended dimensions of the wound corresponding to a selected specific dressing size. An optional layer of activated charcoal cloth (not shown) of similar or slightly smaller dimensions to layer 504 may be provided to allow odor control. An absorbent layer 502, such as a layer of superabsorbent foam material containing cellulose fibers and superabsorbent polyacrylate particles, is provided above layer 504 and is slightly larger in dimensions than layer 504, allowing for overlapping of the superabsorbent material and acting as a leak-proof layer. Above layer 502, a masking or concealing layer 503, such as a layer of three-dimensional knitted spacer fabric, is provided to provide protection from pressure, while allowing partial masking of the top surface of the superabsorbent material to leave colored exudate. In this embodiment, this is smaller in dimension than layer 502 (plan view) and allows visualization of the edge of the absorbent layer, which can be used by a clinician to evaluate whether the covering material needs to be changed.

[0067] The wound dressing 500 may incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layers, acid group providing layers) as described in this section or elsewhere. Those skilled in the art will understand that the wound dressing 500 may incorporate any of the one or more nitric oxide generating layers disclosed in this section or elsewhere in this specification. Those skilled in the art will also understand that one or more nitric oxide generating layers may be incorporated as part of all constituent layers or as part of constituent layers. In some embodiments, the nitric oxide generating layers may be provided below the cover layer 501. In some embodiments, one or more nitric oxide generating layers may be provided above the wound contact layer 505. In certain embodiments, the wound contact layer 505 may be omitted so that one of the nitric oxide generating layers may be configured to be the bottom layer and in contact with the wound surface. In some embodiments, one or more nitric oxide generating layers may be provided below the foam layer 504. In some embodiments, one or more nitric oxide generating layers may replace the foam layer 504. In some embodiments, the dressing 500 may consist only of the cover layer 501 and one or more nitric oxide generating layers. In some embodiments, one or more nitric oxide generating layers or their components (e.g., the nitrite-providing layers described herein) may be separate from the wound dressing 500. For example, one or more nitric oxide generating layers or their components may be provided as separate layers that can be placed on a wound, and the wound dressing 500 may be placed on top of them.

[0068] As described above, one or more nitric oxide generating layers may be incorporated into or used with commercially available dressings such as ALLEVYN® foam, ALLEVYN® Life, ALLEVYN® Adhesive, ALLEVYN® Gentle Border, ALLEVYN® Gentle, ALLEVYN® Ag Gentle Border, ALLEVYN® Ag Gentle, Opsite Post-Op Visible. In some embodiments, the wound dressing 500 may include a cover layer 501, a wound contact layer 505, and a nitric oxide generating layer sandwiched between them. In some embodiments, the wound dressing 500 may include a cover layer 501, an absorbent layer 502, a nitric oxide generating layer beneath the absorbent layer 502, and a wound contact layer 505.

[0069] Further details relating to wound dressings that may be used in combination with or in addition to the embodiments described herein are found in U.S. Patent No. 9,877,872 issued on January 30, 2018, titled "WOUND DRESSING AND METHOD OF TREATMENT," which is incorporated herein by reference in its entirety, including further details relating to embodiments of wound dressings, components and principles of wound dressings, and materials used in wound dressings.

[0070] Multilayer wound dressing with integrated negative pressure source In some embodiments, some or all other components of the TNP system, such as a negative pressure source (e.g., a pump) and power supplies, sensors, connectors, and user interface components (e.g., buttons, switches, speakers, screens), may be integrated with wound dressings, such as those described above in relation to Figures 1 to 3E. In addition, some embodiments relating to wound treatment with wound dressings described herein may also be used in combination with, or in addition to, the embodiments described in International Application No. WO2016 / 174048 and International Patent Application No. PCT / EP2017 / 055225, filed March 6, 2017, entitled "Wound Treatment Apparatus and Methods with Negative Pressure Source Integrated into the Wound Dressing," the disclosure of which is incorporated herein by reference in whole, and includes further details relating to embodiments of wound dressings, components and principles of wound dressings, and materials used in wound dressings and components of wound dressings.

[0071] In some embodiments, the pump and / or other electronic components may be configured to be positioned adjacent to or next to the absorbent and / or permeable layer of the wound dressing, such that the pump and / or other electronic components are positioned away from the wound site, while the pump and / or other electronic components are still part of a single device that will be applied to the patient.

[0072] Nitric oxide layer Figures 4 and 5 illustrate wound dressings 12000, including a nitric oxide generating layer, according to several embodiments. In the illustrated embodiments, the wound dressing 12000 may include a cover layer 12200, an activator layer 12400, and a nitrite-providing layer 12600. In some embodiments, the wound dressing 12000 may include additional layers, as further described herein. Those skilled in the art will understand that various divisions of the dressing may be referred to as “layers,” but such divisions may be of other preferred shapes or configurations. As will be understood by those skilled in the art, embodiments of wound dressings and / or nitric oxide delivery described in this section or elsewhere in this specification may be applied over a wound and / or over surrounding skin, such as in the area surrounding the wound.

[0073] The cover layer 12200 is gas-impermeable but may be breathable and may extend across the width of the wound dressing 12000. For example, the cover layer 12200 may be a polyurethane film (e.g., Elastollan SP9109 or Elastollan SP806) having a pressure-sensitive adhesive on one side, and may be gas-impermeable, and therefore may act to cover the wound and seal the wound cavity on which the wound dressing is placed. Thus, a chamber or sealed wound space is created between the cover layer 12200 and the wound site. In some embodiments, negative pressure may be established within the chamber or sealed wound space created between the cover layer 12200 and the wound site. The cover layer 12200 protects the wound from external bacterial contamination (bacterial barrier) and allows fluid from wound exudate to move through the layer and evaporate from the outer surface of the film. The cover layer 12200 may include two or more layers, for example, a polyurethane film and an adhesive pattern spread on the film. In certain examples, the polyurethane film may be permeable and may be made from a material whose water permeability increases when wet. In some embodiments, the permeability of the cover layer increases when the cover layer is wet. The permeability of the wet cover layer may be up to about 10 times that of the dry cover layer. In some embodiments, the cover layer 12200 may be replaced or supplemented with additional wound dressings as described elsewhere in this specification, thereby positioning the additional wound dressings above the nitric oxide generating layer. The cover layer may also be waterproof so that the dressings incorporating such a cover layer may be used in a shower. The cover layer may be configured so that nitric oxide does not immediately leak through the cover layer, meaning that the cover layer is nitric oxide impermeable or semi-impermeable, thereby trapping the nitric oxide against the tissue so that the nitric oxide can interact with the user's body. Those skilled in the art will understand that the cover layer can be fabricated to be vapor-permeable but nitric oxide-impermeable.

[0074] The nitrite-providing layer 12600 may provide one or more nitric oxide-releasing agents to the wound site. The nitric oxide-releasing agents may include any chemical entity that produces nitric oxide at the wound site when activated or otherwise stimulated to be activated. In some embodiments, the nitric oxide-releasing agents may include nitrite ions, nitrites, organic and inorganic nitrites, or any pharmacologically acceptable nitrite source, thereby reducing the amount of nitrite ions required to produce nitric oxide at the wound site. For example, the nitrite-providing layer 12600 and / or elements may include one or more of ammonium nitrite, lithium nitrite, calcium nitrite, sodium nitrite, and potassium nitrite. In some embodiments, the nitrite-providing layer may be a suitable material layer or element containing alkali metal nitrites and / or alkaline earth metal nitrites. In certain embodiments, the nitrite may include LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2, Ra(NO2)2, or any other suitable nitrite. In some embodiments, precursors of nitrite ions, such as nitrite, nitrate ions, nitroprusside ions, or any pharmaceutically acceptable salts thereof, may be used as the source of the nitrite. In some embodiments, the nitric oxide release agent may include nitrites such as nitro-functionalized compounds.For example, nitric oxide release agents include nitroglycerin, isoamyl nitrite, isobide mononitrate, N-(ethoxycarbonyl)-3-(4-morpholinyl)sidenonimine, 3-morpholinosidenonimine, 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-di-chlorophenyl)-chloride, 1,2,3,4-oxatriazolium, 5-amino-3-(chloro-2-methylphenyl)chloride, 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl) It may contain (nyl)-5-[[[cyanomethylamino]carbonyl]amino]-hydroxyl salt, S-nitroso-N-acetyl-(D,L)-penicillamine, 1-[(4',5'-bis(carboxymethoxy)-2l-nitrophenyl)methoxy]-2-oxo-3,3,diethyl-l-triazendica potassium salt, and [1-(4',5'-bis(carbyomethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3-diethyl-1-triazinediacetoxymethyl ester.

[0075] In some embodiments, the nitric oxide release agent of the nitrite-providing layer 12600 may include diazenium diolates, including O-alkylated diazenium diolates, O-derivativeated diazenium diolates, and non-O-derivativeated diazenium diolates. For example, the nitric oxide release agent may include diethylamine / NO, V-PYRRO / NO, and / or spermine / NO. In some embodiments, the nitric oxide release agent of the nitrite-providing layer 12600 may include S-nitrosothiols, such as S-nitro-glutathione, S-nitroso-N-acetylcysteine, and S-nitroso-acetylpenicillamine. In some embodiments, the nitric oxide release agent of the nitrite-providing layer 12600 may include silica or silica nanoparticles modified with nitric oxide. In some embodiments, the nitric oxide release agent may be a polymer modified with nitric oxide to contain nitric oxide. For example, polyethyleneimine, polypropyleneimine, polybutyleneimine, polyurethane, or polyamide may be modified with nitric oxide to form diazenium diolates. In some embodiments, the nitrite-providing layer 12600 may be constructed from such polymers modified with nitric oxide. Further examples of nitric oxide-releasing agents are provided in International Publication No. WO2006 / 058318 and Liang et al., “Nitric oxide generating / releasing materials”, Future Science OA, 1(1)(2015), which are incorporated herein by reference in whole.

[0076] In some embodiments, the nitrite-providing layer 12600 may contain a nitric oxide-releasing agent (e.g., sodium nitrite) in an aqueous solution. For example, the nitrite-providing layer 12600 may contain a material immersed in a solution of a nitric oxide-releasing agent (e.g., sodium nitrite). In some embodiments, the nitrite-providing layer 12600 may contain a dry nitric oxide-releasing agent (e.g., sodium nitrite) in solid form.

[0077] The nitrite-providing layer 12600 may comprise a mesh, foam, gel, or any other material suitable for containing a nitric oxide-releasing agent. For example, the nitrite-providing layer 12600 may comprise a mesh soaked in a solution of a nitric oxide-releasing agent (e.g., sodium nitrite). The mesh may be knitted, woven, or nonwoven. The mesh may be made from polymer materials, such as viscose, polyamide, polyester, polypropylene, or a combination thereof. In some embodiments, the nitrite-providing layer 12600 may comprise polypropylene, polyester, polyurethane, polyvinyl chloride, polyamide, viscose, polyester, polypropylene, and / or cellulose. As described herein, the nitrite-providing layer 12600 may be constructed from one or more polymers modified with nitric oxide. The nitrite-providing layer 12600 may also be made from a hydrogel without acidic groups to prevent reaction with nitrite ions that release nitric oxide. In some embodiments, the nitrite-providing layer 12600 may be constructed from a colored material so that it may be visible during application to the wound to assist in the positioning of the wound dressing 12000 and to reduce the risk of incomplete removal of the nitrite-providing layer 12600 from the wound after treatment. The nitrite-providing layer 12600 may be completely or semi-permeable to the diffusion of nitric oxide.

[0078] In some embodiments, the nitrite-providing layer 12600 is the bottom layer of the dressing 12000 so that the nitrite-providing layer 12600 can come into contact with the wound. In some embodiments, the nitrite-providing layer 12600 may be positioned within and / or on the wound. The nitrite-providing layer may be constructed so that the nitrite-providing layer 12600 does not substantially adhere to the skin or wound, or does not cause damage to the wound when it comes into contact with the wound. In some embodiments, the dressing 12000 may include one or more layers beneath the nitrite-providing layer 12600, for example, a wound contact layer. In some embodiments, the dressing 12000 may include two or more nitrite-providing layers. For example, the wound dressing 12000 may include two, three, four, five, six, seven or more nitrite-providing layers. In some embodiments, the nitrite-providing layer 12600 may be separate from the wound dressing 12000. For example, the nitrite-providing layer 12600 may be provided as a separate layer that can be placed on the wound, and the wound dressing 12000 may be placed on it. Nitric oxide-releasing agents may be incorporated into the nitrite-providing layer to provide nitrite doses (e.g., sodium nitrite doses) expressed in M ​​(moles) of about 0.01 to 5.0, 0.5 to 4.5, 1.0 to 3.0, 1.0 to 2.0, and / or 1.0 to 1.5. For example, the doses may be about 0.50 M, about 0.01 M, about 1.5 M, about 2 M, or about 2.5 M.

[0079] The activator layer 12400 may contain chemical agents, functional groups, or functional moieties that can activate and / or facilitate the release of nitric oxide from the nitric oxide release agent. For example, a proton or acidic environment promotes the reduction of nitrite to nitric oxide, and the activator layer 12400 may contain an acidic group or acidic moiety that can provide protons in an aqueous environment, thereby lowering the pH at the application site. In certain embodiments, the acidic group or acidic moiety is fixed in the activator layer 12400, for example, on the surface of the activator layer 12400. The acidic group or acidic moiety may be covalently bonded in the activator layer 12400. In some embodiments, the activator layer 12400 may contain an acidic solution. The activator layer 12400 may contain a mesh, foam, gel, or any other material suitable for containing the acidic group or acidic moiety. In some embodiments, the activator layer 12400 may be located above the nitrite-providing layer 12600, or below the nitrite-providing layer 12600. In some embodiments, the activator layer 12400 may contain water, methanol, ethanol, propanol, butanol, pentanol, hexanol, phenol, naphthol, or a proton source such as a polyol, phosphate, succinate, carbonate, acetate, phosphate, propionate, butyrate, fatty acid, amino acid, or ascorbic acid, or any suitable enzymatic or catalytic compound. In some embodiments, body fluids such as blood, lymph, bile, or wound exudate may function as activators and assist the activator layer 12400. In some embodiments, the wound dressing 12000 may not contain the activator layer 12400, and a wound fluid or wound exudate may function as an activator. Further examples of activators for nitric oxide release agents are provided in International Publication No. WO2006 / 058318 and Liang et al., “Nitric oxide generating / releasing materials”, Future Science OA, 1(1)(2015), which are incorporated herein by reference in their entirety.

[0080] In some embodiments, the wound dressing 12000 may comprise two or more nitrite-providing layers and / or two or more activator layers. For example, the wound dressing 12000 may comprise two, three, four, five, six, seven or more nitrite-providing layers and / or activator layers.

[0081] In some embodiments, the activator layer 12400 includes a hydrogel so that the activator layer 12400 can absorb wound exudate. In certain examples, the activator layer 12400 may be constructed from a xerogel. The activator layer 12400 may be constructed from any suitable material disclosed herein. The gel of the activator layer 12400 may be presented in different physical formats. For example, the activator layer 12400 may foam during curing. The hydrogel may be poured into a foam and then cured within the foam. In some embodiments, the activator layer 12400 may be perforated through its thickness. The perforations may be sized to allow fluid absorption and to release a desired therapeutic dose of nitric oxide from the wound dressing. For example, the perforations may have diameters of approximately 0.1 mm to 10 mm, 0.15 mm to 7 mm, 0.2 mm to 5 mm, 0.5 mm to 4 mm, or 0.7 mm to 3 mm. The perforations may be circular, square, triangular, or any other suitable shape. The foamed structure and / or perforations may contribute to the fluid handling capacity of the activator layer.

[0082] In some embodiments, the activating material for the activating layer may be provided as a dispensable composition, for example, a prepolymer solution or in an otherwise moldable form, instead of being provided as an activating layer such as activating layer 12400, so that it can be applied more freely to the wound and / or around the wound. For example, the activating material may be provided as a gel prepolymer solution so that it can be applied by a clinician to or in close proximity to a wound having an irregular shape and size. In some embodiments, the activating material, such as a gel prepolymer solution, may be provided in a syringe and / or applied using a syringe, and the gel prepolymer solution may have a viscosity suitable for dispensing from a syringe. The activating material may also be formulated to cure rapidly and, once applied to or around the wound, no longer flow. The activating material may contain an evaporative solvent such as isopropanol. The activating material may have a suitable secondary curing mechanism, such as a photoinitiated acrylate functional group. In some embodiments, the activating material may be provided as a reactive two-subsystem. For example, the first and second parts may be provided to be mixed immediately before dispensing to result in polymer formation. In some embodiments, the first and second parts may be oppositely charged fluid gels, thereby interacting upon mixing to provide a substantially non-flowing gel. In some embodiments, the activating material may include a material such as a gel that changes in response to environmental changes. For example, the activating material may include a material such as a certain Pluronic so that it can harden when the temperature changes as it is applied to the skin from a dispenser or syringe. The activating material may be applied so that it can interact with nitrite from the nitrite-providing layer 12600 (which may provide nitrite) to generate nitric oxide. Once the activating material is applied and hardened or otherwise non-flowing, the cover layer 12200 may be applied.

[0083] When the coating material 12000 is activated, for example, by arranging the activator layer 12400 in contact with the nitrite-providing layer 12600, the nitric oxide-releasing agent from the nitrite-providing layer 12600 releases nitric oxide. For example, in some embodiments, the nitrite can be reduced to nitric oxide in the presence of an acidic environment provided by the activator layer 12400, as shown below.

[0084] [ka]

[0085] The activator layer 12400 and the nitrite-providing layer 12600 may be positioned so that the nitric oxide-releasing agent can react to provide nitric oxide. For example, the activator layer 12400 and the nitrite-providing layer 12600 may be in contact with each other within the coating 12000 during use. In some embodiments, one or more additional layers may be positioned between the activator layer 12400 and the nitrite-providing layer 12600. In some embodiments, the activator layer 12400 and the nitrite-providing layer 12600 may be fluidically separated from each other before the coating 12000 is applied to the patient to prevent premature release of nitric oxide. For example, the nitrite-providing layer 12600 may be supplied in separate packaging from the rest of the coating 12000. Once the coating 12000 is activated, the nitric oxide-releasing agent from the nitrite-providing layer 12600 may be dispersed within the coating 12000. In some embodiments, the nitric oxide-releasing agent may be dissolved in the wound exudate, which may facilitate the dispersion of the nitric oxide-releasing agent. At least a portion of the nitric oxide-releasing agent will react to release nitric oxide in the presence of the activator in the activator layer 12400. The generated nitric oxide may diffuse into the wound or be delivered to the wound by any preferred mechanism. In some embodiments, the generated nitric oxide may not be delivered immediately or at all, but instead be retained within the dressing, for example, by a selectively permeable membrane, thereby preventing or killing microbial growth within the dressing.

[0086] In some embodiments, the wound dressing 12000 may contain a reducing agent that facilitates the reduction of a nitric oxide-releasing agent (e.g., nitrite ion) to nitric oxide. Physiologically acceptable examples of such reducing agents include, but are not limited to, iodide anions, ascorbic acid, ascorbates (e.g., sodium ascorbate), isoascorbic acid (e.g., sodium isoascorbate), hydroquinone, butylated quinone, tocopherol, butylated hydroquinone, hydroquinone 43 ariants, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, potassium iodide, ascorbic acid variants, isoascorbic acid variants, any other suitable reducing agent, and / or any of the antioxidants and / or reducing agents described herein. The reducing agent may be contained in one or more layers of the wound dressing 12000. For example, the reducing agent may be included in the cover layer 12200, the activator layer 12400, the nitrite supply layer 12600, the wound contact layer (e.g., 222, 505), and / or any suitable layer of the nitric oxide generating wound dressing described herein. The reducing agent may be incorporated into one or more layers by, for example, physical containment, physical mixing, coating, covalent bonding, or any other suitable method. The reducing agent may be incorporated into the suitable layer in w / w% of about 0.01–5.0%, 0.1–4.5%, 1.0–3.0%, 1.0–1.5%, and / or 1.5–2.5%. For example, the w / w% may be about 0.02%, about 0.03%, about 0.8%, about 1.2%, about 1.4%, or about 2.43%. Higher levels of the reducing agent may lead to increased nitric oxide production, but very high levels of the reducing agent may be toxic.

[0087] As described herein, the nitric oxide source layer may contain a nitrite and may be referred herein to as the nitrite delivery layer or nitrite supply layer. As described herein, the activator layer may contain an acid and may be referred herein to as the acid supply layer or acid delivery layer. The nitrite supply layer / nitrite delivery layer / nitrite supply layer and the activator layer / acid supply layer may be referred herein to as the nitric oxide generation layer, collectively or individually.

[0088] Materials and structures for nitric oxide coatings As will be understood by those skilled in the art, the materials and covering constructs described above in relation to the nitric oxide delivery covering 1200 in Figures 4 and 5, and elsewhere in this specification, may include a plurality of suitable constructs and different types of materials. For example, the top layer furthest from the wound may be a top or cover film layer, such as a top or cover layer disclosed herein, such as a polyurethane material. Such a top or cover film may be constructed from the material used for the cover layer of RENASYS drapes, sold by Smith+Nephew. For example, in some embodiments, the cover layer may be an IV3000 top film. Below the top or cover film layer may be a masking or fabric layer, which may be constructed from any suitable material disclosed herein as a masking or fabric layer. The masking layer may be constructed from stretchable and non-stretchable polyester, polyethylene, polypropylene, polypropylethylene, and nonwoven fabrics, as well as suitable blends constructed therefrom. For example, in some embodiments, the masking layer may be a 17gsm polypropylene mask layer. More suitable nonwoven fabrics and blends may also be available. In certain embodiments, the masking layer may be a foam. Beneath the masking layer or fabric layer is an activator layer similar to the activator layers described herein and throughout this specification. Such an activator layer may be constructed from a hydrogel adhesive, optionally containing a central polyester support mesh and / or a support release liner. For example, in some embodiments, the activator layer may be in the form of hydrogel-loaded DuraFiber as described herein. DuraFiber, manufactured by Smith+Nephew, is a commercially available absorbent nonwoven fabric material made from cellulose. In such examples, depending on the size of the covering, an equivalent of about 6 grams of hydrogel can be loaded onto a 10.8 cm × 10.8 cm DuraFiber, which can then be cut into 10 cm × 10 cm pieces, resulting in about 5.14 grams of hydrogel on a 10 cm × 10 cm DuraFiber piece.The activator layer may be constructed from any suitable hydrogel material disclosed herein, such as acrylic acid hydrogel and / or sulfonic acid hydrogel. Beneath the activator layer may be a water-absorbing dispersion layer, which may be constructed from any suitable water-absorbing dispersion layer material disclosed herein, such as those related to Figures 2C-2D. For example, the water-absorbing dispersion layer may be constructed from 3D knit, gauze and / or stretch polyester fibers woven in a net form, similar to the material used in Acticoat Flex by Smith+Nephew, but silver is optional. In some embodiments, the water-absorbing dispersion layer may be constructed from a prepolymer solution having a mixture of water, a surfactant and polyethylene glycol, such as the foam used in Allevyn foam by Smith+Nephew. The masking layer and the water-absorbing dispersion layer may use the same material and be interchangeable. In certain embodiments, the water-absorbing dispersion layer may be pressed into the activator layer and / or cured within the activator layer. Curing the water-absorbing dispersion layer within the activator layer may improve the rate of nitric oxide formation due to faster transport. Below the water-absorbing dispersion layer, there may be a wound contact layer which can be constructed from any suitable material disclosed herein, such as those related to Figures 2C-2D. For example, the wound contact layer may include a silicone adhesive and a perforated polyurethane film. The wound contact layer may include an acrylic adhesive. A nitrite-providing layer constructed from any suitable material disclosed herein may be positioned below the wound contact layer so that the nitrite-providing layer is direct to the wound or other tissue. In some embodiments, the nitrite-providing layer may be in other locations, such as on top of the activator layer and / or elsewhere within the coating. For example, in some embodiments, the nitrite-providing layer may be a separate 17gsm polypropylene mesh saturated with a sodium nitrite solution. In certain embodiments, the ALLEVYN or PICO coatings disclosed in Figures 2 and 3 may be placed directly on top of the activator layer and the underlying nitrite-providing layer. Direct placement of a nitrite-supplying layer on the wound, surrounding area, and / or other tissues may allow for increased direct release of nitric oxide into the tissue.As will be understood by those skilled in the art, embodiments of wound dressings and / or nitric oxide delivery described in this section or elsewhere in this specification may be applied to the wound and / or to the surrounding skin, such as the area around the wound.

[0089] Chemiluminescence Figure 6 shows an exemplary configuration 600 for a chemiluminescence protocol for testing nitric oxide delivery coatings, such as those disclosed above in relation to Figures 4 and 5. The protocol may include a sample box 602, a desiccant 604, an air source 606, a chemiluminescence detector 608, a nitrogen supply unit 610, an air pump 612, a mass flow meter 614, and a T-piece connector 616. In certain embodiments, a ThermoFisher 42i-HL detector may be used as the chemiluminescence detector 608. After preheating the instrument with an airflow under atmospheric pressure, the sample box 602 and the nitrogen supply unit may be connected to the instrument. The nitrogen flow through the mass flow controller may be set to a preferred value such as about 1 to 100, 10 to 90, 25 to 75, 40 to 60, or about 50 mL / min. After flushing the system (e.g., for about 1–60, 10–50, 20–40, or about 30 minutes), the nitrite-providing layer (such as a nitrite mesh) and the activator layer (such as an acid-providing hydrogel) may be placed in the sample chamber 602. In some embodiments, the nitrite mesh has a smaller total area than the activator layer. In certain embodiments, the nitrite-providing layer and / or the activator layer may have a length and / or width of about 0.5–20, 1–10, 2–8, or about 4–6 centimeters. In certain embodiments, the nitrite-providing layer may be 2.5 cm × 2.5 cm, while the activator layer is 3 cm × 3 cm.

[0090] NO / NO2 emission concentrations can be measured at an appropriate rate by a chemiluminescence detector, checking concentrations in ppb or ppm units and monitoring periodically, such as every 1, 2, 5, 10, 30, 60, or 90 seconds. In certain embodiments, NO / NO2 concentrations may be checked in ppm units.

[0091] As will be understood by those skilled in the art, it is desirable for coatings disclosed herein, such as those described in relation to Figures 4 and 5, to maximize NO above NO2. Nitric oxide (NO2) can exhibit antimicrobial properties, but NO2 does not have vasodilatory properties or the ability of NO to activate cell proliferation. Therefore, it is generally desirable to reduce the generation of NO2 as much as possible during nitrite acidification, such as by means of reducing the oxidation of dissolved nitric oxide (NO) by removing oxygen from the hydrogel body where nitrite acidification occurs. Nitric oxide delivery coatings disclosed herein can generate both NO and NO2. In some embodiments, nitric oxide coatings disclosed herein can generate NO and NO2 in NO / NO2 ratios such as about 0.5:1 to 500:1, 1:1 to 400:1, 10:1 to 300:1, 20:1 to 200:1, and 50:1 to 100:1. For example, the ratio could be approximately or at least approximately 0.5:1, 1.01:1, 1.1:1, 1:1, 2:1, 5:1, 10:1, 20:1, 30:1, 50:1, 100:1, 200:1, or 500:1.

[0092] Figure 7 shows an example of an experimental configuration 700 demonstrating nitric oxide delivery from a combination of an activator layer and a nitrite-providing layer while under negative pressure, similar to the dressings described in relation to Figures 4 and 5. As shown in Figure 7, a negative pressure wound therapy pump 702 is connected to a negative pressure wound therapy dressing 704, such as those described herein in Figures 2A–2D. The dressing is sealed over a chamber 706 containing a nitrite test solution 708 that changes color in the presence of NO. Before the application of negative pressure, the test solution did not change color. After running negative pressure for a period of time to ensure that no change in background color occurred, an activator layer (such as an acid-providing hydrogel), such as those described herein, was placed in the chamber and negative pressure was applied. Again, no change in color occurred. Finally, a nitrite-providing layer (such as a sodium nitrite mesh), such as those described herein, was placed on the activator layer without contacting the nitrite-providing layer with the nitrite test solution, and negative pressure was applied. After 15 minutes of negative pressure, the indicator solution changes color, thereby demonstrating that the interaction between the activator layer and the nitric oxide layer can generate nitric oxide even under negative pressure.

[0093] As will be understood by those skilled in the art, negative pressure can be applied to any of the nitric oxide delivery dressings disclosed herein, such as those described in Figures 4 and 5 and elsewhere in this specification. Dressings, such as those described in Figures 2A to 2D, may be arranged on an activator layer and a nitrite-delivering layer placed within the wound, thereby delivering nitric oxide to the wound while simultaneously applying negative pressure wound therapy.

[0094] Figures 8A–8C show examples of chemiluminescence experiments performed using protocols similar to those described above. As will be understood by those skilled in the art, these measurements obtained in these experimental runs are merely illustrative, and the disclosure herein is not limited to such values. Figure 8A shows experimental results when a dry sodium nitrite mesh was tested in the configuration shown in Figure 8A, which includes a polyurethane cover layer covering a stretchable polyester ADL layer positioned on a hydrogel activator layer sandwiched between another stretchable polyester ADL layer on a dry sodium nitrite mesh, as shown in the figure. In this experimental run, after the addition of DI water, the dry sodium nitrite mesh released approximately 550 ppm NO and 75 ppm NO2 at its peak at the 25-minute mark, and the concentrations gradually decreased to approximately 80 ppm NO and 10 ppm NO2 at the 50-minute mark.

[0095] Figure 8B shows experimental results when testing the entire coating design with a pull tab and self-sealing boundary. The pull tab is initially used to separate the nitrite donor layer from the activator layer; therefore, once the tab is removed and the coating is wet, the interaction between the nitrite donor layer and the activator layer generates nitric oxide. In this experimental run, after the addition of DI water, the entire coating design with the pull tab and self-sealing boundary released approximately 84 ppm NO and 15 ppm NO2 at its peak at 17 min sign, with concentrations gradually decreasing to approximately 25 ppm NO and 5 ppm NO2 at 50 min sign.

[0096] Figure 8C shows an example of experimental results for a coating containing a biodegradable film. Here, the biodegradable film was placed between the activator layer and the nitrite-providing layer, thereby generating nitric oxide once the biodegradable layer decomposed. In this experimental run, after the addition of DI water, the coating containing the biodegradable film released approximately 1000 ppm NO and 45 ppm NO2 at its peak at 25 minutes, and the concentrations gradually decreased to approximately 225 ppm NO and 20 ppm NO2 at 50 minutes. The experimental protocol was also used to test an activator layer containing sodium isoascorbate. In this experimental run, after the addition of DI water, the activator layer containing sodium isoascorbate released approximately 52 ppm of NO and 4 ppm of NO2 at its first peak at 80 minutes, 66 ppm of NO and 5 ppm of NO2 at its second and largest peak at 110 minutes, and gradually decreased in concentration to approximately 45 ppm of NO and 2 ppm of NO2 at 160 minutes.

[0097] Figure 9 shows various gsm (g / m 2 Examples of relative peak output in ppm for activator hydrogels (acid provided) with or without a water-absorbing dispersion layer, including polypropylene, polypropylethylene, or stretchable polyester water-absorbing dispersion layer, are shown. Without the water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 55 ppm and 10 ppm, respectively. Those skilled in the art will understand that the water-absorbing dispersion layer can enable improved fluid dispersion and handling over larger areas, such as coatings. With a 17 gsm polypropylene press-fitted water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 20 ppm and 2 ppm, respectively. With a 17 gsm polypropylene cured water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. As described above, curing the water-absorbing dispersion layer can enable increased fluid transport and improved rates of nitric oxide formation. (Polypropylene 30 g / m²) 2 According to the pressure-absorbing water dispersion layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. (Polypropylene 30 g / m²)2 According to the water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. (Polypropylene 40 g / m²) 2 According to the pressure-absorbing water-dispersing layer, the peak NO and NO2 concentrations were approximately 30 ppm and 2 ppm, respectively. (Polypropylene 40 g / m²) 2 In the cured water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 38 ppm and 5 ppm, respectively. (Polypropylethylene 30 g / m²) 2 According to the pressure-absorbing water dispersion layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. (Polypropylethylene 30 g / m²) 2 In the cured water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. In the stretchable polyester pressure-sensitive water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. In the FLEX pressure-sensitive water-absorbing dispersion layer, the peak NO and NO2 concentrations were approximately 55 ppm and 8 ppm, respectively.

[0098] Figures 10A–10D show examples of NO and NO2 concentrations over time for several embodiments incorporating an activator layer and a nitric oxide donor layer. As shown in Figures 10A–10B, activator layers containing approximately 2–3% sodium isoascorbate were tested with or without different pressed or cured water-absorbing dispersion layers. Gels without a water-absorbing dispersion layer produced pNO=785 ppm and pNO2=78 ppm (p indicates the peak). Activator layers with stretch polyester pressed within the gel produced pNO=506 ppm and pNO2=24 ppm. For stretch polyester cured on the activator layer, pNO=625 ppm and pNO2=50 ppm. For polypropylene pressed within the gel, pNO=508 ppm and pNO2=26 ppm. For the polypropylene cured within the gel, the pNO content was 624 ppm and the pNO2 content was 26 ppm.

[0099] Figures 10C and 10D show examples of NO and NO2 concentrations over time for activator layers containing approximately 1-2% sodium isoascorbate, with or without different pressed or cured water-absorbing dispersion layers. The activator layer without ADL produced pNO=334 ppm and pNO2=40 ppm. For the stretchable polyester water-absorbing dispersion layer pressed within the activator layer, pNO=211 ppm and pNO2=10 ppm were obtained. For the stretchable polyester water-absorbing dispersion layer cured within the activator layer, pNO=247 ppm and pNO2=14 ppm were obtained. For the polypropylene water-absorbing dispersion layer pressed within the activator layer, pNO=112 ppm and pNO2=5 ppm were obtained. For the polypropylene water-absorbing dispersion layer cured within the activator layer, pNO=184 ppm and pNO2=8 ppm were obtained. As described elsewhere in this specification, curing a water-absorbing dispersion layer within an activator layer can improve fluid handling and nitric oxide generation compared to nitric oxide generation.

[0100] Xerogel and hydrogel constructs Referential terms may be made herein for xerogels. Xerogels can be formed from gels by drying under unhindered shrinkage conditions. As will be understood by those skilled in the art, xerogels are gels having a very low free water content, i.e., such a low free water content that the minimum reaction to form nitric oxide occurs without the addition of further water and / or liquid. For example, xerogels may be substantially water-free in their dry state. Drying can be completed by any preferred means known in the art (e.g., freeze-drying).

[0101] In certain cases, hydrogels (which may then become xerogels after drying) may be formed with or without glycerol and may contain, if necessary, a standard amount or two, three, or four times the required amount of the crosslinking agent PEG diacrylate. A solution of sodium 2-acrylamido-2-methyl-1-propanesulfonic acid may be present in the xerogel. Hydrogels and xerogels may be prepared by converting 2-acrylamido-2-methyl-1-propanesulfonic acid (SA) (as supplied in MEHQ) to a sodium salt by dissolving it in water, and then forming a solution of 2-acrylamido-2-methyl-1-propanesulfonic acid (NaAMPS) by cooling it in a 10°C water bath to pH 7.0 with 50% NaOH. The hydrogel may contain approximately 5.393% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 1.0 SA), approximately 4.654% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.85 SA), approximately 2.839% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.5 SA), and / or a range of approximately 1.457% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.25 SA) to approximately 7.704% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 1.5 SA). The hydrogel prepolymer can be prepared by pre-dispersing a 2-hydroxy-2-methylpropiophenone photoinitiator in PEG diacrylate with minimal light, and then mixing it for 10-20 minutes with a mixture of 58% aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate (Na AMPS), sodium isoascorbate, pre-ground 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS acid), and glycerol. The AMPS acid may be completely dissolved in the stirred Na AMPS solution before the glycerol is gradually added, and then the photoinitiator / diacrylate mixture may be completely dissolved in a water bath.In certain embodiments, hydrogels may also be prepared using twice the usual amount of photoinitiator / crosslinker and / or omitting glycerol, and / or using three times the amount of prepolymer mixture in the mold to form a gel three times thicker.

[0102] Nitric oxide generating coating material utilizing sodium nitrite Figures 11A to 11E illustrate embodiments of nitric oxide generating wound dressings having various layer arrangements. Those skilled in the art will understand that the various layers shown in Figures 11A to 11E may be ordered in any preferred order, and that the order shown in the figures is merely an example. Furthermore, those skilled in the art will understand that one or more layers may be omitted, and / or the wound dressing may include more than one of the layers shown. In some embodiments, the top layer may be a cover layer 13002, which may have any of the same features, materials, or other details as the cover layer disclosed herein, such as being constructed from a film. The cover layer 13002 may be suitable for sealing the dressing over a wound, and for connecting to a negative pressure source and / or maintaining negative pressure at the wound site. In certain embodiments, the boundary region of the cover layer 13002 may be attached to the skin surrounding the wound to form a seal, so that wound exudate can be contained within the wound dressing 13000. Beneath the cover layer, a masking or concealing layer 13004 (hereinafter referred to as the “masking layer”) may be present to prevent or limit the visibility of the wound or wound exudate through the cover layer 13002. The masking layer 13004 may be positioned beneath at least a portion of the cover layer 13002. In some embodiments, the masking layer 13004 may have any of the same features, materials, or other details as any other embodiment of the masking layer disclosed herein, including, but not limited to, having any viewing windows or holes. Examples of wound dressings having concealing layers and viewing windows are described in International Patent Publications WO2013 / 007973 and WO2014 / 020440, which are incorporated by reference in their entirety. In addition, the masking layer 13004 may be positioned adjacent to the cover layer or, as desired, adjacent to any other dressing layer. In the illustrated embodiment, the masking layer 13004 is positioned between the cover layer 13002 and the activator layer 13006. As described elsewhere in this specification and as will be understood by those skilled in the art, the activator layer may be an acid-providing layer or other preferred layer.In certain embodiments, the masking layer 13004 may be bonded to or integrally formed with the cover layer 13002. The masking layer 13004 may have substantially the same size and shape as the activator layer 13006 and be configured to overlay it. The masking layer 13004 may have a smaller area than the cover layer 13002. In certain embodiments, the masking layer 13004 may be able to horizontally draw up fluid and may also function as a water-absorbing dispersion layer.

[0103] In certain embodiments, the activator layer 13006 may have any of the same features, materials, or other details as any other embodiment of the activator layer disclosed herein. For example, the activator layer 13006 may be an adhesive and may be constructed from a hydrogel or xerogel configured to have a plurality of acidic groups or acidic moieties capable of providing protons in an aqueous environment. As described elsewhere in this specification, under such acidic conditions, nitrite ions from the nitrite-providing layer 13010 may be reduced to nitric oxide for delivery to wound or intact skin. As described elsewhere in this specification and as will be understood by those skilled in the art, the activator layer may be a nitrite-providing layer or other suitable layer. The activator layer 13006 (e.g., a hydrogel layer) may include a plurality of perforations extending through the thickness of the activator layer, as described elsewhere in this specification. Multiple perforations allow wound exudate beneath or around the activator layer to be transported to one or more additional absorbent and / or evaporative layers (e.g., cover layers) above the activator layer, thus enabling or facilitating the passage of wound exudate through the activator layer to prevent excessive accumulation of wound exudate beneath the activator layer 13006. In addition, multiple perforations provide an increased surface area of ​​the activator layer, thereby increasing the absorption rate of the activator layer.

[0104] As shown in Figure 11A, in some embodiments, the water-absorbing dispersion layer 13008 may be positioned between the activator layer 13006 and the nitrite-providing layer 13010. In certain embodiments, the water-absorbing dispersion layer 13008 may be constructed to favorably draw up fluids, such as wound exudate, horizontally as they are absorbed through the layers of the dressing 13000. Such lateral draw-up of the fluid may allow for maximum dispersion of the fluid through the activator layer 13006, allowing the activator layer 13006 to reach its full retention capacity. Furthermore, the water-absorbing dispersion layer 13008 may facilitate the generation of nitric oxide because the nitrite ions dissolved in the fluid can spread more rapidly across the surface of the activator layer 13006. Some embodiments of the water-absorbing dispersion layer 13008 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these materials, and the material may be needle-punched. Some embodiments of the water-absorbing dispersion layer 13008 may contain cellulose in the range of 40 to 160 gsm (or about 40 to about 160 gsm), for example, 80 (or about 80) gsm. Some embodiments of the water-absorbing dispersion layer 13008 may contain polyethylene in the range of 40 to 150 grams / square meter (gsm). In some embodiments, the water-absorbing dispersion layer 13008 may have a thickness of 1.2 mm or about 1.2 mm, or a thickness in the range of about 0.5 mm to about 3.0 mm, about 0.5 mm to about 3.0 mm, 0.7 mm to 2.5 mm, 0.9 mm to 2.1 mm, or 1.1 mm to 1.5 mm. In certain embodiments, the water-absorbing dispersion layer 13008 may be constructed from a material that can withstand compression at the level of negative pressure commonly applied during negative pressure therapy.

[0105] The water-absorbing dispersion layer 13008 may contain a plurality of loosely wrapped fibers that can be arranged within a substantially horizontal fibrous network. In some embodiments, the water-absorbing dispersion layer 13008 may consist of a mixture of two fiber types. One may be a flat fiber that is 20 μm to 50 μm wide, or about 20 μm to about 50 μm wide, and may contain a cellulosic material. The other fiber may be a two-component fiber having an inner core that is 8 μm to 10 μm in diameter, about 8 μm to about 10 μm in diameter, 7 μm to 11 μm in diameter, 6 μm to 12 μm in diameter, or 5 μm to 13 μm in diameter, and an outer layer having a thickness of 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm. The two-component fiber may be a mixture of polyethylene (PE) type material and polyethylene terephthalate (PET). In some embodiments, the core of the two-component fiber may be PET, and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may contain about 60% to about 90% cellulose fibers, for example, about 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, for example, about 25% PE / PET fibers. In some embodiments, the water-absorbing dispersion layer 13008 may contain segmented microfibers.

[0106] The majority of the fiber volume may extend horizontally (i.e., parallel to the top and bottom planes of the material), or substantially or nearly horizontally. In another embodiment, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In yet another embodiment, all or substantially all of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some embodiments, the majority of the fibers, 80% to 90% (or about 80% to about 90%) or more, or even all or substantially all of the fibers, extend over a distance (horizontal or transverse distance) perpendicular to the thickness of the water-absorbing dispersion layer 13008, which is greater than the thickness of the water-absorbing dispersion layer 13008. In some embodiments, the horizontal or transverse distance covered by such fibers is at least twice (or about twice), three times (or about three times), four times (or about four times), five times (or about five times), or ten times (or about ten times) the thickness of the water-absorbing dispersion layer 13008. Such fiber orientation can promote the transverse wicking of fluid through the water-absorbing dispersion layer 13008. This allows for a more even distribution of fluids, such as wound exudate, across the entire water-absorbing dispersion layer 13008. In some embodiments, the ratio of the amount of fluid wicked transversely across the water-absorbing dispersion layer 13008 to the amount of fluid wicked vertically through the water-absorbing dispersion layer 13008 under negative pressure may be 2:1 or about 2:1 or more, or in some embodiments, up to 10:1 or about 10:1 or more.

[0107] Continuing with Figure 11A, in an embodiment, the nitrite supply layer 13010 may be provided beneath the water absorption dispersion layer 13008. Such a nitrite supply layer 13010 may have any of the same features, materials, or other details as any other embodiment of the nitrite supply layer disclosed herein, for example, the nitrite supply layer 13010 may be a nitrite supply layer. For example, the nitrite supply layer may be a wet mesh immersed in a sodium nitrite solution. In some embodiments, the nitrite supply layer 13010 may be dry and may contain a dry nitrite source such as dry sodium nitrite. Such dry sodium nitrite may be loaded into a material layer, which is constructed from a suitable material such as any material disclosed herein. As will be understood by those skilled in the art, dry materials and / or substances are those that do not contain or contain relatively little liquid. For example, polypropylene, polyethylene, or melt-extrudeable fibers may be suitable materials for such a layer. In embodiments, such a nitrite-providing layer 13010 may need to be initially separated from the activator layer 13006 when the activator layer is a hydrogel, in order to avoid reactions and nitric oxide generation before application to the wound and / or skin. As shown in Figure 11A, a dry fluid-absorbing dispersion layer 13008 may play a role in separating the nitrite-providing layer 13010 and the hydrogel activator layer 13006 before application. However, such a dry sodium nitrite-providing layer may be adjacent to the xerogel activator layer 13006, as this would prevent the xerogel from becoming wet. In the case of a xerogel, activation may occur when it comes into contact with a fluid such as wound exudate as the wound exudate is drawn up through the dressing. In the case of hydrogels, when a fluid such as wound exudate comes into contact with the water-absorbing dispersion layer 13008, nitrite ions may then come into contact with the acidic environment generated by the activator layer, thereby generating nitric oxide that can then migrate into the wound and / or skin. In some embodiments, each of the layers, such as the nitrite-providing layer, the activator layer, and any other suitable layer, may be dried and stored before use. Before application to skin or wound, the layers may be moistened with a suitable liquid such as saline solution.

[0108] As illustrated in Figure 11B, to maintain nitric oxide release, several layers containing dry sodium nitrite may be present, for example, a first nitrite-providing layer 13010 and a second nitrite-providing layer 13012, which will be "activated" when the wound fluid reaches and wets the layers, allowing the sodium nitrite to come into contact with the acidic groups of the hydrogel or xerogel of the activator layer 13006, thereby generating nitric oxide. In certain embodiments, there may be two, three, four, five, six or more layers containing dry sodium nitrite. As shown in Figure 11B, a masking layer 13004 may serve to prevent contact between the second nitrite-providing layer 13012 and the activator layer 13006. In certain embodiments, additional water-absorbing dispersions and / or masking layers may be sandwiched between the activator layers to provide an additional source of nitric oxide.

[0109] As illustrated in Figures 11C and 11D, in some embodiments, the activator layer 13006 may be positioned beneath the nitrite-providing layer, thereby wetting the nitrite-providing layer 13010 (e.g., from wound exudate) and allowing it to become dependent on the activating dressing.

[0110] As illustrated in Figure 11E, in some embodiments, the wound dressing 13000 may have a cover layer 13002 as its top layer, as described herein. For example, the cover layer 13002 may include an IV3000 top film and a boundary. A masking or concealing layer 13004 as described herein may be located below at least a portion of the cover layer 13002. For example, the masking layer 13004 may include a 17gsm polypropylene mesh. An activator layer 13006 as described herein may be located below the masking layer 13004. For example, the activator layer 13006 may include a hydrogel-filled DuraFiber, such as a 50% AMPS sodium-based hydrogel, along with sodium isoascorbate as a reducing agent and a diacrylamide crosslinking agent. A nitrite-providing layer 13010 as described herein may be located below the activator layer 13006. The nitrite-providing layer 13010 may be an integral part of the wound dressing 13000, or it may be provided as a separate component used together with the wound dressing 13000 (for example, provided in separate packaging from the wound dressing 13000).

[0111] Hydrogel-based wound dressing formulation that delivers nitric oxide As mentioned above, under normal atmospheric conditions, nitric oxide (NO) is a short-lived and unstable gaseous substance. This instability stems from unpaired electrons in nitrogen, and as an unstable substance with unpaired electrons, nitric oxide can be described as a free radical. However, compared to typical free radicals (e.g., hydroxyl radicals or superoxide) with lifetimes of several milliseconds, nitric oxide is relatively stable and is typically converted to a more stable chemical species within seconds of its formation. Therefore, for example, when gaseous nitric oxide comes into contact with air, it rapidly reacts with oxygen to produce nitrogen dioxide, as follows:

[0112] 2NO + O2 → 2NO2 + N2O4

[0113] Furthermore, while nitric oxide (NO2) can exhibit antibacterial properties, it does not possess vasodilatory properties or the ability to activate cell proliferation. Therefore, it is generally desirable to reduce the generation of nitric oxide as much as possible during nitrite acidification by means of reducing the oxidation of dissolved nitric oxide (NO) by removing oxygen from the hydrogel body where nitrite acidification occurs.

[0114] Under certain conditions, for example, when in a pure gaseous state, NO can be stored for very long periods without significant loss. NO is a highly hydrophobic compound and therefore has limited solubility in water. The maximum solubility of NO in water achievable under normal conditions is about 1.7 mM, and its solubility is similar to that of oxygen. Oxidation of dissolved nitric oxide by dissolved oxygen occurs in aqueous solution. Nevertheless, considering the rate constants and low concentrations of dissolved NO and O2, this reaction is considerably slower than the reaction in a gaseous state where the oxygen concentration is very high. In particular, some embodiments disclosed herein advantageously reduce the oxidation of dissolved nitric oxide (NO) by removing oxygen from the hydrogel body in which acidification of nitrite occurs.

[0115] Those skilled in the art will understand that the nitric oxide generating layers or nitrite-providing layers described herein, in particular those described above and elsewhere in this specification, relating to Figures 1-5, 11A-11E, 12 and 13, may include both a nitric oxide source element (such as a nitrite-providing element disclosed herein) and an activator (such as an acid-providing element disclosed herein), for example, both a nitrite-providing layer such as a nitrite-providing layer disclosed herein and an activator layer such as an acid-providing layer disclosed herein. The interaction between the nitrite-providing element and the acid-providing element may result in the formation of nitric oxide suitable for delivery to a wound via a suitable means. Those skilled in the art will further understand that the following formulations may be used with any of the embodiments described herein, for example, the wound dressings and apparatus of Figures 1-5, 11A-11E, 12 and 13.

[0116] As will be understood by those skilled in the art, hydrogels can be constructed from a variety of polymers, such as polyethylene glycol (PEG), hydrophilic polyurethanes, polyvinyl alcohol, polyvinipyrrolidone, or other suitable polymers. Such hydrogels may be crosslinked via suitable multifunctional reagents, condensation, polymerization, irradiation, physical crosslinking, or other suitable means. Those skilled in the art will understand that, in the case of polyethylene glycol hydrogels, any suitable crosslinking molecule such as N,N'-methylenebisacrylamide may be used. As will be further understood by those skilled in the art, conventional crosslinking agents are used to provide the necessary mechanical stability and to control the adhesive properties of the composition. In certain embodiments, crosslinking agents may include tripropylene glycol diacrylate, ethylene glycol dimethacrylate, alkoxylated triacrylate, polyethylene glycol diacrylate (PEG400 or PEG600), and / or methylenebisacrylamide. Those skilled in the art will also understand that acidic functional groups may be introduced into the hydrogel system to generate nitric oxide. For example, suitable reagents for introducing such functional groups include silane coupling agents (such as those provided by Gelest). In some embodiments, these silane coupling agents can provide triethoxysilane or multisilanol-terminated groups that react with abundant surface hydroxyl groups on cellulosic substrates, resulting in pendant groups having carboxylate / carboxylic acid or sulfonate / sulfonic acid groups. The carboxylate / carboxylic acid and sulfonate / sulfonic acid groups are described in more detail below.

[0117] In some embodiments, the acid-providing layer, such as a hydrogel-based wound dressing formulation, may include a copolymer in which monomers are functionalized with covalently bonded acidic functional groups having formula I.

[0118] [ka]

[0119] (wherein, R 1 is optionally substituted C1-4 alkyl, -CH2COOR 3 , -CH2SO2R 3 , and -CH2P(O)(OR 3 )2, and R 2 is optionally substituted C1-4 alkyl, -COOR 3 , and -SO2R 3 , -PO(OR 3 )2, and R 3 is -H, and is selected from the group consisting of optionally substituted C1-4 alkyl and cations).

[0120] In some embodiments of Formula I, R 3 may be a cation such as a sodium ion, a potassium ion, a lithium ion, an ammonium ion, a trimethylammonium ion, or any other suitable cation.

[0121] In some embodiments of Formula I, the monomer may be crotonic acid, itaconic acid, fumaric acid, maleic acid, vinylphosphonic acid, vinylsulfonic acid and their salts, or any other suitable monomer.

[0122] As described in the embodiments above and disclosed below, suitable monomers exhibiting both unsaturation (i.e., a moiety that can be incorporated into the acrylic copolymer via UV or radical-initiated polymerization) and sufficient acidity can lead to the efficient production of nitric oxide from nitrites. Furthermore, these alternative monomers may offer advantages with respect to some examples that provide multifunctionality. In particular, the carboxylic acid monomers described herein may provide two or more carboxylic acid groups per monomer unit, and thus more acidic functional groups may be presented in an equal amount of material compared to acrylic acid (AA) or 2-acrylamide 2-methylpropanesulfone (AMPS) based systems. In some embodiments, such arrangements may offer advantages in controlling the yield of the desired NO product or other factors in controlling the profile of the product produced upon activation with a nitrite source.

[0123] Those skilled in the art will understand that polymerization of the hydrogels disclosed herein, e.g., 2,2-dimethoxy-2-phenylacetophenone, ferrous sulfate heptahydrate, hydrogen peroxide, potassium sulfite, potassium persulfate, hot thiosulfate, or mixtures thereof, can be initiated using a suitable amount of any suitable initiator. Further details regarding initiators can be found in U.S. Patent No. 4581821, which is incorporated herein by reference. Further examples of photoinitiators include 1-hydroxycyclohexylphenyl ketone and 2-hydroxy-2-methylpropiophenone. The energy source for initiating polymerization may be any suitable energy source described herein, e.g., light (e.g., ultraviolet light), radiation (e.g., gamma radiation), heat, chemicals, or any suitable energy source.

[0124] In certain embodiments, the hydrogel-based wound dressing formulation may include a copolymer in which monomers are functionalized with covalently bonded reducing agent functional groups having formula II.

[0125] [ka]

[0126] (In the formula, R 4 and R 5 These are independently -H, optionally substituted C1-4 alkyl, and optionally substituted C 6-10 Aryl and C which can be optionally replaced. 6-10 Selected from the group including aralkyl, X is selected from the group consisting of optionally substituted C1-4 alkyl, -CH2COO-, -COO-, -CH2SO2-, -SO-, -SO2-, -CH2CONH-, -CONH-, -P(O)(O)-, and -CH2P(O)(O)-, and Y is optionally substituted C1-4 alkyl, optionally substituted C 3-7 Carbocyclyl, PEG chain, sugar unit, optionally substituted C 6-10 Aryl and C which can be optionally replaced. 6-10 Selected from the group consisting of aralkyls, R 6 m is a reducing agent functional group selected from the group consisting of iodide anions, butylated hydroquinone, tocopherol, butylated hydroxylanisole, butylated hydroxytoluene (2,3-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, beta-carotene, or any preferred group). In certain embodiments, m may be an integer between 1 and 2, and n may be an integer between 0 and 4. In some embodiments, m may be in the range of 2 to 10 or more, while n may be in the range of 4 to 10 or more. In certain embodiments, m or n may be any preferred integer.

[0127] In some embodiments of Formula II, the covalently bonded reducing agent functional group of the monomer may include a 3,4-dihydroxyphenyl group, a 2,3-dihydroxyphenyl group, or any other suitable functional group.

[0128] As disclosed in the embodiments described above and elsewhere in this specification, suitable monomers that exhibit covalently bonded functional groups that remain attached to the hydrogel structure and can act as reducing agents in NO production chemistry may offer advantages in terms of safety and control.

[0129] In certain embodiments, nitric oxide can be produced by the chemical reduction of nitrite. Nitrite may be reduced using many different reducing agents, and physiologically acceptable examples of such reducing agents include, but are not limited to, iodide anions, ascorbic acid, butylated quinones, tocopherols, or any suitable reducing agent. Nitrite is a weak acid with a pKa of 3.4, and therefore at a pH of about 3.4, nitrite is composed of nitrite (HNO2) and nitrite anion (NO2). -1 It exists as an equimolar mixture of nitrite anions. At higher pH values, the equilibrium shifts favorably to nitrite anions, and at lower pH values, the equilibrium shifts favorably to nitrite. Since nitrite can be chemically reduced to nitric oxide, the efficiency of converting nitrite to nitric oxide can increase with decreasing pH. Thus, in some embodiments, such conversion rates are negligible at pH about 6, proceed slowly at pH about 5, very fast at pH < 4, and especially fast at pH < 3.

[0130] In embodiments, hydrogel systems primarily based on sodium salts of AMPS containing relatively small amounts of either strongly acidic AMPS acid and / or weakly acidic AA can provide a sufficiently acidic environment. Furthermore, non-thiol reducing agents that are not acidic and have a pKa of about 1 to 4 may be used as reducing agents in these systems. Reducing agents may be present in any suitable component of the wound dressing system. Examples of suitable reducing agents include, but are not limited to, iodide anions, butylated hydroquinone, hydroquinone, hydroquinone 63 ariants, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, ascorbates, ascorbate variants, isoascorbates, isoascorbate variants, and any other suitable reducing agents. The reducing agent is typically present in concentrations of about 0.01%–5% (w / w), 0.01%–0.1% (w / w), 0.05%–0.1% (w / w), 0.1%–0.2% (w / w), 0.3%–0.4% (w / w), 0.1%–5% (w / w), 0.5%–4% (w / w), 1%–3% (w / w), or about 2% (w / w), depending on the coating material. The inclusion of a covalently bonded reducing agent in the monomer, as disclosed in the embodiments above, may advantageously provide safety and regulatory benefits.

[0131] In some embodiments, the hydrogel-based wound dressing formulations described herein include monomers according to formula I and / or formula II. In certain embodiments, the hydrogel-based wound dressing formulations described herein further include oxygen scavengers, such as glucose, glucose peroxidase, iron-based scavengers such as nanoiron particles, boron-based scavengers such as nanoboron particles, and electrolytes such as sodium chloride. The oxygen scavengers may be incorporated into the formulation by any suitable means, for example, by dissolution, absorption, adsorption, and / or attachment to the polymer structure. Such oxygen scavengers may require protection from aqueous environments, such as any of the hydrogels disclosed herein, and therefore may be encapsulated from the aqueous portion or incorporated into the polymer composite within the gel body. Such oxygen scavengers may also advantageously remove oxygen from the hydrogel during storage over a period of time, thereby potentially improving the efficiency of nitric oxide production. In certain embodiments, the dressing may be manufactured in an inert environment to prevent oxygen intrusion during manufacturing. These coatings may also be sealed to prevent oxygen intrusion before application.

[0132] Hydrogel-based wound dressings: As illustrated in Figures 12 and 13, in some embodiments, the hydrogel-based wound dressing system 4100 may be placed on intact skin such as a wound and / or surrounding area and may include a first acid-providing layer 4210 containing a copolymer of monomers having covalently bonded polyfunctional groups, where the monomer is of formula I (wherein R 1 is -CH2SO2R 3 Or -CH2P(O)(OR 3 )2, or any suitable group, R 2 is -SO2R 3 Or -PO(OR 3 )2, or any suitable group, R 3It is functionalized with a covalently bonded acidic functional group having -H and optionally substituted C1-4 alkyl or any preferred group.

[0133] In certain embodiments, the second acid-providing layer 4310 may be located above the first acid-providing layer and contains a copolymer of monomers having covalently bonded polyfunctional groups, wherein the monomer is of formula I (wherein R 1 C is replaced by any choice. 1-4 Alkyl, -CH2COOR 3 It may be R 2 C is replaced by any choice. 1-4 Alkyl and -COOR 3 It may be R 3 C is replaced by -H and optionally. 1-4 It is functionalized with covalently bonded acidic functional groups (which may be alkyl and cationic). Those skilled in the art will understand that the acid-providing layers may be in any order, such as first on second or second on first.

[0134] In some embodiments, hydrogel-based wound formulations and dressing systems may be water-free or substantially water-free. For example, the acid-providing layer described in the embodiments herein may be in the form of either a xerogel (allowing the hydrogel to change its dimensions during the gradual removal / reduction of water content) or an aerogel (where water is rapidly removed via supercritical fluid or freeze-drying, resulting in less impact on the hydrogel's structure). In some embodiments, hydrogel-based wound formulations and dressing systems may have a moisture content (e.g., water content) of less than about 1%, less than about 2%, less than about 3%, less than about 4%, or less than about 5%.

[0135] In certain embodiments, the acidic component in a wound dressing system in the form of a xerogel / aerogel may result in a reduction in the weight of the dressing system, which may be advantageous for wound dressing products (lighter, lower profile products). The physical properties of the system may also be advantageous (e.g., different absorption rates may also reflect a unique NO generation profile). As described above, in certain embodiments, the hydrogel-based wound dressing system 4100 may include a first acid-providing layer 4210 containing a copolymer of monomers having covalently bonded polyfunctional groups, and a second acid-providing layer 4310 above the first acid-providing layer containing a copolymer of monomers having covalently bonded polyfunctional groups. In particular, embodiments of the present disclosure allow for blending or combining two acidic monomers. For example, such embodiments may be achieved through the formulation of a single gel layer, or by constructing gel layers consisting of "stacks" or patterning, thereby allowing different layers / regions to consist of different acidic property types. Such stacked arrangements may include two, three, four, or five or more different acid-providing layers. The stack may include two, three, four, five, or six or more acid-providing layers. In certain embodiments, one or more layers may be non-acidic layers, for example, one, two, three, four, five, or six or more non-acidic layers.

[0136] In embodiments, the release profile can be controlled by fabricating a hydrogel-based wound dressing system consisting of appropriate amounts of both strong and weak acids attached to a polymer structure. In certain embodiments, the hydrogel may be constructed from layers or patterned regions containing strong and / or weak acids. Thus, acids of different intensities may be layered or patterned throughout the entire profile of the finished hydrogel sheet. For example, a strong acid environment may be positioned on the wound-facing side to result in very rapid NO release (efficient nitrite conversion), while a weak acid may be positioned as a subsequent further layer removed from the wound to result in a slower nitrite-to-NO conversion (thus providing a more sustained element of the release profile as the provided nitrite solution is drawn through the hydrogel stack).

[0137] Returning to Figures 12-13, the hydrogel-based wound dressing system 4100 may include a nitrite-providing layer 4410. As shown in the figure, the nitrite-providing layer may be above or below the acid-providing layer(s). In some embodiments, the nitrite source may be a suitable material layer containing alkali metal nitrites and / or alkaline earth metal nitrites. In certain embodiments, the nitrite may include LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2, Ra(NO2)2, or any other suitable nitrite. In certain embodiments, the nitrite-providing layer may contain sodium nitrite. In some embodiments, the other nitrite ion source may be nitrate ions derived from alkali metal salts or alkaline earth metal salts that are enzymatically convertible to nitrites. For example, LiNO3, NaNO3, KNO3, RbNO3, CsNO3, FrNO3, Be(NO3)2, Mg(NO3)2, Ca(NO3)2, Sr(NO3)2, Ba(NO3)2, Ra(NO3)2, or any other suitable molecule.

[0138] In certain embodiments, the acid-providing layer, as described above and elsewhere in this specification, may contain covalently bonded acidic functional groups and, therefore, can generate nitric oxide upon contact with a suitable nitrite source such as an alkali metal nitrite. In embodiments, covalent functionalization, surface coating, or plasma functionalization of a suitable polymer wound dressing material can suitably make the dressing material inherently acidic, thereby efficiently converting nitrites to NO.

[0139] Hydrogels containing and without antioxidants and / or reducing agents, with and without various crosslinking agents. Figure 14 shows process 5000 for hydrogel generation according to several embodiments. The activator layer of the wound dressing described herein may include the hydrogel produced by process 5000. Although several process steps are shown in Figure 14, it should be understood that not all process steps are necessary, and some may be optional. Furthermore, the order in which the process steps in Figure 14 are performed may be modified or rearranged, and additional process steps not shown may be added at any appropriate step of the process. As shown, process 5000 for hydrogel production may include steps 5002 of providing a stirred AMPS sodium solution to produce a mixture, step 5004 of adding an acid to the mixture, step 5006 of adding a wetting agent to the mixture, step 5008 of adding an antioxidant and / or reducing agent to the mixture, step 5010 of adding a crosslinking agent to the mixture, step 5012 of adding an initiator to the mixture, step 5014 of transferring the mixture to a mold, step 5016 of curing the mixture in the mold to produce a hydrogel, and step 5018 of packaging the hydrogel.

[0140] As shown in Figure 14, process 5000 for producing a hydrogel may include step 5002 of providing a stirred AMPS sodium solution (e.g., an aqueous solution of 2-acrylamido-2-methyl-1-propanesulfonate sodium) to produce a mixture. In some embodiments, the AMPS sodium solution includes a 50% w / w solution, but other concentrations may be used. In some embodiments, the container containing the stirred AMPS sodium solution may be surrounded by a water bath maintained at about 10°C to about 15°C, about 10°C, or about 15°C. In some embodiments, the stirred AMPS sodium solution may be stirred to form a significant vortex without introducing air.

[0141] As further shown in Figure 14, process 5000 for generating the hydrogel may additionally include step 5004 of adding an acid to the mixture. The acid may include acrylic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS acid), any suitable acid that can react with the hydrogel structure, and / or combinations thereof. In some embodiments, the acid may include any of the acids described herein and / or combinations of any of the acids described herein.

[0142] As further shown in Figure 14, the process 5000 for producing the hydrogel may additionally include a step 5006 for adding a wetting agent to the mixture. The wetting agent may include glycerol, propylene glycol, any of the wetting agents described herein, and / or any combination thereof. In some embodiments, the step 5006 for adding a wetting agent to the mixture may be omitted.

[0143] As further shown in Figure 14, process 5000 for producing a hydrogel may additionally include step 5008 of adding an antioxidant and / or reducing agent to the mixture. The antioxidant and / or reducing agent may include sodium isoascorbate, iodide anion, butylated hydroquinone, hydroquinone, hydroquinone 68 ariants, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, ascorbic acid, potassium iodide, ascorbate, ascorbic acid variant, isoascorbate, isoascorbic acid variant, any other suitable reducing agent, and / or any of the antioxidants and / or reducing agents described herein. Antioxidants and / or reducing agents may be present in concentrations of about 0.01% to 5% (w / w), 0.01% to 0.1% (w / w), 0.05% to 0.1% (w / w), 0.1% to 0.2% (w / w), 0.3% to 0.4% (w / w), 0.1% to 5% (w / w), 0.5% to 4% (w / w), 1% to 3% (w / w), or about 2% (w / w). In some embodiments, the ratio of the amount of antioxidant and / or reducing agent to the amount of acid may be about 1:2, about 1:1.5, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, or about 1:2 to about 1:0.3. In some embodiments, step 5008, which involves adding antioxidants and / or reducing agents, may be omitted. In some embodiments, step 5008, which involves adding antioxidants and / or reducing agents to the mixture, may be performed near the end of process 5000, such as after step 5010, which involves adding a crosslinking agent to the mixture, or after step 5012, which involves adding an initiator to the mixture, and before step 5014, which involves transferring the mixture to a mold. In such embodiments, the addition of antioxidants and / or reducing agents can be advantageous in preventing or reducing pregelation of the mixture.

[0144] As further shown in Figure 14, process 5000 for producing a hydrogel may additionally include step 5010 of adding a crosslinking agent to the mixture. In some embodiments, the crosslinking agent may include acrylate, dimethacrylate, and / or acrylamide crosslinking agents. In some embodiments, the acrylate crosslinking agent may include PEG diacrylate Mn575. In some embodiments, the dimethacrylate crosslinking agent may include PEG dimethacrylate Mn550. In some embodiments, the acrylamide crosslinking agent may include piperazine diacrylamide. In some embodiments, the crosslinking agent may include tripropylene glycol diacrylate, ethylene glycol dimethacrylate, alkoxylated triacrylate, polyethylene glycol diacrylate (PEG400 or PEG600), and / or methylenebisacrylamide. In some embodiments, the crosslinking agent may include any of the crosslinking agents described herein and / or any combination of the crosslinking agents described herein. In some embodiments, the crosslinking agent may reduce and / or prevent hydrolysis of the hydrogel. For example, dimethacrylate and / or acrylamide crosslinking agents can reduce and / or prevent the hydrolysis of a hydrogel containing the crosslinking agent(s). In some embodiments, the crosslinking agent that reduces and / or prevents the hydrolysis of the hydrogel can improve the mechanical stability of the hydrogel.

[0145] As further shown in Figure 14, process 5000 for generating the hydrogel may additionally include step 5012 of adding an initiator to the mixture. The initiator may include a photoinitiator, a thermal initiator, any of the initiators described herein, or any initiator configured to induce polymerization. In some embodiments, the initiator may include 2-hydroxy-2-methylpropiophenone, 2,2-dimethoxy-2-phenylacetophenone, ferrous sulfate heptahydrate, hydrogen peroxide, potassium bisulfite, potassium persulfate, thermal thiosulfate, and / or mixtures thereof. Further details regarding initiators can be found in U.S. Patent No. 4581821, which is incorporated herein by reference. Further examples of photoinitiators include 1-hydroxycyclohexylphenyl ketone and 2-hydroxy-2-methylpropiophenone.

[0146] As further shown in Figure 14, process 5000 for producing a hydrogel may additionally include step 5014 of transferring the mixture to a mold. Process 5000 may additionally include step 5016 of curing the mixture in the mold to produce a hydrogel. The mold may include a Teflon-coated aluminum mold or any mold suitable for releasing the hydrogel after it has been formed. The energy source for initiating polymerization / curing may be any suitable source as described herein, e.g., light (such as ultraviolet light), radiation (such as gamma), heat, chemicals, or any suitable energy source.

[0147] As further shown in Figure 14, the process 5000 for producing the hydrogel may additionally include a step 5018 for packaging the hydrogel. In some embodiments, packaging the hydrogel may include packaging a wound dressing containing the hydrogel. In some embodiments, packaging the hydrogel may be carried out in the absence of oxygen and / or in a low-oxygen environment. In some embodiments, packaging the hydrogel may be carried out under reduced pressure and / or vacuum. In some embodiments, packaging the hydrogel may be carried out in an inert environment and / or in the presence of an inert gas (e.g., argon and / or nitrogen). In some embodiments, the packaging used to package the hydrogel may be airtight and / or may prevent oxygen outside the packaging from interacting with the hydrogel and / or wound dressing until the packaging is opened. In some embodiments, the packaging used to package the hydrogel may be oxygen-excluding. In some embodiments, oxygen scrubbing may be used to remove oxygen from the packaging. In some embodiments, the packaging may include foil packaging. In some embodiments, the packaging may include an oxygen absorber packaged in a hydrogel and / or a wound dressing containing a hydrogel. Once sealed within the packaging, the oxygen absorber can remove oxygen from the wound dressing and / or its components, such as the hydrogel / activator layer and the nitrite-providing layer. In some embodiments, once sealed, the oxygen absorber can remove oxygen from within the packaging. In some embodiments, sodium isoascorbate in a hydrogel containing sodium isoascorbate can capture oxygen in the wound dressing and / or its components, such as the nitrite-providing layer and / or the activator layer, and / or reduce the oxygen content. In some embodiments, sodium isoascorbate in a hydrogel containing sodium isoascorbate can capture residual oxygen content within the packaging.In some embodiments, a hydrogel containing sodium isoascorbate may contain a sacrificial amount of sodium isoascorbate to capture and / or reduce oxygen in and / or around the wound dressing and its components, as described herein.

[0148] In some embodiments, process 5000 for generating the hydrogel may additionally include a step of adding an oxygen scavenger to the mixture before transferring the mixture to a mold, as in step 5014. The oxygen scavenger may include glucose, glucose peroxidase, iron-based scavengers, any of the oxygen scavengers described herein, and / or any mixture thereof. In some embodiments, the oxygen scavenger may include an antioxidant described herein, such as sodium isoascorbate.

[0149] In some embodiments, one or more steps of process 5000 may be carried out in an environment that minimizes the oxygen content of the hydrogel produced by process 5000. In some embodiments, one or more steps of process 5000 may be carried out in the absence of oxygen and / or in a low-oxygen environment. In some embodiments, one or more steps of process 5000 may be carried out under reduced pressure and / or vacuum. In some embodiments, one or more steps of process 5000 may be carried out in an inert environment and / or in the presence of an inert gas such as argon and / or nitrogen. In some embodiments, the hydrogel after being produced by process 5000 may be degassed and / or subjected to a vacuum cycle. In some embodiments, the nitrite supply layer and / or its components described herein (e.g., a sodium nitrite solution saturating the mesh of the nitrite supply layer) may be degassed and / or subjected to a vacuum cycle. In some embodiments, the wound dressing described herein may be degassed and / or subjected to a vacuum cycle. In some embodiments, one or more steps of process 5000 may be carried out in a low-light environment and / or an environment that minimizes curing of the mixture until desired in step 5016 of process 5000. In some embodiments, the dissolved oxygen content in the hydrogel produced by process 5000 may be about 200 ppb, about 250 ppb, about 300 ppb, about 400 ppb, about 500 ppb, or less than about 1000 ppb. In some embodiments, a wound dressing containing a hydrogel produced and packaged by process 5000 with minimized oxygen exposure / content may increase the nitric oxide generating capacity of the wound dressing. In some embodiments, a wound dressing containing a hydrogel produced and packaged by process 5000 with minimized oxygen exposure / content may increase the ratio of nitric oxide to nitrogen dioxide produced by the wound dressing (e.g., when the wound dressing is placed on a wound).

[0150] In some embodiments, the hydrogel produced by process 5000 may include rheometrically evaluated Tan D values ​​below approximately 0.35, approximately 0.45, approximately 0.55, approximately 0.65, and / or below any approximate Tan D value that provides optimal hydrogel properties. In some embodiments, the wound dressing containing the hydrogel produced by process 5000 may include rheometrically evaluated Tan D values ​​below approximately 0.35, approximately 0.45, approximately 0.55, approximately 0.65, and / or below any approximate Tan D value that provides optimal wound dressing properties. In some embodiments, the wound dressing comprising the hydrogel produced by process 5000 may have a rheometry-evaluated Tan D value that remains below approximately 0.35, approximately 0.45, approximately 0.55, approximately 0.65, and / or any approximate Tan D value that provides optimal wound dressing properties, from the time it is packaged until the package is opened. In some embodiments, the wound dressing comprising the hydrogel produced by process 5000 may remain substantially colorless from the time it is packaged until the package is opened.

[0151] The hydrogel produced by process 5000 may be used in any of the wound dressings described herein. In some embodiments, the activator layer (and / or acid-providing layer) described herein may include the hydrogel produced by process 5000. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 may additionally include the nitrite-providing layer described herein. In some embodiments, the hydrogel produced by process 5000 may be configured to donate protons to the nitrite-providing layer to produce the nitric oxide described herein. In some embodiments, the nitrite-providing layer may include sodium nitrite. In some embodiments, the nitrite-providing layer may comprise a mesh. In some embodiments, the nitrite-providing layer may comprise a saturated polypropylene mesh. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 may additionally include any other layers and / or embodiments of the wound dressing described herein, such as a water-absorbing dispersion layer, a cover layer, and / or a masking layer.

[0152] As will be understood by those skilled in the art, a hydrogel having the desired properties may be produced by utilizing any amount of the embodiments / components described in process 5000 for producing a hydrogel. For example, in some embodiments, a standard amount or two, three, or four times the required amount of crosslinking agent may be used in process 5000. In another example, in some embodiments, a standard amount or two times the required amount of initiator may be used in process 5000. In yet another example, in some embodiments, a standard amount or two, three, or any excess amount of antioxidant and / or reducing agent may be used in process 5000. Furthermore, the hydrogel produced by process 5000 may have any desired thickness, length, and width. In some embodiments, the hydrogel may consist of one, two, three, or more layers, which may be prepared by successively transferring the mixture into a mold and curing one layer on top of another, or by placing the produced hydrogel on top of another. In some embodiments, each layer of a hydrogel consisting of multiple layers may consist of the same or different formulations.

[0153] In some embodiments, the hydrogel may contain antioxidants and / or reducing agents, as described in process 5000 for generating the hydrogel. The antioxidants and / or reducing agents may promote the generation of nitric oxide by the wound dressing containing the hydrogel. In some embodiments, a wound dressing containing a hydrogel with antioxidants and / or reducing agents may produce a greater amount of nitric oxide than that produced by a wound dressing containing a hydrogel without antioxidants and / or reducing agents. In some embodiments, a wound dressing containing a hydrogel with antioxidants and / or reducing agents may produce 2, 5, 10, or 20 times more nitric oxide than that produced by a hydrogel without antioxidants and / or reducing agents. In some embodiments, a wound dressing containing a hydrogel with antioxidants and / or reducing agents may produce a nitric oxide-to-nitrogen dioxide ratio greater than that produced by a wound dressing containing a hydrogel without antioxidants and / or reducing agents. In some embodiments, wound dressings comprising a hydrogel having an antioxidant and / or reducing agent can produce a ratio of nitric oxide to nitric oxide of at least 1:1, 2:1, 3:1, 4:1, or 5:1. As described herein, wound dressings that produce more nitric oxide than nitric oxide may be desirable.

[0154] Those skilled in the art will understand that the hydrogels produced and / or packed as described above can be used with any of the embodiments described herein, such as the wound dressings and apparatus shown in Figures 1-5, 11A-11E, 12, and 13.

[0155] Examples of hydrogels with various crosslinking agents that do not contain antioxidants and / or reducing agents. Figure 15 shows continuous-time data for nitric oxide and nitrogen dioxide produced by a hydrogel without the reducing agent sodium isoascorbate. An exemplary process for preparing the hydrogel used to generate the data in Figure 15 is described below.

[0156] method A 50% aqueous solution of sodium 2-acrylamide-2-methyl-1-propanesulfonate (Na AMPS) was added to a suitably sized beaker surrounded by a water bath controlled at 15°C, equipped with an overhead propeller-type stirrer. After the AMPS acid dissolved, the following components: pre-ground 2-acrylamide-2-methyl-1-propanesulfonate (AMPS acid) and glycerol (slowly added) were added with stirring to form a significant vortex without aspiration of air. Subsequently, a selected crosslinking agent (listed in the materials section) was added, followed by the 2-hydroxy-2-methylpropiophenone photoinitiator. To facilitate the dissolution of the less soluble piperazine diacrylamide within a reasonable time, this crosslinking agent was added before the AMPS acid and glycerol, which were added only after its dissolution. The mixture was stirred for 10-20 minutes. All hydrogel mixtures used were standard 0.5 SA formulations.

[0157] The prepared prepolymer mixture was molded into a 3 mm thick hydrogel sheet by transferring 41.2 ml (53.4 g) of the mixture to an 11 × 11 × 3 cm Teflon-coated aluminum mold via a 50 ml Eppendorf pipette. First, the mold was placed on a single shelf in a UVC cabinet, then the prepolymer mixture was transferred to the mold, and subsequently exposed to UVC floodlight illumination (UVC output: approximately 1.4 mW / cm2) for 60 seconds. The cured sheet was removed from the mold and placed between silicone release paper in a sealed bag, and a batch reference was assigned.

[0158] The hydrogel sheets were cut into either 2.5 cm discs for rheometry or 3 × 3 cm squares for NOx determination (for NO and NO2 data shown in Figure 15). The gel discs or squares were triple-packed in foil packaging and sealed with either vacuum, air, or nitrogen as shown. The vacuum, nitrogen, and air-sealed pouches were subjected to gamma sterilization or left unsterilized and stored at 25C / 60%RH or 40C / 75%RH. At various time points, the gels were removed from storage and triple-evaluated for rheometry and NOx output determination.

[0159] Chemiluminescent NOx generation results: Hydrogels containing / not containing sodium isoascorbate Figure 15 shows a 1M sodium nitrite aqueous solution (NaNO). 2(水溶液) This shows the chemiluminescent Nox generation of a typical acidic AMPS-based hydrogel without sodium isoascorbate when it is brought into contact with a saturated polypropylene mesh.

[0160] As shown in Figure 15, hydrogels without sodium isoascorbate produced more nitrogen dioxide (NO2) than nitric acid (NO) upon contact with a saturated mesh. More specifically, hydrogels without sodium isoascorbate produced peaks of approximately 83,000 ppb for nitrogen dioxide and approximately 27,000 ppb for nitric acid, with the peaks occurring almost simultaneously after contact with the saturated mesh (approximately 3 minutes after contact, as shown). Quantitatively, the ratio of nitric oxide to nitrogen dioxide produced at the peaks was approximately 1:3. As shown in Figure 15, after the peaks in nitrogen dioxide and nitric acid production, the production of each decreased over time, with nitrogen dioxide production decreasing somewhat faster than nitric acid production, but its production remaining higher than that of nitric oxide.

[0161] Chemiluminescent NO / NO2 generation results: Sodium nitrite and sodium isoascorbate dispersed in PEG400 Figure 16 shows an example of chemiluminescent NO / NO2 production over 79 minutes of an exemplary acidic hydrogel having 1.0 SA in contact with a suspension produced by dispersing 0.1 g of NaNO2 and 0.1 g of NaISO (sodium isoascorbate) in 2 g of polyethylene glycol (PEG) 400. As will be understood by those skilled in the art, the materials / structures in Figures 16–18D are merely examples for use in the embodiments / examples described herein.

[0162] As shown in Figure 16, during the 46–73 minute period corresponding to the application of the PEG400 / NO2 / NaISO suspension to the hydrogel, more nitric oxide (NO) was generated than nitric oxide (NO2). These results demonstrate the suitability of PEG400 as a water-miscible anhydrous carrier for NaNO2 and NaISO mixtures and demonstrate that contact between the PEG400 / NO2 / NaISO suspension and the acidic hydrogel enabled the generation of nitric oxide. Furthermore, at approximately 22–34 minutes, corresponding to the measurement of nitric oxide generated from the PEG400 / NO2 / NaISO suspension, it was demonstrated that no detectable nitric oxide was generated from the PEG400 / NO2 / NaISO suspension before contact with the acidic hydrogel.

[0163] Antimicrobial activity results: Sodium nitrite and sodium isoascorbate dispersed in PEG400 Figures 17A–17C show examples of evaluation of the antimicrobial activity of exemplary coatings consisting of an IV3000 top layer, a hydrogel / DuraFiber composite having 1.0SA or 0.7SA, and a polypropylene (pp) mesh embedded with a PEG400 / NO2 / NaISO suspension. The 1.0SA gel can be prepared with the following components (parts by weight per 100g batch): 63.32g sodium AMPS, 0.0323g piperazine diacrylamide, 5.436g AMPS(H+), 31.19g glycerol, and 0.01629g 2-hydroxy-2-methylpropiophenone. 0.7SA gel can be prepared with the following components (parts by weight per 100g batch): 65.28g sodium AMPS, 0.0317g piperazine diacrylamide, 3.923g AMPS(H+), 30.74g glycerol, and 0.01756g 2-hydroxy-2-methylpropiophenone.

[0164] Figure 17A shows the arrangement of coating layers evaluated in the direct inoculation seal test model. 1 / 5 contains an additional 3.3% bovine serum albumin (BSA). の Triptycase soy agar (TSA) or 1 / 5 のAn insert plate containing Sabouraud dextrose agar (SDA) was prepared. Overnight cultures of the test organisms Pseudomonas aeruginosa (PA) and Candida albicans (CA) were prepared to generate an inoculum of 4 × 10⁸ CFU / ml. A 25 mm × 25 mm 17PP mesh (blank) was placed in the center of the plate and 1 M NaNO₂ was administered in either 1:1 W / W NaISO or 1:0.5 NaISO suspended in PEG400. 5 μl of the appropriate inoculum was added directly onto the composite / hybrid coating (totaling approximately 2 × 10⁶ CFU), the composite coating was made to a size of 50 mm × 50 mm, and a 6 g 1.0 SA or 0.7 SA gel was loaded. A 75 mm × 75 mm IV3000 top film was placed directly on top of the mesh to cover the steel insert, and a seal was formed within 1–3 minutes after the coating was applied. The treatment was carried out at 24 hours and 72 hours in incubation at 32°C. To evaluate microbial growth, composite material / IV3000 / PP mesh was added to 40 ml of neutralizing agent (D / E broth), fed into a gastric tube at high setting for 2 minutes, and serial dilutions were collected counted on pour plate / Petri film. All covering material elements were prepared on the same day as the experiment, gamma sterilization was not performed, and an inert atmosphere was not used.

[0165] Figure 17B shows the assembled covering material from Figure 17A for evaluating antimicrobial activity when viewed from above, and indicates the dimensions of each layer.

[0166] Figure 17C summarizes the results of the microbial evaluation in terms of mean Log10 reduction compared to the inoculated control. The DuraFiber control condition without hydrogel was determined to be inactive, as it failed to inhibit the growth of any of the test organisms. The condition containing a PP mesh embedded with 1M NaNO2 in either 1:1 W / W sodium isoascorbate or 1:0.5 NaISO suspended in PEG400 showed results comparable to previously investigated forms where NaNO2 and NaISO were not localized. The condition containing 1.0SA and hydrogel had higher-than-expected innate activity against Candida, but did not reduce to the detection limit, indicating that the NaNO2 / NaISO mixture achieved target-level activity in this model. Therefore, it was feasible to rearrange NaISO from hydrogel to mesh, co-localize it with NaNO2, and maintain the reduction of microbial growth.

[0167] Considering the results of the microbial activity evaluation, when the NaNO2:NaISO ratio (w / w) was 1:1 on the mesh, the agar area remained transparent, but this was not as apparent when the ratio decreased to 1:0.5.

[0168] Chemiluminescent NO / NO2 generation results: Sodium nitrite and sodium isoascorbate dispersed in various water-miscible anhydrous carriers. Figures 18A to 18D show exemplary chemiluminescent NO / NO2 production when a 3×3 cm composite of DuraFiber, loaded with approximately 6 g of 1.0 SA acidic hydrogel, is brought into contact with a 2.5×2.5 PP mesh embedded with a 50 μL suspension prepared by dispersing 0.1 g of NaNO2 and 0.1 g of NaISO in various water-miscible anhydrous carriers.

[0169] Figure 18A shows the generation of nitric oxide using PEG400 as a water-miscible anhydrous carrier, Figure 18B shows the results when PEG600 is used as a water-miscible anhydrous carrier, Figure 18C shows the results when a 50 / 50 w / w blend of PEG300 and PEG1500 (FLEX) is used as a water-miscible anhydrous carrier, Figure 18D shows the results when a 41 / 1 w / w blend of PEG400 and PEG4000 (SORB) is used as a water-miscible anhydrous carrier, and Figure 18E combines the results of Figures 18A to 18D on a single graph.

[0170] Exemplary wound dressing components and formulations An exemplary wound dressing may include a mesh component containing co-localized nitrite and antioxidant / reducing components. An exemplary wound dressing may include a mesh component containing embedded, co-localized sodium nitrite and sodium isoascorbate. An exemplary wound dressing may include sodium isoascorbate monohydrate. An exemplary wound dressing may include anhydrous sodium isoascorbate. The mesh component may have any number of sodium nitrite doses from about 0.5 M to about 2.5 M. An exemplary embodiment may include a 2.5 × 2.5 cm mesh loaded with any amount of nitrite and antioxidant / reducing agent suspended in a suitable carrier, from 1 to 5 mg each. An exemplary wound dressing may include a mesh component embedded with a 1:1 W / W suspension of sodium nitrite to sodium isoascorbate. An exemplary wound dressing may include a mesh component embedded with a 1:0.5 W / W suspension of sodium nitrite to sodium isoascorbate. An exemplary wound dressing may include a mesh component embedded with a 1:0.25 W / W suspension of sodium nitrite to sodium isoascorbate. The exemplary wound dressing may include a mesh component embedded with a suspension of sodium nitrite to sodium isoascorbate, where sodium nitrite and sodium isoascorbate are present in any ratio of sodium nitrite to sodium isoascorbate in the range of 1:0.1 to 1:4 W / W. An exemplary wound dressing may include a mesh component where the embedding suspension is a paste. An exemplary wound dressing may include a mesh component where the embedding suspension contains a water-soluble / water-miscible carrier. In some embodiments, the embedding suspension may be a paste. An exemplary wound dressing may include a mesh component where the embedding fluid / carrier is PEG200, PEG400, PEG600, or any blend of PEGs, triacetin, or glycerol. An exemplary wound dressing may include a mesh component in which the embedding carrier is dried through the use of molecular sieves and other techniques known in the art.An exemplary wound dressing can provide greater stability to the reducing agent because the mesh component embedded with the reducing agent and nitrite-providing component is stored under dry conditions. The exemplary wound dressing can reduce undesirable discoloration species by storing the mesh component embedded with the reducing agent and nitrite-providing component under dry conditions. In the exemplary wound dressing, the nitrite-providing layer may be provided as a separate layer in packaging separate from the wound dressing packaging. The exemplary wound dressing can provide more consistent nitric oxide production than wound dressings where the reducing agent, such as sodium isoascorbate, ferrous sulfate, or a derivative of vitamin C, is stored under aqueous conditions and undergoes a higher level of degradation. An exemplary wound dressing with a reduced agent kept dry before combination with the activation layer can reduce degradation induced by free radical action generated upon irradiation with an aqueous solution. The exemplary wound dressing may have preferable stability after sterilization compared to wound dressings where the reducing agent is stored under aqueous conditions. The exemplary wound dressing may include a cover layer, a water-absorbing dispersion layer, and / or a masking layer. An exemplary wound dressing may include an IV3000 top film and border as a cover layer, as well as a 17gsm polypropylene mesh component. The polypropylene mesh can be any mesh in the range of 5gsm to 200gsm. Exemplary wound dressings may use mesh materials other than polypropylene, including polyethylene and fluorinated materials such as polyvinylidene fluoride (PVDF). The cover layer may be configured to form a seal around the wound, and the cover layer may be breathable. In some embodiments, the wound dressing is vacuum-packed. In some embodiments, the wound dressing may contain a surfactant.

[0171] An exemplary wound dressing may include an activated layer containing an acidic hydrogel. An exemplary wound dressing may include an activated layer containing a composite material further comprising a gelled fiber substrate loaded with an acidic hydrogel. An exemplary wound dressing may include a substrate such as DuraFiber or Opsite POST-OP pad material. An exemplary wound dressing may include an aqueous solution of 2-acrylamido-2-methyl-1-propanesulfone and 2-acrylamido-2-methyl-1-propanesulfonic acid (SA). An exemplary wound dressing may include a hydrogel having any number of acidic components in the range of 2.0 SA to 0.5 SA. A 1.0 SA gel can be prepared with the following components (parts by weight per 100g batch): 63.32 g of AMPS sodium, 0.0323 g of piperazine diacrylamide, 5.436 g of AMPS(H+), 31.19 g of glycerol, and 0.01629 g of 2-hydroxy-2-methylpropiophenone. A 0.7 SA gel can be prepared with the following components (parts by weight per 100g batch): 65.28 g of AMPS sodium, 0.0317 g of piperazine diacrylamide, 3.923 g of AMPS(H+), 30.74 g of glycerol, and 0.01756 g of 2-hydroxy-2-methylpropiophenone. An exemplary wound dressing may include an activator layer configured to donate protons to a nitrite-providing layer to generate nitric oxide. An exemplary wound dressing comprising a nitrite-providing layer containing colocalized sodium nitrite and sodium isoascorbate may be configured to produce a greater nitric oxide-to-nitric oxide ratio than a wound dressing comprising a nitrite-providing layer in which sodium nitrite and sodium isoascorbate are not colocalized. The exemplary wound dressing may include activation of the nitric oxide chemistry by fluids in a separate ampoule of wound exudate, water provided by an aqueous hydrogel, and / or aqueous reagent. The exemplary wound dressing may include an application method in which an anhydrous suspension is loaded onto the area of ​​the dressing, thereby coming into contact with the acidic gel and initiating the generation of nitric oxide.An exemplary wound dressing may include an application method in which an anhydrous suspension and an acidic gel are held separate from each other by a removable handle, and after removal of the handle, the dressing is manipulated to come into contact with the anhydrous suspension and the acidic gel, thereby initiating nitric oxide generation. The exemplary wound dressing may also include a pocket comprising a composite layer loaded with an acidic hydrogel, in which the anhydrous suspension may be loaded into the pocket to initiate nitric oxide generation. The anhydrous suspension may be loaded into the pocket as part of a mesh component, or it may be applied directly to the pocket in the absence of a mesh component.

[0172] Exemplary wound dressings may involve grinding sodium nitrite and sodium isoascorbate powders to increase the surface area of ​​solid particles in a solvated dispersion, making them available for reaction and inhibiting precipitation from the suspension. Exemplary wound dressings may also involve the use of dispersants / surfactants, etc.

[0173] term Any of the above-mentioned patents and applications, as well as other references, including any that may be listed in the attached application documents, are incorporated herein by reference. Aspects of this disclosure may be modified, as necessary, to provide further implementations using the various systems, functions, and concepts of the references described herein.

[0174] Features, materials, properties, or groups described in relation to a particular aspect, embodiment, or example should be understood to be applicable to any other aspect, embodiment, or example described herein, insofar as they do not conflict with such other aspects, embodiments, or examples. All features disclosed herein (including any accompanying claims, abstract, and drawings), or any steps of any method or process disclosed herein, may be combined in any combination except for any combination in which at least some of such features or steps are mutually exclusive. The subject matter of protection is not limited to the details of any embodiment described herein. The subject matter of protection extends to any novel features or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or to any novel steps or any novel combination of steps of any method or process disclosed herein.

[0175] While certain embodiments are described, these embodiments are presented merely as examples and are not intended to limit the scope of protection. In fact, the novel methods and systems described herein may be embodied in various other forms. Furthermore, various omissions, substitutions, and modifications may be made to the methods and systems described herein. Those skilled in the art will recognize that, depending on the embodiment, the actual steps taken in the illustrated or disclosed process may differ from the steps shown in the figures. Depending on the embodiment, certain steps from the steps described above may be omitted, and others may be added. For example, the actual steps or the order of steps taken in the disclosed process may differ from those shown in the figures. Depending on the embodiment, certain steps from the steps described above may be omitted, and others may be added. Furthermore, the features and characteristics of the particular embodiments disclosed above may be combined in different ways to form additional embodiments, all of which remain within the scope of this disclosure.

[0176] This disclosure includes certain embodiments, examples, and uses, but those skilled in the art will understand that this disclosure extends beyond the scope of the specifically disclosed embodiments to other alternative embodiments or uses, as well as obvious variations and equivalents thereof, including embodiments that do not necessarily provide all of the features and advantages described herein. Therefore, the scope of this disclosure is not intended to be limited by the embodiments described, but may be defined by the claims presented herein or thereafter.

[0177] Conditional statements such as “can,” “could,” “might,” or “may,” unless otherwise specifically stated or interpreted within the context in which they are used, are typically intended to convey that a particular embodiment includes a particular feature, element, or step, while other embodiments do not. Therefore, such conditional statements are generally not intended to suggest that a feature, element, or step is required to some extent in one or more embodiments, or that logic for determining whether or not these features, elements, or steps are included in any particular embodiment, or should be implemented in any particular embodiment, with or without user input or instruction, is necessarily included in one or more embodiments. Terms such as “comprising,” “including,” and “having” are synonyms and are used in an inclusive, non-restrictive manner, not excluding additional elements, characteristics, actions, and behaviors. Furthermore, the term "or" is used in an inclusive sense (rather than an exclusive sense), meaning, for example, when used to connect a list of elements, it means one, some, or all of the elements listed. Similarly, the terms "and / or" encompass all of the following interpretations of the word in relation to the enumeration of two or more items: any one of the items in the enumeration, all of the items in the enumeration, and any combination of the items in the enumeration. In addition, the term "each," as used herein, may mean, in addition to its usual meaning, any subset of the set of elements to which the term "each" applies. Moreover, the words "herein," "above," "below," and similar words, as used in this application, mean the entire application and not any particular part thereof.

[0178] Conjunctional phrases such as "at least one of X, Y, and Z" are to be interpreted separately, in the context generally used to indicate that an item, term, etc., can be either X, Y, or Z, unless otherwise specifically stated. Therefore, such conjunctional phrases are not typically intended to suggest that a particular embodiment requires the presence of at least one X, at least one Y, and at least one Z.

[0179] As used herein, the terms "approximately," "about," "generally," and "substantially" refer to values, quantities, or characteristics that, when used herein, approximate a given value, quantity, or characteristic that still performs the desired function or produces the desired result. For example, the terms "approximately," "about," "generally," and "substantially" may refer to quantities that are less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of a given quantity. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" refer to values, quantities, or characteristics that deviate from being exactly parallel by 15 degrees or less, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degrees.

[0180] Any of the embodiments described herein may be used with or without a canister. Any of the embodiments of the dressing described herein can absorb and store wound exudate.

[0181] The scope of this disclosure is not intended to be limited by the description of any particular embodiment, and may be defined by the claims. The language of these claims should be interpreted broadly based on the language used herein, and not limited to the examples described herein or in the proceedings of this application, which should be interpreted non-exclusively.

[0182] Various modifications to the embodiments described herein may be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the spirit or scope of this disclosure. Therefore, the disclosure is not intended to limit itself to the embodiments shown herein, but should be given the broadest scope consistent with the principles and features disclosed herein. Certain embodiments of the disclosure are covered by the set of claims listed below or presented later.

[0183] Specific embodiments of this disclosure are included in the claims presented last in this specification or in any other claims presented at a later date.

Claims

1. A wound treatment device for treating wounds, A wound dressing, A nitrite-providing layer comprising mesh components, wherein the mesh components comprise colocalized nitrite and antioxidant / reducing agents, A wound dressing comprising an activator layer containing a hydrogel, A wound treatment device wherein the activator layer is configured to supply protons to the nitrite supplying layer to generate nitric oxide.

2. The wound treatment device according to claim 1, wherein the nitrite and antioxidant / reducing agent are embedded within the mesh component.

3. The wound treatment apparatus according to claim 2, wherein the nitrite and antioxidant / reducing agent are solubilized and / or suspended in an anhydrous carrier before being embedded in the mesh component, and the anhydrous carrier is soluble in water or miscible.

4. The wound treatment device according to claim 3, wherein the water-miscible anhydrous carrier is selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, a blend of PEGs having different molecular weights, glycerol, triacetin, acetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylamine, ethylene glycol, formic acid, furfuryl alcohol, methanol, methyldiethanolamine, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propanoic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol.

5. The wound treatment apparatus according to any one of claims 1 to 4, wherein the mesh component of the nitrite supply layer is stored in a dry state.

6. The wound treatment device according to any one of claims 1 to 5, wherein the antioxidant / reducing agent co-localized with the nitrite within the mesh components of the nitrite-providing layer is more stable than the antioxidant / reducing agent not stored in a dry state.

7. The wound treatment device according to any one of claims 1 to 6, wherein the antioxidant / reducing agent demonstrates greater stability after sterilization compared to the stability of the antioxidant / reducing agent in a sterile wound treatment device where the antioxidant / reducing agent is not stored in a dry state.

8. The wound treatment device according to any one of claims 1 to 7, wherein the antioxidant / reducing agent is configured to produce less discoloration than a wound treatment device in which the antioxidant / reducing agent is not stored in a dry state.

9. The wound treatment device according to any one of claims 1 to 8, wherein the mesh includes a covered polypropylene mesh.

10. The wound treatment device according to any one of claims 1 to 9, wherein the activator layer comprises a composite material including a gelled fiber substrate loaded with an acidic hydrogel.

11. The wound treatment device according to claim 10, wherein the hydrogel further comprises an aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate and 2-acrylamido-2-methyl-1-propanesulfonic acid.

12. A wound treatment device according to any one of claims 1 to 12, further comprising a water-absorbing dispersion layer.

13. The wound treatment device according to any one of claims 1 to 13, further comprising a cover layer configured to form a seal around the wound.

14. The wound treatment device according to claim 14, wherein the cover layer is breathable.

15. The wound treatment device according to any one of claims 1 to 15, further comprising a masking layer, wherein the masking layer is configured to at least partially limit the visibility of the wound.

16. The wound treatment device according to any one of claims 1 to 15, wherein the nitrite is sodium nitrite.

17. The wound treatment device according to any one of claims 1 to 16, wherein the antioxidant / reducing agent is sodium isoascorbate, ferrous sulfate, or a derivative of vitamin C.

18. A wound treatment device according to any one of claims 1 to 17, further comprising a surfactant.

19. The wound treatment device according to any one of claims 1 to 18, wherein the mesh component comprises a 2.5 × 2.5 cm mesh loaded with any amount of nitrite and antioxidant / reducing agent, each of which is 1 to 5 mg, and the nitrite and antioxidant / reducing agent are suspended in a suitable carrier.

20. A method for treating wounds, This includes applying a wound dressing to the wound, wherein the wound dressing is A nitrite-providing layer comprising mesh components, wherein the mesh components comprise colocalized nitrite and antioxidant / reducing agents, A method comprising: an activator layer containing a hydrogel, wherein the activator layer is configured to donate protons to the nitrite-providing layer to generate nitric oxide.

21. The method according to claim 20, wherein the nitrite and antioxidant / reducing agent are embedded within the mesh component.

22. The method according to claim 21, wherein the nitrite and antioxidant / reducing agent are solubilized and / or suspended in an anhydrous carrier before being embedded in the mesh component, and the anhydrous carrier is soluble in water or miscible.

23. The method according to claim 22, wherein the water-miscible anhydrous carrier is selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, a blend of PEGs having different molecular weights, glycerol, triacetin, acetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylamine, ethylene glycol, formic acid, furfuryl alcohol, methanol, methyldiethanolamine, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propanoic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol.

24. The method according to any one of claims 20 to 23, wherein the mesh components of the nitrite supply layer are stored in a dry state.

25. The method according to any one of claims 20 to 24, wherein the antioxidant / reducing agent co-localized with the nitrite within the mesh components of the nitrite-providing layer is more stable than the antioxidant / reducing agent not stored in a dry state.

26. The method according to any one of claims 20 to 25, wherein the antioxidant / reducing agent demonstrates higher stability after sterilization compared to the stability of the antioxidant / reducing agent in a sterile wound dressing in which the antioxidant / reducing agent is not stored in a dry state.

27. The method according to any one of claims 20 to 26, wherein the wound dressing is configured to produce less discoloration than a wound dressing in which the antioxidant / reducing agent is not stored in a dry state.

28. The method according to any one of claims 20 to 27, wherein the mesh includes a covered polypropylene mesh.

29. The method according to any one of claims 20 to 28, wherein the activator layer comprises a composite material including a gelled fiber substrate loaded with an acidic hydrogel.

30. The method according to claim 29, wherein the hydrogel further comprises an aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate and 2-acrylamido-2-methyl-1-propanesulfonic acid.

31. The method according to any one of claims 20 to 30, wherein the wound dressing further comprises a water-absorbing dispersion layer.

32. The method according to any one of claims 20 to 31, wherein the wound dressing further comprises a cover layer configured to form a seal around the wound.

33. The method according to claim 32, wherein the cover layer is breathable.

34. The method according to any one of claims 20 to 33, wherein the wound dressing further comprises a masking layer, the masking layer configured to at least partially limit the visibility of the wound.

35. The method according to any one of claims 20 to 34, wherein the nitrite is sodium nitrite.

36. The method according to any one of claims 20 to 35, wherein the antioxidant / reducing agent is sodium isoascorbate, ferrous sulfate, or a derivative of vitamin C.

37. A wound treatment device according to any one of claims 20 to 36, further comprising a surfactant.

38. The method according to any one of claims 20 to 37, wherein the mesh component comprises a 2.5 × 2.5 cm mesh loaded with any amount of nitrite and antioxidant / reducing agent, each of which is 1 to 5 mg, and the nitrite and antioxidant / reducing agent are suspended in a suitable carrier.

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