Wound dressing

Abstract

The disclosed embodiments relate to a wound dressing that can generate nitric oxide. The wound dressing may include: a cover layer; an activator layer, such as an acid providing layer; and a nitrite providing layer. The activator layer may include acidic groups and may be a hydrogel, xerogel, or other suitable material. The nitrite providing layer may include a mesh component embedded with nitrite and an antioxidant / reducing agent, such as sodium erythorbate. The nitrite ions of the nitrite providing layer can react with the acidic groups of the activation layer to generate nitric oxide. In addition, wound dressings can be produced and stored such that degradation of antioxidants / reductants is reduced and thus stable nitric oxide production is achieved.

Description

BACKGROUND TECHNICAL FIELD

[0001] Disclosed herein are materials, devices, methods, and systems, such as therapeutic compositions, wound care materials, uses thereof, and methods of treatment using the same. In some examples, the materials, devices, and systems described herein include wound dressings configured for nitric oxide (NO) delivery and / or other active delivery. BACKGROUND

[0002] Nitric oxide (NO) is a well-known molecule with multiple biological functions. For example, nitric oxide affects vasodilation of blood vessels, stimulates angiogenesis, affects host immune responses, and exhibits potent broad-spectrum antimicrobial and antibiofilm activity. Due to these multiple effects, NO exhibits potent effects on tissues, and increasing the amount of NO can support wound, particularly chronic wound, healing acceleration.

[0003] Additionally, diabetic patients generally have lower levels of nitric oxide compared to healthy patients, and reduced supply of nitric oxide in diabetic patients is a compounding factor in healing chronic ulcers. Reduced supply of nitric oxide can result in vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can also result in reduced blood flow to the extremities, which can make diabetic patients more likely to develop neuropathy and non-healing ulcers, and have a greater risk of lower extremity amputation.

[0004] Accordingly, there is a need for improved mechanisms for delivering effective doses of nitric oxide to wounds. Under normal circumstances, nitric oxide (NO) is a free radical that has a short lifetime and is converted to more stable chemicals within seconds after production. Thus, for example, if gaseous nitric oxide is exposed to air, the gaseous nitric oxide will be rapidly oxidized to produce nitrogen dioxide (NO2). Accordingly, it can be difficult to maintain high concentrations of nitric oxide within a wound dressing or other similar structure for extended periods of time. Thus, a device or wound dressing having one or more layers containing a more stable composition can effectively generate nitric oxide over time after activation for stable and sustained delivery of nitric oxide to biological tissue. Of particular interest are mechanisms for delivering nitric oxide in combination with the use of wound dressings, particularly negative pressure wound dressings, and / or while undergoing negative pressure wound therapy and / or other appropriate therapy. SUMMARY

[0005] Embodiments of the present 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 appreciate that the applications of the materials, devices, methods, and systems described herein are not limited to a particular tissue or a particular injury.

[0006] In some embodiments, a wound dressing for treating a wound can comprise: a cover layer configured to form a seal around a wound; an activator layer; a dry nitrite providing layer that is free or relatively free of liquid; and a collection distribution layer.

[0007] In certain embodiments, the wound dressing can further comprise a masking layer configured to at least partially limit visualization of the wound. The dry nitrite providing layer can comprise a nitrite salt. The nitrite salt can comprise sodium nitrite. The dry nitrite providing layer can further comprise an antioxidant / reducing agent. The reducing agent can be sodium erythorbate. The nitrite salt and antioxidant / reducing agent of the dry nitrite providing layer can be co-located on a mesh component. The nitrite salt and antioxidant / reducing agent can be co-located on the mesh component by embedding a mixture of the nitrite salt and reducing agent within the mesh component. The activator layer can be located above the nitrite providing layer. In some embodiments, the nitrite providing layer can be located above the activator layer. The collection distribution layer can be located between the activator layer and the dry nitrite providing layer. The activator layer can comprise a hydrogel or a xerogel. The wound dressing can comprise a second dry nitrite providing layer. The wound dressing can be configured to generate nitric oxide when the wound dressing is placed over a wound. In some embodiments, the wound dressing can be configured to not generate nitric oxide prior to being placed over a wound.

[0008] In some aspects, a wound treatment apparatus for treating a wound is provided. In some embodiments, the wound treatment apparatus can include a nitrite providing layer comprising a mesh component. In some embodiments, the mesh component can include co-located nitrite salt and antioxidant / reducing agent. In some embodiments, the wound treatment apparatus can include an activator layer comprising a hydrogel. In some embodiments, the activator layer can be configured to provide protons to the nitrite providing layer to generate nitric oxide. In some embodiments, the nitrite salt and antioxidant / reducing agent can be embedded within the mesh component. In some embodiments, the nitrite salt and antioxidant / reducing agent can be dissolved and / or suspended in an anhydrous carrier prior to embedding within the mesh component. In some embodiments, the anhydrous carrier can be soluble or miscible in water. In some embodiments, the anhydrous water-miscible carrier can be selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, a blend of PEGs with different molecular weights, glycerol, glyceryl triacetate, 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, propionic acid, propylene glycol, pyridine, tetrahydrofuran, triethylene glycol. In some embodiments, the anhydrous water-miscible carrier can further include a surfactant. In some embodiments, the mesh component of the nitrite providing layer can be stored in a dry state. In some embodiments, the antioxidant / reducing agent co-located with the nitrite salt in the mesh component of the nitrite providing layer can have higher stability compared to the antioxidant / reducing agent that is not stored in a dry state. In some embodiments, the antioxidant / reducing agent can exhibit higher stability after sterilization compared to the stability of the antioxidant / reducing agent in a sterilized wound dressing in which the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the wound treatment apparatus can be configured to form less color than a wound treatment apparatus in which the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the mesh can comprise a coated polypropylene mesh. In some embodiments, the activator layer can comprise a composite comprising a gelling fiber substrate loaded with an acidic hydrogel. In some embodiments, the hydrogel can further comprise a 2-acrylamido-2-methyl-1-propanesulfonic acid sodium aqueous solution and 2-acrylamido-2-methyl-1-propanesulfonic acid. In some embodiments, the wound treatment apparatus can further comprise a collection distribution layer. In some embodiments, the wound treatment apparatus can further comprise a cover layer configured to form a seal around a wound.In some embodiments, the cover layer can be moisture permeable. In some embodiments, the wound treatment apparatus can further include a masking layer that can be configured to at least partially limit visualization of the wound. In some embodiments, the nitrite salt can be sodium nitrite. In some embodiments, the antioxidant / reducing agent can be sodium erythorbate, ferric sulfate, or a derivative of Vitamin C. The derivative of Vitamin C can include L-ascorbic acid, sodium ascorbylphosphate, magnesium ascorbylphosphate, ascorbyl glucoside, tetrahexyldecyl ascorbate, ethylated L-ascorbic acid, or any suitable derivative of Vitamin C. In some embodiments, the mesh component includes a 2.5 x 2.5 cm mesh loaded with any amount between 1-5 mg of each of the nitrite salt and the antioxidant / reducing agent, wherein the nitrite salt and the antioxidant / reducing agent are suspended in a suitable carrier.

[0009] In some aspects, a method for treating a wound is provided. In some embodiments, the method can include applying a wound dressing to a wound. In some embodiments, the wound dressing can include a nitrite-providing layer including a mesh component. In some embodiments, the wound dressing can include a nitrite-providing layer including a mesh component. In some embodiments, the mesh component can include co-located nitrite salt and antioxidant / reducing agent. In some embodiments, the wound dressing can include an activator layer including a hydrogel. In some embodiments, the activator layer can be configured to provide protons to the nitrite-providing layer to generate nitric oxide. In some embodiments, the nitrite salt and antioxidant / reducing agent can be embedded within the mesh component. In some embodiments, the nitrite salt and antioxidant / reducing agent can be dissolved and / or suspended in an anhydrous carrier prior to being embedded within the mesh component. In some embodiments, the anhydrous carrier can be soluble or miscible in water. In some embodiments, the anhydrous water-miscible carrier can be selected from the group consisting of polyethylene glycol (PEG) 200, PEG 400, PEG 600, a blend of PEGs with different molecular weights, glycerol, glyceryl triacetate, 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, propionic acid, propylene glycol, pyridine, tetrahydrofuran, triethylene glycol. In some embodiments, the anhydrous water-miscible carrier can further include a surfactant. In some embodiments, the mesh component of the nitrite-providing layer can be stored in a dry state. In some embodiments, the antioxidant / reducing agent co-located with the nitrite salt in the mesh component of the nitrite-providing layer can have higher stability compared to the antioxidant / reducing agent not stored in a dry state. In some embodiments, the antioxidant / reducing agent can exhibit higher stability after sterilization compared to the stability of the antioxidant / reducing agent within a sterilized wound dressing where the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the wound dressing can be configured to form less color than a wound treatment device where the antioxidant / reducing agent is not stored in a dry state. In some embodiments, the mesh can include a coated polypropylene mesh. In some embodiments, the activator layer can include a composite including a gelled fiber substrate loaded with an acidic hydrogel. In some embodiments, the hydrogel can further include a 2-acrylamido-2-methyl-1-propanesulfonic acid sodium aqueous solution and 2-acrylamido-2-methyl-1-propanesulfonic acid. In some embodiments, the wound dressing can further include a collection distribution layer.In some embodiments, the wound dressing can further include a cover layer configured to form a seal around the wound. In some embodiments, the cover layer can be moisture vapor permeable. In some embodiments, the wound dressing can further include a masking layer that can be configured to at least partially restrict visualization of the wound. In some embodiments, the nitrite salt can be sodium nitrite. In some embodiments, the antioxidant / reducing agent can be sodium erythorbate, ferric sulfate, or a derivative of Vitamin C. In some embodiments, the mesh component includes a 2.5 x 2.5 cm mesh loaded with any amount between 1-5 mg of each of the nitrite salt and the antioxidant / reducing agent, wherein the nitrite salt and the antioxidant / reducing agent are suspended in a suitable carrier.

[0010] Alternative or additional embodiments described herein provide a composition including one or more of the features of the foregoing description or any description elsewhere herein.

[0011] Alternative or additional embodiments described herein provide a wound contact layer including one or more of the features of the foregoing description or any description elsewhere herein.

[0012] Alternative or additional embodiments described herein provide a wound dressing including one or more of the features of the foregoing description or any description elsewhere herein.

[0013] Alternative or additional embodiments described herein provide a wound treatment system including one or more of the features of the foregoing description or any description elsewhere herein.

[0014] Alternative or additional embodiments described herein provide a method of treating a wound including one or more of the features of the foregoing description or any description elsewhere herein. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 schematic view of an example of a negative pressure wound treatment system;

[0016] Figure 2A An embodiment of a negative pressure wound treatment system employing a pump, a flexible fluid connector, and a wound dressing capable of absorbing and storing wound exudate is shown;

[0017] Figure 2B An embodiment of a negative pressure wound treatment system employing a flexible fluid connector and a wound dressing capable of absorbing and storing wound exudate is shown;

[0018] Figure 2C A cross-section of an embodiment of a fluid connector connected to a wound dressing is shown;

[0019] Figure 2D A cross-section of an embodiment of a wound dressing is shown;

[0020] Figures 3A-3D An embodiment of a wound dressing capable of absorbing and storing wound exudate to be used without negative pressure is shown;

[0021] Figure 3E A cross-section of an embodiment of a wound dressing capable of absorbing and storing wound exudate to be used without negative pressure is shown;

[0022] Figure 4 An exploded view of an embodiment of a wound dressing that can generate nitric oxide;

[0023] Figure 5 A cross-section view of a wound dressing of Figure 4 ;

[0024] Figure 6 An example of a chemiluminescence experimental protocol setup is shown;

[0025] Figure 7 shows a negative pressure and nitric oxide delivery experiment;

[0026] Figure 8A An example of chemiluminescence experimental results for a sodium nitrate grid is depicted;

[0027] Figure 8B An example of chemiluminescence experimental results for a full dressing design with pull tab and self-sealing border is depicted;

[0028] Figure 8C An example of chemiluminescence experimental results for a dressing containing a degradable membrane is depicted;

[0029] Figure 9 An example of a graph showing peak NO and NO2 output for an acrylic adhesive containing a hydrogel is depicted;

[0030] Figures 10A-10D An example of chemiluminescence experimental results for a nitric oxide dressing is depicted;

[0031] Figures 11A-11E An embodiment of a wound dressing configured to generate nitric oxide is depicted;

[0032] Figure 12 An embodiment of a hydrogel-based wound dressing system is shown;

[0033] Figure 13 An embodiment of a hydrogel-based wound dressing system is shown;

[0034] Figure 14 An example process for hydrogel production is depicted;

[0035] Figure 15 Examples of chemiluminescence experimental results for representative acidic AMPS-based hydrogels without sodium erythorbate are depicted when in contact with polypropylene mesh soaked in aqueous sodium nitrite solution;

[0036] Figure 16 Examples of chemiluminescence results for acidic hydrogels with 1.0SA in contact with a suspension generated by dispersing 0.1 g sodium nitrite and 0.1 g sodium erythorbate in 2 g PEG400 are depicted. The gel of 1.0SA can be made from the following components (parts by weight for a 100 g batch): 63.32 g AMPS sodium; 0.0323 g Piperazine dipropylamide; 5.436 g AMPS(H+); 31.19 g glycerol and 0.01629 g 2-hydroxy-2-methylpropiophenone. The top line on the graph is NO2, the bottom line is NO;

[0037] Figure 17A A top view of the experimental set-up for evaluating the antimicrobial activity of a dressing composed of IV3000 top layer, hydrogel / DURAFIBER composite with 1.0SA or 0.7SA and polypropylene (pp) mesh embedded with a suspension of PEG400 / sodium nitrite / sodium erythorbate is shown. The gel of 0.7SA can be made from the following components (parts by weight for a 100 g batch): 65.28 g AMPS sodium; 0.0317 g Piperazine dipropylamide; 3.923 g AMPS(H+); 30.74 g glycerol and 0.01756 g 2-hydroxy-2-methylpropiophenone. The topmost line on the graph is NOX, the middle line is NO and the bottom line is NO2;

[0038] Figure 17B A top view of the experimental set-up for evaluating the antimicrobial activity of a dressing composed of IV3000 top layer, hydrogel / DURAFIBER composite with 1.0SA or 0.7SA and polypropylene (pp) mesh embedded with a suspension of PEG400 / sodium nitrite / sodium erythorbate is shown. The gel of 0.7SA can be made from the following components (parts by weight for a 100 g batch): 65.28 g AMPS sodium; 0.0317 g Piperazine dipropylamide; 3.923 g AMPS(H+); 30.74 g glycerol and 0.01756 g 2-hydroxy-2-methylpropiophenone. The topmost line on the graph is NOX, the middle line is NO and the bottom line is NO2; Figure 17A

[0039] Figure 17C Examples of chemiluminescence results for acidic hydrogels with 1.0SA in contact with a suspension generated by dispersing 0.1 g sodium nitrite and 0.1 g sodium erythorbate in 2 g PEG400 are depicted. The gel of 1.0SA can be made from the following components (parts by weight for a 100 g batch): 63.32 g AMPS sodium; 0.0323 g Piperazine dipropylamide; 5.436 g AMPS(H+); 31.19 g glycerol and 0.01629 g 2-hydroxy-2-methylpropiophenone. The top line on the graph is NO2, the bottom line is NO; Figures 17A-17B

[0040] Examples of chemiluminescence results for acidic hydrogels with 1.0SA in contact with a suspension generated by dispersing 0.1 g sodium nitrite and 0.1 g sodium erythorbate in 2 g PEG400 are depicted. The gel of 1.0SA can be made from the following components (parts by weight for a 100 g batch): 63.32 g AMPS sodium; 0.0323 g Piperazine dipropylamide; 5.436 g AMPS(H+); 31.19 g glycerol and 0.01629 g 2-hydroxy-2-methylpropiophenone. The top line on the graph is NO2, the bottom line is NO; Figures 18A-18D

[0041] Figure 18A ​​The production of nitric oxide is shown, where PEG 400 is used as the anhydrous water miscible carrier. The top-most plotted line is NOX, the middle line is NO, and the bottom is NO2;

[0042] Figure 18B The results are shown when PEG 600 is used as the anhydrous water miscible carrier. The top-most plotted line is NOX, the middle line is NO, and the bottom line is NO2;

[0043] Figure 18C The results are shown when a 50 / 50 w / w blend of PEG 300 and PEG 1500 (FLEX) is used as the anhydrous water miscible carrier. The top-most plotted line is NOX, the middle line is NO, and the bottom line is NO2;

[0044] Figure 18D The results are shown when a 41 / 1 w / w blend of PEG 400 and PEG 4000 (SORB) is used as the anhydrous water miscible carrier. The top-most plotted line is NOX, the middle line is NO, and the bottom line is NO2;

[0045] Figure 18E The results of Figures 18A-18D are combined on a single graph. DETAILED DESCRIPTION

[0046] SUMMARY

[0047] Embodiments described herein relate to materials, devices, methods, and systems incorporating or including or utilizing one or more compositions and / or materials that are effective to generate gas (e.g., nitric oxide) over time after activation. Embodiments herein can relate to devices and / or wound dressings having one or more layers containing a composition and / or material that is effective to generate nitric oxide over time after activation. For example, one or more nitric oxide generating layers can include a nitrite delivery layer containing a nitrite salt and can release nitrite ions such that the nitrite ions can generate nitric oxide upon reaction with an acid.

[0048] In some embodiments, in addition to a nitrite delivery layer, one or more nitric oxide generating layers can include an acid group providing layer. One or more nitric oxide generating layers can be used as a stand-alone component to be positioned separately at a wound site, or can be incorporated into any number of multi-layer wound dressings and wound therapy devices, such as described herein below with respect to Figures 1 through 18E Embodiments of the present disclosure are generally applicable for use in ambient conditions, in negative or reduced pressure therapy systems, or in pressurized therapy systems.

[0049] Some preferred embodiments described herein incorporate or utilize or have one or more nitric oxide generating layers. Such one or more nitric oxide generating layers can have one or more of the following functional features: inflammation-related activity, blood flow-related activity, antimicrobial, anti- planktonic, and anti-biofilm activity, ease of application or / and removal as a unit, cuttability / tearability, conformability to the three-dimensional contours of a wound surface, abrasion resistance, compatibility with negative pressure wound therapy or / and compression wound therapy, exudate management, ability to promote autolytic debridement of a wound, ability to promote wound healing, and self-indication of compositional or functional change. Antimicrobial activity, such as in vitro antimicrobial activity, can include one or more of the following: broad-spectrum antimicrobial activity, anti-biofilm activity, rapid killing of microorganisms, sustained killing of microorganisms; and microorganisms can include one or more of the following: gram-negative bacteria, gram-positive bacteria, fungi, yeast, viruses, algae, archaea, and protozoa.

[0050] Certain preferred embodiments described herein provide a wound treatment system. Such a wound treatment system can include a nitric oxide generating layer configured to be sized to be positioned over a wound and / or a periwound area. Those skilled in the art will appreciate that when a device / dressing / layer is described as being placed on or over a wound, such a device / dressing / layer can extend over and treat a periwound area. In some cases, stimulating a periwound area and / or a wound edge can play a role in initiating a wound healing process, and the wound healing process can be activated by delivering nitric oxide to the periwound area and / or wound edge. Delivering nitric oxide to the periwound area and / or wound edge can be directed, for example, to epithelial cell activity to promote migration of an epithelial tongue; vasodilation of microcirculation in the skin surrounding the wound to promote perfusion by providing oxygen and nutrients; and neovascularization to promote granulation tissue formation. The wound treatment system described herein can also include a second wound dressing configured to be positioned separately over the nitric oxide generating layer. The nitric oxide generating layer can have an adhesive adhered to an undersurface; and the adhesive can be configured such that the nitric oxide generating layer can be placed adjacent to a wound. The second wound dressing, if used, can be adhered to the skin surrounding the wound, and can be the same size, or can be larger than the nitric oxide generating layer, such that the nitric oxide generating layer will touch or be placed adjacent to the wound and / or periwound area. The second wound dressing can alternatively or additionally be configured to form a seal to the skin surrounding the wound, such that the nitric oxide generating layer will touch or be placed adjacent to the wound. The wound treatment system can also include a negative pressure source configured to supply negative pressure through the second wound dressing and through the wound contact layer to the wound.

[0051] Certain other preferred embodiments described herein provide a multi-layer wound dressing, such as described herein in the specification with respect to Figures 1 through 13 described herein. Such multi-layer wound dressings can incorporate one or more nitric oxide generating layers as component layers thereof, or alternatively can include a composite or laminate that includes one or more nitric oxide generating layers as part of one of the component layers thereof. The multi-layer wound dressing can include a nitric oxide generating layer as described above or elsewhere herein; a transport layer and / or an absorbent layer over / under the one or more nitric oxide generating layers; a wound contact layer under the one or more nitric oxide generating layers; and a cover layer over the transport layer and / or absorbent layer. The wound dressing can also include a negative pressure port on or over the cover layer. The one or more nitric oxide generating layers can have a perimeter shape that is substantially the same as a perimeter shape of the cover layer. Alternatively, the one or more nitric oxide generating layers can have a perimeter shape that is smaller than a perimeter shape of the cover layer.

[0052] One of skill in the art will appreciate that a nitric oxide generating composition, such as any of those disclosed herein in this “SUMMARY” section or elsewhere in the specification, can be loaded within one or more nitric oxide generating layers in any suitable form, such as via adsorption, absorption, chemical and / or physical attachment entanglement, and / or via a powder form. One of skill in the art will further appreciate that a reactive composition, for example any of those disclosed herein in this section or elsewhere in the specification, can be incorporated into any suitable absorbent layer disclosed herein in this section or elsewhere in the specification, and / or any suitable transport layer disclosed herein in this section or elsewhere in the specification, and / or any foam layer disclosed herein in this section or elsewhere in the specification, by any suitable means.

[0053] In certain embodiments, the wound treatment systems and multi-layer wound dressings disclosed above or elsewhere in the specification can incorporate or include a nitric oxide generating layer. As described herein in this section or elsewhere in the specification, particularly below, the nitric oxide generating layer can be configured to be activated to release nitric oxide. At least a portion of the released nitric oxide can be released, for example, by diffusion. To facilitate the release and diffusion of nitric oxide, the nitric oxide generating layer can be placed proximate to a wound.

[0054] Some preferred embodiments described herein in the specification provide a method of treating a wound, intact tissue, or other suitable location. Such a method can include placing a nitric oxide generating layer alone or by placing a multi-layer wound dressing having a nitric oxide generating layer over a wound. The method can include adhering the nitric oxide generating layer alone and / or the multi-layer wound dressing having a nitric oxide generating layer to healthy skin surrounding the wound. The method can also include one or more of the following steps: another wound dressing can be placed over the nitric oxide generating layer alone or the multi-layer wound dressing having a nitric oxide generating layer placed over the wound. Wound exudate or any wet or aqueous medium other than wound exudate can be provided to reach and / or access the nitric oxide generating layer. Wound exudate or any wet or aqueous medium other than wound exudate can be diffused or wicked into a wound dressing having a nitric oxide generating layer or into a wound dressing disposed over the nitric oxide generating layer. Negative pressure can be applied to the nitric oxide generating layer alone or the multi-layer wound dressing having a nitric oxide generating layer such that wound exudate is drawn directly into the nitric oxide generating layer, or into a wound dressing having a nitric oxide generating layer, or into a wound dressing disposed over the nitric oxide generating layer.

[0055] One skilled in the art will appreciate that the wound dressings, devices, and systems disclosed herein in this “SUMMARY” section or elsewhere in the specification can include one or more layers, compositions, materials, or components that generate a gas other than nitric oxide in addition to or instead of a nitric oxide generating layer, composition, or material. For example, a wound dressing or device can include one or more layers that are effective to generate a vasodilator, such as carbon monoxide or hydrogen sulfide, over time after activation.

[0056] It will be further appreciated by those skilled in the art that, where appropriate, carbon monoxide and / or hydrogen sulfide can be used in place of or in combination with the nitric oxide delivery elements (e.g., layers). Further details regarding the generation and delivery of carbon monoxide and / or hydrogen sulfide can be found in Chapter 6 of the text 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 can be generated from elements / layers containing cleavable / releasable hydrogen sulfide, diallylthiosulfinates, 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 providing complexes of carbon monoxide bound to suitable metals such as chromium, molybdenum, tungsten, manganese, rhenium, iron, ruthenium, cobalt, rhodium, and iridium. Such complexes can be triggered to release carbon monoxide in an enzymatic manner, can be photocleavable, and / or respond to interaction with suitable ligands to induce release of carbon monoxide.

[0057] Methods of treating wounds

[0058] Some preferred embodiments described in the specification herein provide a method of treating a wound, intact tissue, or other suitable location. Such a method can include placing one or more nitric oxide generating layers alone or by placing a multi-layer wound dressing having one or more nitric oxide generating layers over a wound. The method can include adhering the one or more nitric oxide generating layers alone and / or the multi-layer wound dressing having one or more nitric oxide generating layers to healthy skin around a wound, e.g., the area around the wound. The method can also include one or more of the following steps: another wound dressing can be placed over the one or more nitric oxide generating layers alone or the multi-layer wound dressing having one or more nitric oxide generating layers placed over a wound. Wound exudate or any wet or aqueous medium other than wound exudate can be provided to reach and / or access the one or more nitric oxide generating layers. The wound exudate or any wet or aqueous medium other than wound exudate can be diffused or wicked into a wound dressing having the one or more nitric oxide generating layers or into a wound dressing disposed over the one or more nitric oxide generating layers. Negative pressure can be applied to the one or more nitric oxide generating layers alone or the multi-layer wound dressing having one or more nitric oxide generating layers as described in the “Negative Pressure Wound Therapy (NPWT) Systems” section below or elsewhere in the specification herein such that wound exudate is drawn directly into the one or more nitric oxide generating layers, or into a wound dressing having the one or more nitric oxide generating layers, or into a wound dressing disposed over the one or more nitric oxide generating layers.

[0059] The method of treating a wound, intact tissue, or other suitable location as described above or elsewhere herein can also include delivering negative pressure to the wound through a wound contact layer as described in the “Negative Pressure Wound Therapy (NPWT) Systems” section below or elsewhere in the specification herein. The wound contact layer can 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, the method of treating a wound, intact tissue, or other suitable location can include applying positive (pressurizing) pressure to the wound through a wound contact layer. Alternatively, the method can include programmatically varying ambient pressure, negative pressure, and pressurizing pressure to the wound through a wound contact layer.

[0060] In some embodiments, the method of treating a wound, intact tissue, or other suitable location can include using a wound contact layer or a wound treatment system or wound dressing including a wound contact layer under ambient conditions independent of a negative pressure wound therapy system as described above or elsewhere herein.

[0061] In some embodiments, the method of treating a wound, intact tissue, or other suitable location can reduce wound bioburden, e.g., at least in vitro, by reducing the number of viable microorganisms (CFU / sample) within the first 4 hours after application of the wound contact layer. In some examples, the number of viable microorganisms can be reduced by four logs or more, 48 to 72 hours after positioning the wound dressing in contact with the microorganisms.

[0062] Negative pressure wound therapy (NPWT) systems

[0063] It will be appreciated that embodiments of the present disclosure are generally applicable, but not limited to, use in topical negative pressure (“TNP”) therapy systems. In brief, negative pressure wound therapy facilitates the closure and healing of a variety of forms of “hard-to-heal” wounds by virtue of: reducing tissue edema, promoting blood flow and granulation tissue formation, removing excess exudate; and can reduce bacterial load (thereby reducing the risk of infection). In addition, the therapy allows for reduced disturbance of the wound, thereby enabling faster healing. TNP therapy systems can also facilitate the healing of surgically closed wounds by removing fluid and by helping to stabilize tissue in close proximity to the closure site. Another beneficial use of TNP therapy can be found in grafts and flaps, in which case it is important to remove excess fluid and to bring the graft into close proximity with the tissue in order to ensure tissue viability.

[0064] As used herein, a level of reduced pressure or negative pressure, such as -X mmHg, refers to a level of pressure relative to normal ambient atmospheric pressure, which can 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. Additionally, a negative pressure that is “less” or “smaller” than -X mmHg corresponds to a pressure that is closer to atmospheric pressure (e.g., -40 mmHg is smaller than -60 mmHg). A negative pressure that is “more” or “larger” than -X mmHg corresponds to a pressure that is further from atmospheric pressure (e.g., -80 mmHg is larger than -60 mmHg). In some embodiments, a local ambient atmospheric pressure is used as a reference point, and such local atmospheric pressure can not necessarily be, for example, 760 mmHg.

[0065] The negative pressure range for some embodiments of the present disclosure can be approximately -80 mmHg, or between about -20 mmHg and about -200 mmHg. It should be noted that these pressures are referenced to normal ambient atmospheric pressure, which can be 760 mmHg. Thus, an actual -200 mmHg would be about 560 mmHg. In some embodiments, the pressure range can be between about -40 mmHg and about -150 mmHg. Alternatively, a pressure range of up to -75 mmHg, up to -80 mmHg, or more than -80 mmHg can be used. Additionally, in other embodiments, a pressure range of less than -75 mmHg can be used. As an alternative, the negative pressure device can supply a pressure range of more than about -100 mmHg, or even -150 mmHg.

[0066] In some embodiments of the wound closure devices described herein, increased wound contraction can result in increased tissue expansion in the surrounding wound tissue. This effect can be enhanced by varying the force applied to the tissue over time: for example, by varying the negative pressure applied to the wound over time, which can be combined with increasing the tension applied to the wound via various embodiments of the wound closure device. In some embodiments, for example, the negative pressure can be varied over time using a sinusoidal wave, a square wave, or in synchronization with one or more patient physiological indicators (e.g., a heartbeat). Examples of such applications in which additional disclosure relating to the foregoing can be found include U.S. Patent No. 8,235,955, entitled “Wound treatment apparatus and method,” published August 7, 2012; and U.S. Patent No. 7,753,894, entitled “Wound cleansing apparatus with stress,” published July 13, 2010. The disclosure of both of these patents is hereby incorporated by reference herein in its entirety.

[0067] Embodiments of the wound dressings, wound dressing components, wound treatment apparatuses, and methods described herein can also be used in combination with or supplement those described in International Application No. PCT / IB2013 / 001469, entitled "APPARATUSES AND METHODS FOR NEGATIVE PRESSURE WOUND THERAPY," published November 28, 2013 as WO 2013 / 175306 A2, and International Application No. PCT / IB2013 / 002060, entitled "WOUND DRESSING," filed July 31, 2013, published as WO 2014 / 020440, the disclosures of which are incorporated by reference herein in their entireties. Embodiments of the wound dressings, wound treatment apparatuses, and methods described herein can also be used in combination with or supplement those described in U.S. Patent No. 9,061,095, entitled "WOUND DRESSING AND METHOD OF USE," published June 23, 2015, and U.S. Application Publication No. 2016 / 0339158, entitled "FLUIDIC CONNECTOR FOR NEGATIVE PRESSURE WOUND THERAPY," published November 24, 2016, the disclosures of which are incorporated by reference herein in their entireties, including additional details regarding embodiments of wound dressings, wound dressing components, and principles and materials for wound dressings.

[0068] Further, some embodiments relating to TNP wound therapy including a wound dressing in combination with a pump or associated electronics described herein can also be used in combination with or supplement those described in International Publication No. WO 2016 / 174048 Al, entitled "REDUCED PRESSURE APPARATUSES," published November 3, 2016, the entire contents of which are incorporated by reference herein. In some of these embodiments, the pump or associated electronics can be integrated into the wound dressing to provide a single article application to a wound.

[0069] Multi-layer wound dressings for NPWT

[0070] Figure 1An example of a negative pressure wound treatment system 700 is shown. The system includes a wound cavity 710 covered by a wound dressing 720, which can be a dressing according to any of the examples described herein. The dressing 720 can be positioned on, inside, over, or around the wound cavity 710, and further seal the wound cavity such that a negative pressure can be maintained therein. For example, a film layer of the wound dressing 720 can provide a substantially fluid-impermeable seal over the wound cavity 710. In some embodiments, a wound filler, such as a foam or gauze layer, can be used to pack the wound. The wound filler can include one or more nitric oxide generating layers (e.g., a nitrite delivery layer, an acid group providing layer) as described elsewhere in this section or elsewhere in the specification. For example, in a traditional negative pressure wound treatment system utilizing a foam or gauze, such as the Smith & Nephew RENASYS negative pressure wound treatment system utilizing a foam (RENASYS-F) or gauze (RENASYS-G), the foam or gauze can be supplemented with a nitric oxide generating layer as described above. When supplementing a foam or gauze layer or other wound filler material, the one or more nitric oxide generating layers can be inserted into the wound separately, or can be pre-attached to the wound filler material for insertion into the wound.

[0071] A single or multi-lumen tube or conduit 740 connects the wound dressing 720 with a negative pressure device 750, which is configured to supply a reduced pressure. The negative pressure device 750 includes a source of negative pressure. The negative pressure device 750 can be a canisterless device (meaning that exudate is collected in the wound dressing and / or passed through the tube 740 to be collected at another location). In some embodiments, the negative pressure device 750 can be configured to include or support a canister. Additionally, in any of the embodiments disclosed herein, the negative pressure device 750 can be wholly or partially embedded in, mounted to, or supported by the wound dressing 720.

[0072] The conduit 740 can be any suitable article configured to provide at least a substantially sealed fluid flow path or passage between the negative pressure device 750 and the wound cavity 710 in order to supply a reduced pressure to the wound cavity. The conduit 740 can be formed from polyurethane, PVC, nylon, polyethylene, silicone, or any other suitable rigid or flexible material. In some embodiments, the wound dressing 720 can have a port configured to receive an end of the conduit 740. For example, the port can include a hole in a film layer. In some embodiments, the conduit 740 can otherwise pass through and / or under a film layer of the wound dressing 720 to supply a reduced pressure to the wound cavity 710 in order to maintain a desired level of reduced pressure in the wound cavity. In some embodiments, at least a portion of the conduit 740 is integral with or attached to the wound dressing 720.

[0073] Figure 2A An embodiment of a negative pressure wound therapy system 10 using a wound dressing 100 coupled with a fluid connector 110 is shown. Further examples relating to negative pressure wound therapy including wound dressings combined with pumps as described herein may also be used in combination with or complement those described in U.S. Patent No. 9,061,095, which is incorporated herein by reference in its entirety. Here, the fluid connector 110 may include an elongated conduit, more preferably a bridging member 120 having a proximal end 130 and a distal end 140, and an applicator 180 at the distal end 140 of the bridging member 120. System 10 may include a negative pressure source, such as a pump or 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 can 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 the PICO sold by Smith & Nephew. TM Pump. Pump 150 can be connected to bridging member 120 via tubing, or pump 150 can be directly connected to bridging member 120. In use, dressing 100 is placed over a properly prepared wound, which in some cases may be filled with wound-filling material, such as the foam or gauze described above. The applicator 180 of fluid connector 110 has a sealing surface that is positioned over an orifice in dressing 100 and seals to the top surface of dressing 100. Before, during, or after fluid connector 110 is connected to dressing 100, pump 150 is connected to a connector of tubing via tubing, or directly to bridging member 120. Pump is then activated, thereby supplying negative pressure to the wound. Negative pressure can be applied until the desired level of wound healing is achieved.

[0074] like Figure 2B As shown, the fluid connector 110 preferably includes an enlarged distal end or head 140 in fluid communication with the dressing 100, as will be described in more detail below. In one embodiment, the enlarged distal end is circular or annular. The head 140 is shown here positioned near the edge of the dressing 100, but may be positioned anywhere on the dressing. For example, some embodiments may provide a centered or off-center position not on or near the edge or corner of the dressing 100. In some embodiments, the dressing 10 may include two or more fluid connectors 110, each including one or more heads 140 in fluid communication with it. In a preferred embodiment, the head 140 may be measured 30 mm along its widest edge. The head 140 forms at least a portion of the applicator 180 described above, which is configured to seal the top surface of the wound dressing.

[0075] Figure 2CA cross-section is shown through a wound dressing 100 and a fluid connector 110, similar to the wound dressing 10 described in International Patent Publication WO2013175306 A2, which is incorporated herein by reference in its entirety. The wound dressing 100 may be any combination of features of any wound dressing embodiment disclosed herein or any number of wound dressing embodiments disclosed herein, and may be positioned above the wound site to be treated. The dressing 100 may be positioned to form a sealed cavity above the wound site. In a preferred embodiment, the dressing 100 includes a top or overlay layer, or a backing layer 220 attached to an optional wound contact layer 222, both described in more detail below. These two layers 220, 222 are preferably connected or sealed together to define an internal space or chamber. This internal space or chamber may include additional structures adapted to distribute or deliver negative pressure, store wound exudate and other fluids removed from the wound, and other functions, which will be explained in more detail below. Examples of such structures described below include a transport layer 226 and an absorbent layer 221.

[0076] As used herein, the upper layer, top layer, or above layer refers to the layer furthest from the surface of the skin or wound when the dressing is in use and positioned on the wound. Therefore, the lower surface, lower layer, bottom layer, or below layer refers to the layer closest to the surface of the skin or wound when the dressing is in use and positioned on the wound.

[0077] like Figure 2C As shown, the wound contact layer 222 may be a polyurethane layer, a polyethylene layer, or other flexible layer, which is perforated, for example, by a heat-pressing process, a laser ablation process, an ultrasonic process, or some other method, or otherwise made permeable to liquids and gases. The wound contact layer 222 has a lower surface 224 and an upper surface 223. The perforation 225 preferably includes a through-hole in the wound contact layer 222, which allows fluid to flow through the layer 222. The wound contact layer 222 helps prevent tissue from growing inward into other materials of the wound dressing. Preferably, the perforation is small enough to meet this requirement while still allowing fluid to flow through it. For example, perforations formed as slits or holes ranging in size from 0.025 mm to 1.2 mm are considered small enough to help prevent tissue from growing inward 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 integrity of the entire dressing 100 while also creating an airtight seal around the absorbent pad to maintain negative pressure at the wound site.

[0078] Some embodiments of the wound contact layer 222 can also serve as a carrier for optional lower and upper adhesive layers (not shown). For example, a lower pressure sensitive adhesive can be provided on the lower surface 224 of the wound dressing 100, while an upper pressure sensitive adhesive layer can be provided on the upper surface 223 of the wound contact layer. The pressure sensitive adhesive can be a silicone, hot melt, hydrocolloid or acrylic based adhesive or other such adhesive, can be formed on both sides of the wound contact layer, or optionally on a selected side, or not on either side. In use of a lower pressure sensitive adhesive layer, it can be helpful to adhere the wound dressing 100 to the skin around the wound site. In some embodiments, the wound contact layer can comprise a perforated polyurethane film. The lower surface of the film can be provided with a silicone pressure sensitive adhesive, and the upper surface can be provided with an acrylic pressure sensitive adhesive, which can help the dressing to retain its integrity. In some embodiments, the polyurethane film layer can be provided with adhesive layers on both its upper and lower surfaces, and all three layers can be perforated together.

[0079] A transmission layer 226 can be located above the wound contact layer 222. In some embodiments, the transmission layer can be a porous material. As used herein, the transmission layer can be referred to as a spacer layer, and the terms can be used interchangeably to refer to the same component described herein. This transmission layer 226 allows for the transmission of fluids, including liquids and gases, away from the wound site into the upper layers of the wound dressing. In particular, the transmission layer 226 preferably ensures that an open air channel can be maintained to convey negative pressure over the wound area even when the absorbent layer has absorbed a significant amount of exudate. The layer 226 should preferably remain open at typical pressures that will be applied during negative pressure wound therapy as described above, so that the entire wound site is subjected to an even negative pressure. The layer 226 can be formed of a material having a three-dimensional structure. For example, a knitted or woven spacer fabric (e.g., Baltex 7970 weft knitted polyester) or a nonwoven fabric can be used. The three-dimensional material can include a 3D spacer fabric material similar to the materials described in International Publication WO 2013 / 175306 A2 and International Publication WO 2014 / 020440, the disclosures of which are incorporated by reference in their entirety.

[0080] In certain embodiments, the wound dressing 100 can incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layers, acid group providing layers) as described herein in this section or elsewhere in the specification. Those skilled in the art will appreciate that the wound dressing 100 can incorporate any of the one or more nitric oxide generating layers disclosed herein in this section or elsewhere in the specification. Those skilled in the art will also appreciate that the one or more nitric oxide generating layers can be incorporated as an entire component layer or as a portion of a component layer. In some embodiments, the one or more nitric oxide generating layers can be disposed beneath the transmission layer 226. In some embodiments, the one or more nitric oxide generating layers can be disposed above the wound contact layer 222. In certain embodiments, the one or more nitric oxide generating layers can replace the transmission layer 226, such that the one or more nitric oxide generating layers are disposed between the absorbent layer 221 (described further below) and the wound contact layer 222. In some embodiments, the one or more nitric oxide generating layers can supplement or replace the absorbent layer 221. In some embodiments, the wound dressing 100 does not have a wound contact layer 222, and the one or more nitric oxide generating layers can be the lowermost layer of the wound dressing 100. The one or more nitric oxide generating layers can have the same or substantially similar size and shape as the transmission layer 226 and / or the absorbent layer 221. In some embodiments, the one or more nitric oxide generating layers or components thereof (e.g., a nitrite providing layer as described herein) can be separate from the wound dressing 100. For example, the one or more nitric oxide generating layers or components thereof can be disposed as a separate layer that can be placed over a wound, and the wound dressing 100 can be placed thereover.

[0081] The one or more nitric oxide generating layers can be configured to be flexible, but sufficiently rigid to withstand negative pressure such that the one or more nitric oxide generating layers do not collapse excessively and thereby can adequately transmit negative pressure to a wound when the wound dressing 100 is supplied with negative pressure. The one or more nitric oxide generating layers can be configured to include a sufficient number or size of pores to enable transmission of negative pressure. The one or more nitric oxide generating layers can include, for example, a port or a hole beneath the port to transmit negative pressure and / or wound fluid. Further, the one or more nitric oxide generating layers can have a suitable thickness to transmit a suitable negative pressure to a wound. For example, the one or more nitric oxide generating layers can 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, the one or more nitric oxide generating layers can have a thickness of about 2 mm.

[0082] In some embodiments, an absorbent material layer 221 is provided over the transmission layer 226. The absorbent material can comprise a foam or nonwoven natural or synthetic material, and can optionally comprise a superabsorbent material, forming a reservoir for fluid, particularly liquid, removed from the wound site. In some embodiments, the layer 221 can also assist in wicking fluid towards the backing layer 220.

[0083] The material of the absorbent layer 221 can also prevent liquid collected in the wound dressing 100 from flowing freely within the dressing, and preferably acts to contain any liquid collected within the dressing. The absorbent layer 221 also assists in distributing fluid throughout the layer via wicking, so that fluid is absorbed from the wound site and stored throughout the absorbent layer. This assists in preventing pooling in areas of the absorbent layer. The capacity of the absorbent material must be sufficient to manage the rate of exudate from the wound when under a pressure negative pressure. As in use, the absorbent layer is subjected to a negative pressure, the material of the absorbent layer is selected to absorb liquid in this situation. There are many materials capable of absorbing liquid under negative pressure, for example superabsorbent materials. The absorbent layer 221 can typically be an ALLEVYN TM Foam, Freudenberg 114-224-4 or Chem-Posite TM 11C-450. In some embodiments, the absorbent layer 221 can comprise a composite comprising superabsorbent powder, fibrous material such as cellulose, and binder fibres. In preferred embodiments, the composite is an air-laid, thermally bonded composite.

[0084] In some embodiments, the absorbent layer 221 is a layer of nonwoven cellulose fibres with superabsorbent material in the form of dry particles dispersed throughout. The use of cellulose fibres introduces a rapid wicking element, which assists in rapidly and evenly distributing liquid absorbed by the dressing. The juxtaposition of the multi-stranded fibres results in strong capillary action in the fibrous mat, which assists in distributing the liquid. In this way, the superabsorbent material is effectively supplied with liquid. The wicking also assists in bringing the liquid into contact with the overlying cover layer, to help increase the transpiration rate of the dressing.

[0085] An orifice, hole, or aperture 227 is preferably provided in the backing layer 220 to allow negative pressure to be applied to the dressing 100. A fluid connector 110 is preferably attached or sealed to the top of the backing layer 220 over the aperture 227 created in the dressing 100 and delivers negative pressure via the aperture 227. A length of tubing can be coupled to the fluid connector 110 at a first end and to a pump unit (not shown) at a second end to allow fluid to be pumped out of the dressing. In the case where the fluid connector is adhered to the top layer of the wound dressing, a length of tubing can be coupled at the first end of the fluid connector such that the tubing or conduit extends away from the fluid connector parallel or substantially parallel to the top surface of the dressing. The fluid connector 110 can be adhered and sealed to the backing layer 220 using an adhesive, such as an acrylic, cyanoacrylate, epoxy, UV-curable, or hot melt adhesive. The fluid connector 110 can be formed from a soft polymer, such as polyethylene, polyvinyl chloride, silicone, or polyurethane, having a Shore A hardness of 30 to 90. In some embodiments, the fluid connector 110 can be made from a soft or conformable material.

[0086] Optionally, the absorbent layer 221 includes at least one through hole 228 positioned to be located under the fluid connector 110. In some embodiments, the through hole 228 can be the same size as the opening 227 in the backing layer, or can be larger or smaller. As shown in Figure 2C the single through hole can be used to create the opening located under the fluid connector 110. It will be appreciated that multiple openings can alternatively be used. Further, if more than one port is used in accordance with certain embodiments of the disclosure, one or more openings can be created in the absorbent layer in registration with each respective fluid connector. Although not necessary for certain embodiments of the disclosure, the through hole in the superabsorbent layer can provide a fluid flow path that remains unimpeded especially as the absorbent layer approaches saturation.

[0087] As shown in Figure 2C the orifice or through hole 228 is preferably provided in the absorbent layer 221 under the aperture 227 such that the aperture is directly connected to the transmission layer 226. This allows the negative pressure applied to the fluid connector 110 to communicate with the transmission layer 226 without passing through the absorbent layer 221. This ensures that the negative pressure applied to the wound site is not impeded by the absorbent layer as it absorbs wound exudate. In other embodiments, no orifice can be provided in the absorbent layer 221, or alternatively, multiple orifices can be provided located under the aperture 227. In other alternative embodiments, an additional layer (e.g., another transmission layer or a shield layer as described in International Patent Publication WO 2014 / 020440, the entire contents of which are incorporated by reference) can be provided over the absorbent layer 221 and under the backing layer 220.

[0088] The backing layer 220 is preferably gas-impermeable but moisture-permeable, and extends across the width of the wound dressing 100. For example, a backing layer 220 of a polyurethane membrane (e.g., Elastollan SP9109) with a pressure-sensitive adhesive on one side is gas-impermeable, and this layer is thus used to cover the wound and seal the wound cavity, upon which the wound dressing is placed. In this way, an effective chamber is created between the backing layer 220 and the wound site, in which negative pressure can be established. For example, by adhesive or welding techniques, the backing layer 220 is preferably sealed to the wound contact layer 222 in the boundary region surrounding the circumference of the dressing, ensuring that no air is drawn in through the boundary region. The backing layer 220 protects the wound from external bacterial contamination (bacterial barrier) and allows fluid from wound exudate to pass through this layer and evaporate from the outer surface of the membrane. The backing layer 220 preferably comprises two layers: a polyurethane membrane and an adhesive pattern coated on the membrane. The polyurethane membrane is preferably moisture-permeable and may be made of a material that has increased water permeability when wetted. In some embodiments, the moisture permeability of the backing layer increases as the backing layer becomes wet. The moisture permeability of the wet backing layer may be up to about ten times greater than that of the dry backing layer.

[0089] The absorbent layer 221 may have a larger area than the delivery layer 226, such that the absorbent layer covers the edge of the delivery layer 226, thereby ensuring that the delivery layer does not contact the backing layer 220. This provides an external channel for the absorbent layer 221, which directly contacts the wound contact layer 222, facilitating faster absorption of exudate into the absorbent layer. Furthermore, this channel ensures that no fluid can accumulate around the periphery of the wound cavity, which could otherwise permeate through the seal around the dressing, leading to leakage. Figure 2C As shown, the absorbent layer 221 may be defined to be smaller than the periphery of the backing layer 220, such that the boundary or border region is defined between the edge of the absorbent layer 221 and the edge of the backing layer 220.

[0090] like Figure 2C As shown, one embodiment of the wound dressing 100 includes an aperture 228 in an absorbent layer 221 located below the fluid connector 110. In use, for example when negative pressure is applied to the dressing 100, the wound-facing portion of the fluid connector can thus come into contact with the delivery layer 226, which thus helps to deliver negative pressure to the wound site even when the absorbent layer 221 is filled with wound fluid. Some embodiments allow the backing layer 220 to adhere at least partially to the delivery layer 226. In some embodiments, the aperture 228 is at least 1-2 mm larger in diameter than the wound-facing portion or the aperture 227 of the fluid connector 11.

[0091] Specifically, for embodiments having a single fluid connector 110 and a through-hole, it may be preferable that the fluid connector 110 and the through-hole are located as follows: Figure 2BThe eccentric position shown in FIG. 1 1. Such a position can allow the dressing 100 to be positioned on a patient such that the fluid connector 1 10 is elevated relative to the rest of the dressing 100. So positioned, the fluid connector 1 10 and filter 214 are less likely to come into contact with wound fluid that can prematurely occlude the filter 214, to the detriment of the delivery of negative pressure to the wound site.

[0092] Similar to the embodiments of wound dressings described above, some wound dressings include a perforated wound contact layer with silicone adhesive on the skin contact side and acrylic adhesive on the back side. In some embodiments, the wound contact layer can be composed of polyurethane, polyethylene, or polyester. A transmission layer is positioned over the boundary layer. An absorbent layer is positioned over the transmission layer. The absorbent layer can include a superabsorbent nonwoven (NW) pad. The absorbent layer can overhang the transmission layer at the perimeter by about 5 mm. The absorbent layer can have an aperture or through hole toward one end. The aperture can be about 10 mm in diameter. A backing layer is positioned over the transmission layer and absorbent layer. The backing layer can be a high moisture vapor transmission rate (MVTR) film, patterned with acrylic adhesive. The high MVTR film and the wound contact layer enclose the transmission layer and absorbent layer, creating a perimeter border of about 20 mm. The backing layer can have a 10 mm aperture over the aperture in the absorbent layer. A fluid connector can be joined over the hole, the fluid connector including a liquid-impermeable, gas-permeable semi-permeable membrane (SPM) overlying the aforementioned aperture.

[0093] Figure 2D An embodiment of a wound dressing is depicted that is similar to the wound dressing of Figures 2A-2C Referring to Figure 2D , a masking or obscuring layer 2107 can be positioned under at least a portion of the backing layer 2140. In some embodiments, the obscuring layer 2107 can have any of the same features, materials, or other details as any other embodiment of an obscuring layer disclosed herein, including but not limited to having any viewing windows or apertures. Examples of wound dressings having obscuring layers and viewing windows are described in International Patent Publication WO 2014 / 020440, the entirety of which is incorporated by reference in its entirety. Additionally, the obscuring layer 2107 can be positioned adjacent to the backing layer, or can be positioned adjacent to any other desired dressing layer. In some embodiments, the obscuring layer 2107 can be adhered to the backing layer or integrally formed with the backing layer. Preferably, the obscuring layer 2107 is configured to have approximately the same size and shape as the absorbent layer 2110 so as to cover the absorbent layer. Thus, in these embodiments, the area of the obscuring layer 2107 will be less than the area of the backing layer 2140.

[0094] Preferably, the absorbent layer 2110 and the obscuring layer 2107 include at least one through-hole 2145 positioned to be under the port 2150. Of course, the respective holes through these different layers 2107, 2140, and 2110 can have different sizes relative to one another. As Figure 2D shown in FIG. 26, a single through-hole can be used to create an opening under the port 2150. In certain embodiments, the port can be replaced or used in combination with a fluid connector depicted in, for example, Figure 2C FIG. 27. It will be recognized that multiple openings can alternatively be used. Further, if more than one port is used in accordance with certain embodiments of the present disclosure, one or more openings can be created in the absorbent layer and the obscuring layer in registration with each respective port. Although not necessary for certain embodiments of the present disclosure, the use of a through-hole in the superabsorbent layer can provide a fluid flow path that remains unimpeded, among other things, when the absorbent layer 2110 approaches saturation.

[0095] An aperture or through-hole 2144 can be provided in the absorbent layer 2110 and the obscuring layer 2107, under the aperture 2144, such that the aperture is directly connected to the transmission layer 2105. This allows negative pressure applied to the port 2150 to be transmitted to the transmission layer 2105 without passing through the absorbent layer 2110. This ensures that negative pressure applied to the wound site is not inhibited by the absorbent layer as it absorbs wound exudate. In other embodiments, no aperture can be provided in the absorbent layer 2110 and / or the obscuring layer 2107, or alternatively, multiple apertures can be provided under the aperture 2144.

[0096] In some embodiments, the obscuring layer 2107 can help reduce the unsightly appearance of the dressing during use by using a material that imparts partial obscuring or masking of the dressing surface. In one embodiment, the obscuring layer 2107 only partially obscures the dressing to allow the clinician to obtain the information they need by observing the spread of exudate on the surface of the dressing. The partially masking nature of this embodiment of the obscuring layer enables a skilled clinician to perceive the different colors caused by exudate, blood, byproducts, etc. in the dressing, allowing visual assessment and monitoring of the extent of spread on the dressing. However, since the color change of the dressing from its clean state to one containing exudate is only a slight change, the patient is unlikely to notice any aesthetic difference. Reducing or eliminating the visual indication of wound exudate from the patient's wound can have a positive impact on their health, such as reducing stress.

[0097] In some embodiments, the obscuring layer can be formed from a nonwoven fabric (e.g., polypropylene) and can be thermally bonded using a diamond pattern with 19% bond area. In various embodiments, the obscuring layer can be hydrophobic or hydrophilic. Depending on the application, in some embodiments, a hydrophilic obscuring layer can provide increased moisture vapor transmission. However, in some embodiments, a hydrophobic obscuring layer can still provide sufficient moisture vapor transmission (i.e., through appropriate material selection, thickness of the obscuring layer) while also allowing dyes or pigments to better remain in the obscuring layer. As such, the dyes or pigments can be trapped beneath the obscuring layer. In some embodiments, this can allow the obscuring layer to be colored in a lighter color or white. In preferred embodiments, the obscuring layer is hydrophobic. In some embodiments, the obscuring layer material can be sterilized using ethylene oxide. Other embodiments can be sterilized using gamma irradiation, electron beam, steam, or other alternative sterilization methods. Additionally, in various embodiments, the obscuring layer can be colored or pigmented, for example, in a medical blue color. The obscuring layer can also be comprised of multiple layers, including a pigmented layer laminated or fused to a stronger uncolored layer. Preferably, the obscuring layer is odorless and exhibits minimal fiber shedding.

[0098] Multi-layer dressings for use without negative pressure

[0099] Figures 3A-3D Various embodiments of a wound dressing 500 that can be used to heal a wound without negative pressure are shown. Figure 3E A cross-section of a wound dressing in Figures 3A-3D is shown. As shown in the dressing of Figures 3A-3E The wound dressing can have multiple layers similar to the dressing described with reference to Figures 2A-2D except that the dressing of Figures 3A-3E does not include a port or fluid connector. Figures 3A-3E The wound dressing of may include a cover layer 501 and an optional wound contact layer 505 as described herein. In some embodiments, the cover layer 501 can be permeable to moisture and / or air. The wound dressing can include various layers between the wound contact layer 505 and the cover layer 501. For example, the dressing can include one or more absorbent layers or one or more transmission layers as described herein with reference to Figures 2A-2D .

[0100] As Figures 3A-3EAs shown in FIG. 5, the dressing 500 can include a perforated wound contact layer 505 and a top film 501. Additional components of the wound dressing 500 include a foam layer 504 of appropriate size, e.g., a polyurethane water cellular foam layer, to cover a wound corresponding to the recommended size of a particular dressing size selected. An optional activated charcoal cloth layer (not shown) of a size similar to or slightly smaller than the layer 504 can be provided to allow odor control. An absorbent layer 502, such as a layer of superabsorbent air-laid material containing cellulose fibers and superabsorbent polyacrylate particles, is disposed over the layer 504, has a size slightly larger than the layer 504, and allows the superabsorbent material to overlap and act as a leak prevention. A masking or shielding layer 503, e.g., a layer of three-dimensionally woven spacer fabric, is disposed over the layer 502, providing protection from pressure while allowing the top surface of the superabsorbent, which will retain colored exudate, to be partially masked. In this embodiment, the size of this layer (in plan view) is smaller than the layer 502 to allow the edges of the absorbent layer to be visible, which can be used by a clinician to assess whether the dressing needs to be changed.

[0101] The wound dressing 500 can incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layers, acid group providing layers) as described herein in this section or elsewhere. Those skilled in the art will appreciate that the wound dressing 500 can incorporate any of the one or more nitric oxide generating layers disclosed herein in this section or elsewhere in the specification. Those skilled in the art will also appreciate that the one or more nitric oxide generating layers can be incorporated as an entire component layer or as part of a component layer. In some embodiments, the nitric oxide generating layer(s) can be disposed beneath the cover layer 501. In some embodiments, the one or more nitric oxide generating layers can be disposed above the wound contact layer 505. In certain embodiments, the dressing 500 can not include the wound contact layer 505, such that one of the nitric oxide generating layers can be the lowermost layer and be configured to access the wound surface. In some embodiments, the one or more nitric oxide generating layers can be disposed beneath the foam layer 504. In some embodiments, the one or more nitric oxide generating layers can replace the foam layer 504. In some embodiments, the dressing 500 can include only the cover layer 501 and the one or more nitric oxide generating layers. In some embodiments, the one or more nitric oxide generating layers or components thereof (e.g., nitrite providing layers as described herein) can be separate from the wound dressing 500. For example, the one or more nitric oxide generating layers or components thereof can be disposed as a separate layer that can be placed on a wound, and the wound dressing 500 can be placed thereon.

[0102] As previously described herein, the one or more nitric oxide generating layers can be incorporated into or used with commercially available dressings, such as ALLEVYN TM foam, ALLEVYN TMLife, ALLEVYN TM Adhesive, ALLEVYN TM Gentle Border, ALLEVYN TM Gentle, ALLEVYN TM Ag Gentle Border, ALLEVYN TM Ag Gentle, Opsite Post-Op Visible. In some embodiments, the wound dressing 500 can include a cover layer 501, a wound contact layer 505, and a nitric oxide generating layer sandwiched therebetween. In some embodiments, the wound dressing 500 can 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.

[0103] Further details regarding wound dressings that can be used in combination with or supplemental to the embodiments described herein are found in U.S. Patent No. 9,877,872, entitled “WOUND DRESSING AND METHOD OF TREATMENT,” issued January 30, 2018, the disclosure of which is hereby incorporated by reference in its entirety, including further details related to embodiments of wound dressings, components and principles of wound dressings, and materials for use in wound dressings.

[0104] Multi-layer wound dressings with integrated negative pressure source

[0105] In some embodiments, a negative pressure source (e.g., a pump) and some or all other components of a TNP system (e.g., a power source, sensors, connectors, user interface components (such as buttons, switches, speakers, screens, etc.), and the like) can be integrated with a wound dressing (e.g., the dressings described above Figures 1-3E Further, some embodiments related to wound treatment including the wound dressings described herein can also be used in combination with or supplemental to those described in International Application WO 2016 / 174048 and International Patent Application PCT / EP2017 / 055225, entitled “WOUND TREATMENT APPARATUSES AND METHODS WITH NEGATIVE PRESSURE SOURCE INTEGRATED INTO THE WOUND DRESSING,” filed March 6, 2017, the disclosure of which is hereby incorporated by reference in its entirety, including further details related to embodiments of wound dressings, components and principles of wound dressings, and materials for use in wound dressings and components of wound dressings.

[0106] In some embodiments, the pump and / or other electronic components can be configured to be positioned adjacent to or next to the absorbent layer and / or the transmission layer in the wound dressing, such that the pump and / or other electronic components are still part of a single device to be applied to the patient, with the pump and / or other electronics positioned away from the wound site.

[0107] Nitric oxide generating layer

[0108] Figures 4-5 A wound dressing 12000 including a nitric oxide generating layer is shown in accordance with some embodiments. In the illustrated embodiment, the wound dressing 12000 can include a cover layer 12200, an activator layer 12400, and a nitrite providing layer 12600. In some embodiments, the wound dressing 12000 can include additional layers as further described herein. Those of skill in the art will appreciate that although the various segments of the dressing can be referred to as “layers,” such segments can have other suitable shapes or configurations. As will be appreciated by those of skill in the art, the wound dressing and / or nitric oxide delivery embodiments described herein in this section or elsewhere in the specification can be applied over the skin over and / or around the wound, such as over the area around the wound.

[0109] The cover layer 12200 can be gas impermeable but moisture permeable, and can extend across the width of the wound dressing 12000. For example, a cover layer 12200 that is a polyurethane film (e.g., Elastollan SP9109 or Elastollan SP806) with a pressure sensitive adhesive on one side can be gas impermeable, and the layer thus serves to cover the wound and seal the wound cavity onto 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, a negative pressure can 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 liquid from the wound exudate to be transported through this layer and evaporated from the outer surface of the film. The cover layer 12200 can comprise two or more layers, for example, a polyurethane film and a pattern of adhesive spread onto the film. In certain examples, the polyurethane film can be moisture permeable, and can be made of a material that has an increased water permeability when wetted. In some embodiments, the moisture permeability of the cover layer increases when the cover layer becomes wet. The moisture permeability of a wet cover layer can be up to about ten times greater than the moisture permeability of a dry cover layer. In some embodiments, the cover layer 12200 can be replaced or supplemented with an additional wound dressing described elsewhere herein, such that the additional wound dressing is positioned over the nitric oxide generating layer. The cover layer can also be rainproof, such that a dressing incorporating such a cover layer can be used in the shower. The cover layer can be configured such that nitric oxide does not immediately escape through the cover layer, meaning that the cover layer is nitric oxide impermeable or semi-impermeable, thereby retaining the nitric oxide in the tissue such that the nitric oxide can interact with the user's body. Those skilled in the art will appreciate that the cover layer can be made to be both vapor permeable and nitric oxide impermeable.

[0110] The nitrite providing layer 12600 can provide one or more nitric oxide releasing agents at the wound site. The nitric oxide releasing agents can include any chemical entity that will generate nitric oxide at the wound site when activated or otherwise stimulated to activate. In some embodiments, the nitric oxide releasing agents can include nitrite ions, nitrite salts, organic and inorganic nitrites, or any pharmacologically acceptable source of nitrite such that nitrite ions can be reduced to generate nitric oxide at the wound site. For example, the nitrite providing layer 12600 and / or element can comprise one or more of ammonium nitrite, lithium nitrite, calcium nitrite, sodium nitrite, potassium nitrite. In some embodiments, the nitrite providing layer can be a suitable layer of material or element comprising an alkali metal nitrite and / or an alkaline earth metal nitrite. In certain embodiments, the nitrite salts can include: LiN02, NaN02, KN02, RbN02, CsN02, FrN02, Be(N02)2, Mg(N02)2, Ca(N02)2, Sr(N02)2, Ba(N02)2, Ra(N02)2, or any other suitable nitrite salt. In some embodiments, a precursor of nitrite ions, such as nitrous acid, nitrate ions, nitroprusside ions, or any pharmacologically acceptable salt thereof can be used as a source of nitrite. In some embodiments, the nitric oxide releasing agents can include nitrite salts such as nitro-functionalized compounds. For example, the nitric oxide releasing agents can include nitroglycerin, isosorbide dinitrate, mononitrate isosorbide, N-(ethoxycarbonyl)-3-(4-morpholinyl) sydnonimine; 3-morpholinosydnonimine; 1,2,3,4-oxadiazolium; 5-amino-3-(3,4-di-chlorophenyl)-chloride; 1,2,3,4-oxadiazolium; 5-amino-3-(chloro-2-methyl-phenyl) chloride; 1,2,3,4-oxadiazolium 3-(3-chloro-2-methylphenyl)-5-[[[cyanomethylamino] carbonyl] amino]-hydroxide inner salt; S-nitroso-N-acetyl-(D,L)-penicillamine; l-[(4',5'-bis(carboxymethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3, diethyl-l-triazenedi-potassium salt; and [l-(4',5'-bis(carboxymethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3-diethyl-l-triazene diacetoxymethyl ester.

[0111] In some embodiments, the nitrite-providing layer 12600 can include a nitric oxide releasing agent. In some embodiments, the nitric oxide releasing agent can include a diol diazepine salt, including an O-alkylated diol diazepine salt, an O-derivatized diol diazepine salt, and a non-O-derivatized diol diazepine salt. For example, the nitric oxide releasing agent can include diethylamine / NO, V-PYRRO / NO, and / or spermine / NO. In some embodiments, the nitric oxide releasing agent of the nitrite-providing layer 12600 can include an S-nitrosothiol, such as S-nitroso-gluthathione, S-nitroso-N-acetylcysteine, S-nitroso-acetylpentiamine. In some embodiments, the nitric oxide releasing agent of the nitrite-providing layer 12600 can include a silicon dioxide or silicon dioxide nanoparticle modified with nitric oxide. In some embodiments, the nitric oxide releasing agent can be a polymer modified with nitric oxide to include nitric oxide. For example, polyethyleneimine, polypropyleneimine, polybutyleneimine, polyurethane, or polyamide can be modified with nitric oxide to form a diol diazepine salt. In some embodiments, the nitrite-providing layer 12600 can be composed of such a polymer modified with nitric oxide. Further examples of nitric oxide releasing agents are provided in International Publication No. WO 2006 / 058318 and Liang et al., “Nitric oxide generating / releasing materials”, Future Science OA, 1(1) (2015), which are incorporated by reference herein in their entirety.

[0112] In some embodiments, the nitrite-providing layer 12600 can include a nitric oxide releasing agent (e.g., sodium nitrite) in an aqueous solution. For example, the nitrite-providing layer 12600 can include a material that absorbs a solution of a nitric oxide releasing agent (e.g., sodium nitrite). In some embodiments, the nitrite-providing layer 12600 can include a dry nitric oxide releasing agent (e.g., sodium nitrite) in solid form.

[0113] The nitrite-providing layer 12600 can include a mesh, a foam, a gel, or any other material suitable for containing a nitric oxide releasing agent. For example, the nitrite-providing layer 12600 can include a mesh that has absorbed a solution of a nitric oxide releasing agent (e.g., sodium nitrite). The mesh can be knitted, woven, or non-woven. The mesh can be made of a polymeric material, such as viscose, polyamide, polyester, polypropylene, or a combination thereof. In some embodiments, the nitrite-providing layer 12600 can include polypropylene, polyester, polyurethane, polyvinyl chloride, polyamide, viscose, polyester, polypropylene, and / or cellulose. As described herein, the nitrite-providing layer 12600 can be composed of one or more polymers modified with nitric oxide. The nitrite-providing layer 12600 can also be made of a hydrogel that does not have acidic groups to prevent the release of nitric oxide from reaction with nitrite ions. In some embodiments, the nitrite-providing layer 12600 can be composed of a colored material, such that the nitrite-providing layer 12600 can be visible to aid in the positioning of the wound dressing 12000 during application to a wound and to reduce the risk of incomplete removal of the nitrite-providing layer 12600 from the wound after treatment. The nitrite-providing layer 12600 can be fully permeable or semi-permeable to the diffusion of nitric oxide.

[0114] In some embodiments, the nitrite-providing layer 12600 is the lowermost layer of the dressing 12000, such that the nitrite-providing layer 12600 can contact a wound. In some embodiments, the nitrite-providing layer 12600 can be positioned within and / or above a wound. The nitrite-providing layer can be configured such that the nitrite-providing layer 12600 does not substantially adhere to skin or a wound, or cause damage to a wound when in contact with the wound. In some embodiments, the dressing 12000 can include one or more layers, such as a wound contact layer, beneath the nitrite-providing layer 12600. In some embodiments, the wound dressing 12000 can include two or more nitrite-providing layers. For example, the wound dressing 12000 can include 2, 3, 4, 5, 6, 7, or more nitrite-providing layers. In some embodiments, the nitrite-providing layer 12600 can be separate from the wound dressing 12000. For example, the nitrite-providing layer 12600 can be provided as a separate layer that can be placed on a wound, and the wound dressing 12000 can be placed thereon. The nitric oxide releasing agent can be incorporated into the nitrite-providing layer to provide a nitrite dose (e.g., a sodium nitrite dose) 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, in units of M (moles). For example, the dose can be about 0.50 M, about 0.01 M, about 1.5 M, about 2 M, or about 2.5 M.

[0115] The activator layer 12400 can contain a chemical agent, functional group, or moiety that can activate and / or facilitate the release of nitric oxide from the nitric oxide releasing agent. For example, protons or an acidic environment facilitate the reduction of nitrite to nitric oxide, and the activator layer 12400 can include an acidic group or moiety that can provide protons in an aqueous environment, thereby lowering the pH at the application site. In certain embodiments, the acidic group or moiety is immobilized at the activator layer 12400, for example, on the surface of the activator layer 12400. The acidic group or moiety can be covalently bonded at the activator layer 12400. In some embodiments, the activator layer 12400 can include an acidic solution. The activator layer 12400 can include a mesh, foam, gel, or any other material suitable for containing an acidic group or moiety. In some embodiments, the activator layer 12400 is positioned above the nitrite-providing layer 12600, or the activator layer 12400 can be positioned below the nitrite-providing layer 12600. In some embodiments, the activator layer 12400 can comprise a proton source such as water, methanol, ethanol, propanol, butanol, pentanol, hexanol, phenol, naphthol, or a polyol; an aqueous acidic buffer such as a phosphate, succinate, carbonate, acetate, formate, propionate, butyrate, a fatty acid, an amino acid, or ascorbic acid; or any suitable enzymatic or catalytic compound. In some embodiments, a bodily fluid such as blood, lymph, bile, or wound exudate can act as an activator, and can assist the activator layer 12400. In some embodiments, the wound dressing 12000 can not include an activator layer 12400, and a wound fluid or wound exudate can act as an activator. Additional examples of activators for nitric oxide releasing agents are provided in International Publication No. WO 2006 / 058318 and Liang et al., “Nitric oxide generating / releasing materials,” Future Science OA, 1(1) (2015), which are incorporated by reference herein in their entireties.

[0116] In some embodiments, the wound dressing 12000 can include two or more nitrite-providing layers and / or two or more activator layers. For example, the wound dressing 12000 can include 2, 3, 4, 5, 6, 7, or more nitrite-providing layers and / or activator layers.

[0117] In some embodiments, the activator layer 12400 comprises a hydrogel, such that the activator layer 12400 can absorb wound exudate. In certain examples, the activator layer 12400 can be comprised of a xerogel. The activator layer 12400 can be comprised of any suitable material disclosed herein. The gel of the activator layer 12400 can be present in different physical forms. For example, the activator layer 12400 can be foamed during curing. The hydrogel can be poured into a foam, which is then cured in the foam. In some embodiments, the activator layer 12400 can be perforated through its thickness. The size of the perforations can be set to allow fluid absorption and to allow release of the required therapeutic dose of nitric oxide from the wound dressing. For example, the perforations can have a diameter sized to be between about 0.1 mm and 10 mm, between 0.15 mm and 7 mm, between 0.2 mm and 5 mm, between 0.5 mm and 4 mm, or between 0.7 mm and 3 mm. The perforations can have a circular shape, a square shape, a triangular shape, or any other suitable shape. The foamed construction and / or the perforations can aid the fluid handling capacity of the activator layer.

[0118] In some embodiments, the activator material for the activator layer can be provided as a dispensable composition, such as a prepolymer solution or other moldable form, rather than as an activator layer such as activator layer 12400, so that it can be more freely applied over and / or around a wound. For example, the activator material can be provided as a gel prepolymer solution so that it can be closely applied to a wound or around a wound having an irregularly shaped size by a clinician. In some embodiments, the activator material, such as a gel prepolymer solution, can be provided in and / or applied with a syringe, and the gel prepolymer solution can have a viscosity suitable for dispensing from a syringe. The activator material can also be formulated so that it can quickly solidify and no longer flow once applied to a wound or around a wound. The activator material can include an evaporative solvent, such as isopropyl alcohol. The activator material can have a suitable secondary solidification mechanism, such as, for example, a light- initiated acrylate functionality. In some embodiments, the activator material can be provided as a reactive two-part system. For example, a first part and a second part can be provided to mix immediately prior to dispensing to create a polymer. In some embodiments, the first part and the second part can be oppositely charged flowable gels so that they can interact upon mixing to provide a substantially non-flowing gel. In some embodiments, the activator material can include a material that changes in response to an environmental change, such as a gel. For example, the activator material can include a material such as certain pluronics so that it can be solidified upon a change in temperature once applied to the skin from a dispenser or syringe. The activator material can be applied so that it can interact with nitrite from nitrite-providing layer 12600 (which can provide nitrite) to generate nitric oxide. Once the activator material is applied and solidified or otherwise not flowing, the cover layer 12200 can be applied.

[0119] Once the dressing 12000 is activated, such as by placing 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 the acidic environment provided by the activator layer 12400, as shown below:

[0120]

[0121] The activator layer 12400 and the nitrite-providing layer 12600 may be positioned such that the nitric oxide releaser 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 dressing 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 fluidly isolated from each other before the dressing 12000 is applied to a patient to prevent premature release of nitric oxide. For example, the nitrite-providing layer 12600 may be disposed in a separate package from the rest of the dressing 12000. Once the dressing 12000 is activated, the nitric oxide releaser from the nitrite-providing layer 12600 may be dispersed within the dressing 12000. In some embodiments, the nitric oxide releaser may be dissolved in wound exudate, and the wound exudate may promote the dispersion of the nitric oxide releaser. In the presence of the activator in the activator layer 12400, at least a portion of the nitric oxide releaser will react to release nitric oxide. The generated nitric oxide may diffuse into the wound or be delivered to the wound via any suitable mechanism. In some embodiments, the generated nitric oxide may not be delivered immediately or at all, but may be retained within a dressing, for example, by means of a selectively permeable membrane, such that the nitric oxide may prevent the growth of microorganisms within the dressing or kill microorganisms within the dressing.

[0122] In some embodiments, the wound dressing 12000 can include a reducing agent to facilitate reduction of the nitric oxide releasing agent (e.g., nitrite ions) to nitric oxide. Physiologically acceptable examples of such reducing agents include, but are not limited to: iodide ions, ascorbic acid, ascorbate salts (e.g., sodium ascorbate), erythorbate salts (e.g., sodium erythorbate), hydroquinone, butylated hydroquinone, tocopherols, butylated hydroxyquinolines, hydroquinone variants, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, potassium iodide, ascorbate variants, erythorbate variants, any other suitable reducing agent, and / or any of the antioxidants and / or reducing agents described herein. The reducing agent can be included in one or more layers of the wound dressing 12000. For example, the reducing agent can be included in the cover layer 12200, the activator layer 12400, the nitrite providing 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 can be incorporated into the one or more layers, for example, by physical entrapment, physical blending, coating, covalent bonding, or any other suitable method. The reducing agent can be incorporated in the appropriate layer at about: 0.01 to 5.0%, 0.1 to 4.5%, 1.0 to 3.0%, 1.0 to 1.5%, and / or 1.5 to 2.5% w / w%. For example, the w / w% can be about 0.02%, about 0.03%, about 0.8%, about 1.2%, about 1.4%, or about 2.43%. Higher levels of reducing agent can result in increased production of nitric oxide; however, very high levels of reducing agent can become toxic.

[0123] As described herein, the nitric oxide source layer can include nitrite and can be referred to in this specification as a nitrite delivery layer or a nitrite providing layer. As described herein, the activator layer can include an acid and can be referred to in this specification as an acid providing layer or an acid delivery layer. The nitrite providing layer / nitrite delivery layer / nitrite providing layer and the activator layer / acid providing layer can be collectively referred to or individually referred to in this specification as a nitric oxide generating layer.

[0124] Nitric oxide dressing materials and configurations

[0125] As will be appreciated by those skilled in the art, the above with respect to Figures 4-5The nitric oxide delivery dressing 1200 and the materials and dressing configurations described elsewhere in the specification can include a number of suitable configurations and different types of materials. For example, the topmost layer furthest from the wound can be a top film layer or cover film layer, such as the top or cover layers disclosed herein, such as a polyurethane material. Such a top film or cover film can be composed of the material used in the cover layer of the RENASYS Drape sold by Smith + Nephew. For example, in some embodiments, the cover layer can be an IV3000 top film. Beneath the top film layer or cover film layer can be a masking layer or fabric layer, which can be composed of any suitable material disclosed herein as a masking layer or fabric layer. The masking layer can be composed of a stretch and non-stretch polyester, polyethylene, polypropylene, polypropyl ethylene, and nonwovens, and suitable blends of their configurations. For example, in some embodiments, the masking layer can be a 17 gsm polypropylene masking layer. Additional suitable nonwovens and blends can also be utilized. In certain embodiments, the masking layer can be a foam. Beneath the masking layer or fabric layer is an activator layer, similar to the activator layers described herein and throughout the specification. Such an activator layer can be composed of a hydrogel adhesive, optionally including a central polyester support grid and / or a support release liner. For example, in some embodiments, the activator layer can be in the form of DURAFIBER loaded with a hydrogel as described herein. DURAFIBER by Smith + Nephew is a commercially available absorbent nonwoven made from cellulose. In such an example, approximately 6 grams of an equivalent of hydrogel can be loaded onto a 10.8 cm x 10.8 cm piece of DURAFIBER, which can be cut into 10 cm x 10 cm, resulting in approximately 5.14 grams of hydrogel on a 10 cm x 10 cm piece of DURAFIBER. The activator layer can be composed of any suitable hydrogel material disclosed herein, such as an acrylic hydrogel and / or a sulfonic acid hydrogel. Beneath the activator layer can be a collection distribution layer, which can be composed of any suitable collection distribution layer material disclosed herein (e.g., with respect to Figures 2C-2D ) the collection distribution layer can be composed of a 3-D knit, gauze, and / or stretch polyester fiber woven into a mesh form, similar to the material used by Smith + Nephew in Acticoat Flex, but silver is optional. In some embodiments, the collection distribution layer can be composed of a mixture of a pre-polymer solution with water, a surfactant, and polyethylene glycol (e.g., the foam used by Smith + Nephew in Allevyn Foam). The masking layer and the collection distribution layer can use the same material and be interchangeable. In certain embodiments, the collection distribution layer can be pressed into and / or cured into the activator layer. Curing the collection distribution layer into the activator layer can increase the rate of nitric oxide formation due to more rapid transport. Beneath the collection distribution layer, there can be a backing layer, which can be composed of any suitable backing layer material disclosed herein (e.g., with respect toFigures 2C-2D ) Any suitable material disclosed herein. For example, the wound contact layer can include a silicone adhesive and a perforated polyurethane film. The wound contact layer can include an acrylic adhesive. A nitrite providing layer composed of any suitable material disclosed herein can be positioned beneath the wound contact layer such that the nitrite providing layer is directly against the wound or other tissue. In some embodiments, the nitrite providing layer can be in other locations, for example, above the activator layer and / or elsewhere in the dressing. For example, in some embodiments, the nitrite providing layer can be a separate 17 gsm polypropylene mesh saturated with a sodium nitrite solution. In certain embodiments, the ALLEVYN or PICO dressings disclosed in FIGS. 2-3 can be placed directly above the activator layer and the underlying nitrite providing layer. Placing the nitrite providing layer directly against the wound, the area surrounding the wound, and / or other tissue can allow for increased direct release of nitric oxide into the tissue. As will be appreciated by one of skill in the art, the wound dressings and / or nitric oxide delivery embodiments described herein in this section or elsewhere in the specification can be applied over the wound and / or over the skin surrounding the wound, such as over the area surrounding the wound.

[0126] Chemiluminescence

[0127] Figure 6 An example setup 600 for testing a chemiluminescence protocol for a nitric oxide delivery dressing as disclosed above with respect to Figure 4 and 5 An example setup 600 for testing a chemiluminescence protocol for a nitric oxide delivery dressing as disclosed above with respect to The sample cell 602 and nitrogen source can be connected to the apparatus after pre-heating the device with air flow at atmospheric pressure. The nitrogen flow through the mass flow controller can be set to a suitable value, such as between about: 1 to 100, 10 to 90, 25 to 75, 40 to 60 mL / min, or about 50 mL / min. After purging the system (such as for about 1 to 60, 10 to 50, 20 to 40, or about 30 minutes), a nitrite providing layer (such as a nitrite mesh) and an activator layer (such as an acid-providing hydrogel) can be placed in the sample cell 602. In embodiments, the total area of the nitrite mesh is less than the activator layer. In particular embodiments, the nitrite providing layer and / or the activator layer can have a length and / or width of about 0.5 to 20, 1 to 10, 2 to 8, or about 4 to 6 centimeters. In certain embodiments, the nitrite providing layer can be 2.5 cm x 2.5 cm, while the activator layer is 3 cm x 3 cm.

[0128] NO / NO2release concentrations can be measured by a chemiluminescent detector at an appropriate rate, such that the concentration is checked and monitored periodically (e.g., about every 1, 2, 5, 10, 30, 60, or 90 seconds) in ppb or ppm units. In certain embodiments, the NO / NO2concentration can be checked in ppm units.

[0129] As will be appreciated by those skilled in the art, for the dressings disclosed herein, such as with respect to the dressings described Figures 4-5 It is desirable to maximize NO over NO2for the dressings disclosed herein. While nitric oxide (NO2) can exert antimicrobial properties, NO2does not have vasodilatory properties nor does it have the ability to activate cell proliferation as does NO. Thus, it is generally desirable to minimize the production of NO2in the acidification of nitrite, such as by means to reduce the oxidation of dissolved nitric oxide (NO) such as by removing oxygen from the hydrogel body in which the acidification of nitrite is occurring. The nitric oxide delivery dressings disclosed herein can produce both NO and NO2. In some embodiments, the nitric oxide dressings disclosed herein can produce NO and NO2at a ratio such as about 0.5: 1 to 500: 1, 1: 1 to 400: 1, 10: 1 to 300: 1, 20: 1 to 200: 1, 50: 1 to 100: 1, of NO / NO2. For example, the ratio can be about or at least about 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.

[0130] FIG. 7 illustrates an example of an experimental setup 700 demonstrating nitric oxide delivery from a combination of an activator layer and a nitrite provision layer under negative pressure, similar to the dressings described with respect to Figure 4 and 5 As shown in FIG. 7, a negative pressure wound therapy pump 702 is connected to a negative pressure wound therapy dressing 704 as 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. Prior to the application of negative pressure, the test solution does not change color. After running negative pressure for a period of time to ensure that no background color change is occurring, an activator layer as described herein (such as an acid-providing hydrogel) is placed in the chamber and negative pressure is applied. Again, no color change occurs. Finally, a nitrite provision layer as described herein (such as a sodium nitrite mesh) is placed onto the activator layer without the nitrite provision layer touching the nitrite test solution, and negative pressure is applied. After 15 minutes of negative pressure, the indicator solution changes color, indicating that the interaction between the activator layer and the nitric oxide layer can produce nitric oxide, even under negative pressure.

[0131] As will be appreciated by those skilled in the art, negative pressure can be applied to any of the nitric oxide delivery dressings disclosed herein, e.g. Figures 4-5 The dressings described elsewhere in the specification. The dressings, such as Figures 2A-2D The dressings described in the'000' section, can be placed over the activator layer and the nitrite-providing layer placed in the wound, thereby delivering nitric oxide to the wound while applying negative pressure wound therapy.

[0132] Figures 8A through 8C Examples of chemiluminescence experiment runs using a similar protocol to the one described above are shown. As will be appreciated by those skilled in the art, these measurements made in these experiment runs are merely exemplary, and the disclosure herein is not limited to such values. Figure 8A Experimental results are shown when testing a dry sodium nitrate mesh embodiment having the arrangement shown in the '000' section, which includes a polyurethane cover layer overlying a stretched polyester ADL layer, which is over a hydrogel activator layer, which is sandwiched between another stretched polyester ADL layer, which is over a dry sodium nitrate mesh. In this experiment run, after the addition of DI water, the dry sodium nitrate mesh released approximately 550 ppm of NO and 75 ppm of NO2 at its peak at the 25 minute mark, and the concentration slowly decreased to approximately 80 ppm of NO and 10 ppm of NO2 at the 50 minute mark. Figure 8A

[0133] Figure 8B Experimental results are shown when testing a complete dressing design having a pull-out tab and a self-sealing border. The pull-out tab is used to initially separate the nitrite-providing layer from the activator layer, so that upon removal of the tab and the dressing becoming wet, the interaction between the nitrite-providing layer and the activator layer produces nitric oxide. In this experiment run, after the addition of DI water, the complete dressing design having a pull-out tab and a self-sealing border released approximately 84 ppm of NO and 15 ppm of NO2 at its peak at the 17 minute mark, and the concentration slowly decreased to approximately 25 ppm of NO and 5 ppm of NO2 at the 50 minute mark.

[0134] Figure 8C ​Examples showing experimental results for dressings containing degradable films are shown. Here, the degradable film was placed between the activator layer and the nitrite providing layer, such that nitric oxide was generated once the degradable layer ruptured. In this experimental run, the dressing containing the degradable film released approximately 1000 ppm of NO and 45 ppm of NO2 at its peak at the 25 minute mark, and slowly decreased in concentration to approximately 225 ppm of NO and 20 ppm of NO2 at the 50 minute mark after the addition of DI water. The activator layer containing sodium erythorbate was also tested using this experimental protocol. In this experimental run, the activator layer containing sodium erythorbate released approximately 52 ppm of NO and 4 ppm of NO2 at its first peak at the 80 minute mark, 66 ppm of NO and 5 ppm of NO2 at its second and largest peak at the 110 minute mark, and slowly decreased in concentration to approximately 45 ppm of NO and 2 ppm of NO2 at the 160 minute mark after the addition of DI water.

[0135] Figure 9 Examples showing the relative peak output in ppm for activator hydrogels (providing acid) with or without a collection distribution layer, including polypropylene, polypropylene ethylene, or stretched polyester collection distribution layers with various gsm (g / m 2 ) of the collection distribution layer. Without a collection distribution layer, the peak NO and NO2 concentrations were approximately 55 ppm and 10 ppm, respectively; however, one skilled in the art will appreciate that a collection distribution layer can allow for improved fluid distribution and handling throughout a larger area such as a dressing. With a 17 gsm polypropylene pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 20 ppm and 2 ppm, respectively. With a 17 gsm polypropylene solidified collection distribution layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. As described above, a solidified collection distribution layer can allow for increased fluid transport and increased nitric oxide formation rate. With a polypropylene 30 g / m 2 pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. With a polypropylene 30 g / m 2 solidified collection distribution layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. With a polypropylene 40 g / m 2 pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 30 ppm and 2 ppm, respectively. With a polypropylene 40 g / m 2 solidified collection distribution layer, the peak NO and NO2 concentrations were approximately 38 ppm and 5 ppm, respectively. With a polypropylene ethylene 30 g / m 2 pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. With a polypropylene ethylene 30 g / m 2With the solidified collection distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. With the stretched polyester pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. With the FLEX pressed collection distribution layer, the peak NO and NO2 concentrations were approximately 55 ppm and 8 ppm, respectively.

[0136] Figures 10A through 10D Examples of NO and NO2 concentrations over time for several embodiments incorporating an activator layer and a nitric oxide providing layer are shown. As shown in FIG. 1, an activator layer containing approximately 2-3% sodium erythorbate was tested with or without different collection distribution layers that were either pressed or solidified. The gel without a collection distribution layer produced pNO = 785 ppm and pNO2 = 78 ppm. The activator layer with stretched polyester pressed into the gel produced pNO = 506 ppm and pNO2 = 24 ppm. For the case of stretched polyester solidified on the activator layer, pNO = 625 ppm; pNO2 = 50 ppm. For the case of polypropylene pressed into the gel, pNO = 508 ppm, pNO2 = 26 ppm. For the case of polypropylene solidified into the gel, pNO = 624 ppm, pNO2 = 26 ppm. Figures 10A-10B

[0137] Examples of NO and NO2 concentrations over time for several embodiments incorporating an activator layer and a nitric oxide providing layer are shown. As shown in FIG. 1, an activator layer containing approximately 2-3% sodium erythorbate was tested with or without different collection distribution layers that were either pressed or solidified. The gel without a collection distribution layer produced pNO = 785 ppm and pNO2 = 78 ppm. The activator layer with stretched polyester pressed into the gel produced pNO = 506 ppm and pNO2 = 24 ppm. For the case of stretched polyester solidified on the activator layer, pNO = 625 ppm; pNO2 = 50 ppm. For the case of polypropylene pressed into the gel, pNO = 508 ppm, pNO2 = 26 ppm. For the case of polypropylene solidified into the gel, pNO = 624 ppm, pNO2 = 26 ppm. Figures 10C-10D

[0138] Xerogel and hydrogel configurations

[0139] ​Throughout the specification, reference can be made to a xerogel. A xerogel can be formed from a gel by drying without blocking shrinkage. As will be appreciated by those skilled in the art, a xerogel is a gel having a very low free water content, so low that little reaction to form nitric oxide will occur without the addition of additional water and / or liquid. For example, a xerogel can be substantially free of water in the dry state. Drying can be accomplished by any suitable means known in the art, for example, freeze-drying.

[0140] In certain examples, a hydrogel (which can subsequently become a xerogel upon drying) can be generated with or without glycerol, and can contain a standard amount or twice, thrice, or four times the required amount of crosslinker PEG diacrylate as desired. A solution of 2-acrylamido-2-methyl-1 -propanesulfonic acid sodium salt can be present in the xerogel. The hydrogel and xerogel can be produced by converting 2-acrylamido-2-methyl-1 -propanesulfonic acid (SA) as supplied, stabilized with MEHQ, into the sodium salt by dissolving in water, then neutralizing to pH 7.0 with 50% NaOH and cooling the solution of neutralized acid (NaAMPS) with a 10C water bath. The hydrogel can contain between about 5.393 wt% 2-acrylamido-2-methyl-1 -propanesulfonic acid (equivalent to 1.0 SA), about 4.654 wt% 2-acrylamido-2-methyl-1 -propanesulfonic acid (equivalent to 0.85 SA), about 2.839 wt% 2-acrylamido-2-methyl-1 -propanesulfonic acid (equivalent to 0.5 SA), and / or about 1.457 wt% 2-acrylamido-2-methyl-1 -propanesulfonic acid (equivalent to 0.25 SA) to about 7.704 wt% 2-acrylamido-2-methyl-1 -propanesulfonic acid (equivalent to 1.5 SA). The hydrogel prepolymer can be prepared by pre-dispersing 2-hydroxy-2-methylpropione photoinitiator under micro light into PEG diacrylate, then mixing with a mixture of 58% 2-acrylamido-2-methyl-1 -propanesulfonic acid sodium aqueous solution (Na AMPS), sodium erythorbate, pre-milled 2-acrylamido-2-methyl-1 -propanesulfonic acid (AMPS acid), and glycerol for 10-20 minutes. The AMPS acid can be fully dissolved in the stirring Na AMPS solution, then glycerol is added slowly, and then the photoinitiator / diacrylate mixture in a water bath. In certain embodiments, the hydrogel can also be prepared in a mold with twice the normal amount of photoinitiator / crosslinker and / or omitting glycerol and / or using three times the amount of prepolymer mixture to form a gel three times as thick.

[0141] Nitric oxide generating dressings utilizing sodium nitrite

[0142] Figures 11A-11EEmbodiments of nitric oxide generating wound dressings having various layer arrangements are depicted. Those skilled in the art will appreciate that Figures 11A-11E The various layers depicted in FIG. 13 can be ordered in any suitable order, and the order depicted in the figure is merely an example. Further, those skilled in the art will appreciate that one or more layers can be omitted, and / or the wound dressing can include multiples of one or more of the layers shown. In some embodiments, the uppermost layer can be a cover layer 13002, which can have any of the same features, materials, or other details as the cover layers disclosed herein, e.g., composed of a film. The cover layer 13002 can be adapted to seal the dressing over a wound, and to be connected to a source of negative pressure and / or to maintain negative pressure at the wound site. In certain embodiments, a border region of the cover layer 13002 can be attached to the skin around the wound, thereby forming a seal such that wound exudate can be contained within the wound dressing 13000. Beneath the cover layer, there can be a masking or obscuring layer 13004 (referred to herein as a "masking layer") to prevent or limit visualization of the wound or wound exudate through the cover layer 13002. The masking layer 13004 can be positioned beneath at least a portion of the cover layer 13002. In some embodiments, the masking layer 13004 can have any of the same features, materials, or other details as any other embodiment of a masking layer disclosed herein, including but not limited to having any viewing windows or apertures. Examples of wound dressings having obscuring layers and viewing windows are described in International Patent Publications WO 2013 / 007973 and WO 2014 / 020440, the entire contents of which are incorporated by reference. Additionally, the masking layer 13004 can be positioned adjacent to the cover layer, or can be positioned adjacent to any other dressing layer as desired. In the embodiment shown, the masking layer 13004 is positioned between the cover layer 13002 and an activator layer 13006. As explained elsewhere herein and as will be appreciated by those skilled in the art, the activator layer can be an acid providing layer or other suitable layer. In certain embodiments, the masking layer 13004 can be adhered to or integrally formed with the cover layer 13002. The masking layer 13004 can be configured to have substantially the same size and shape as the activator layer 13006 so as to cover the activator layer. The masking layer 13004 can have an area that is less than the cover layer 13002. In some embodiments, the masking layer 13004 can wick fluid horizontally, and can also function as a collection distribution layer.

[0143] In particular embodiments, the activator layer 13006 can have any feature, material, or other detail in common with any other embodiment of an activator layer disclosed herein. For example, the activator layer 13006 can be an adhesive and can be composed of a hydrogel or xerogel configured to have a plurality of acidic groups or moieties that can provide protons in an aqueous environment. As explained elsewhere in this specification, under such acidic conditions, nitrite ions from the nitrite-providing layer 13010 can be reduced to nitric oxide for delivery to a wound or intact skin. As explained elsewhere herein and as will be appreciated by one of skill in the art, the activator layer can be a nitrite-providing layer or other suitable layer. The activator layer 13006 (e.g., a hydrogel layer) can include a plurality of perforations extending through the thickness of the activator layer, as described elsewhere herein. The plurality of perforations can allow or facilitate passage of wound exudate through the activator layer, such that wound exudate below or around the activator layer can be transported to one or more additional absorbent layers and / or one or more evaporation layers (e.g., cover layers) above the activator layer, thereby preventing excessive build-up of wound exudate below the activator layer 13006. Additionally, the plurality of perforations can provide increased surface area of the activator layer, thereby increasing the absorbency of the activator layer.

[0144] As Figure 11AAs shown in FIG. 1300, in some embodiments, a collection distribution layer 13008 can be placed between the activator layer 13006 and the nitrite-providing layer 13010. In certain embodiments, the collection distribution layer 13008 can be configured so as to advantageously wick fluid horizontally as fluid (e.g., wound exudate) is absorbed through the layers of the dressing 13000. This lateral wicking of fluid can allow the fluid to be maximally distributed through the activator layer 13006, enabling the activator layer 13006 to reach its full holding capacity. In addition, the collection distribution layer 13008 can facilitate nitric oxide generation, as nitrite ions dissolved in the fluid can be more rapidly spread across the surface of the activator layer 13006. Some embodiments of the collection distribution layer 13008 can include viscose fibers, polyester, polypropylene, cellulose, or a combination of some or all of these, and the material can be needle punched. Some embodiments of the collection distribution layer 13008 can include cellulose in the range of 40-160 gsm (or about 40 to about 160 gsm), such as 80 (or about 80) gsm. Some embodiments of the collection distribution layer 13008 can include polyethylene in the range of 40-150 grams per square meter (gsm). In some embodiments, the collection distribution layer 13008 can have a thickness of 1.2 mm or about 1.2 mm, or can have 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 collection distribution layer 13008 can be composed of a material that resists compression at the levels of negative pressure typically applied during negative pressure therapy.

[0145] The acquisition distribution layer 13008 can include a plurality of loosely packed fibers that can be arranged in a substantially horizontal network of fibers. In some embodiments, the acquisition distribution layer 13008 can be composed of a mixture of two fiber types. One fiber can be a flat fiber that can have a width of 20 microns to 50 microns, or about 20 microns to about 50 microns, and can include a cellulose-based material. The other fiber can be a bi-component fiber having an inner core of 8 pm to 10 pm in diameter, about 8 pm to about 10 pm in diameter, 7 pm to 11 pm in diameter, 6 pm to 12 pm in diameter, or 5 pm to 13 pm in diameter, and an outer layer of 1 pm to 2 pm in thickness, about 1 pm to about 2 pm in thickness, 1 pm to 2.3 pm, 0.8 pm to 2.5 pm, or 0.5 pm to 3 pm in thickness. The bi-component fiber can be a mixture of a polyethylene (PE) type material and a polyethylene terephthalate (PET). In some embodiments, the inner core of the bi-component fiber can be PET and the outer layer can be PE. The PE / PET fiber can have a smooth surface morphology, while the cellulose fiber can have a relatively rough surface morphology. In some embodiments, the ADL material can include about 60% to about 90% cellulose fiber, such as about 75% cellulose fiber, and can include about 10% to about 40% PE / PET fiber, such as about 25% PE / PET fiber. In some embodiments, the acquisition distribution layer 13008 can include split microfibers.

[0146] Most of the fiber volume may extend horizontally (i.e., parallel to the planes of the top and bottom surfaces of the material), or substantially or generally horizontally. In another embodiment, 80%-90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally or substantially or generally horizontally. In another embodiment, all or substantially all of the fiber volume may extend horizontally or substantially or generally horizontally. In some embodiments, most, 80%-90% (or about 80% to about 90%) of the fibers or more, or even all or substantially all of the fibers, span a distance (horizontal or lateral distance) perpendicular to the thickness of the collection distribution layer 13008, said distance being greater than the thickness of the collection distribution layer 13008. In some embodiments, the horizontal or lateral distance spanned by such fibers is 2 times (or about 2 times) or greater, 3 times (or about 3 times) or greater, 4 times (or about 4 times) or greater, 5 times (or about 5 times) or greater, or 10 times (or about 10 times) or greater than the thickness of the collection distribution layer 13008. The orientation of these fibers facilitates lateral wicking of fluid through the collection distribution layer 13008. This allows fluids, such as wound exudate, to be distributed more evenly throughout the collection distribution layer 13008. In some embodiments, the ratio of the amount of fluid wicked laterally across the collection distribution layer 13008 to the amount of fluid wicked vertically through the collection distribution layer 13008 under negative pressure can be 2:1 or greater, or about 2:1 or greater, or in some embodiments up to 10:1 or greater, or about 10:1 or greater.

[0147] continue Figure 11A In an embodiment, a nitrite-providing layer 13010 may be provided below the collection and distribution layer 13008. This nitrite-providing layer 13010 may have any of the same features, materials, or other details as any other embodiment of the nitrite-providing layer disclosed herein; for example, the nitrite-providing layer 13010 may be a nitrite-providing layer. For example, the nitrite-providing layer may be a wet grid impregnated with a sodium nitrite solution. In some embodiments, the nitrite-providing layer 13010 may be dry and includes a dry nitrite source, such as dried sodium nitrite. Such dried sodium nitrite may be loaded into a material layer composed of a suitable material such as any of the materials disclosed herein. As those skilled in the art will understand, the dry material and / or substance is a material and / or substance that is free of or relatively free of liquid. For example, polypropylene, polyethylene, or melt-extruded fibers may be suitable materials for such layers. In an embodiment, when the activator layer is a hydrogel, such a nitrite-providing layer 13010 may initially need to be separated from the activator layer 13006 to avoid reacting and generating nitric oxide before being applied to wounds and / or skin. Figure 11AAs depicted, a dried fluid collection and distribution layer 13008 can be used to separate the nitrite-providing layer 13010 and the hydrogel activator layer 13006 before application. However, such a dried nitrite-providing layer may be adjacent to the dry gel activator layer 13006 because the dry gel is not wet. In the case of a dry gel, activation can occur upon contact with a fluid such as wound exudate when the wound exudate is wicked through a dressing. In the case of a hydrogel, once a fluid such as wound exudate comes into contact with the collection and distribution layer 13008, nitrite ions can come into contact with the acidic environment created by the activator layer, thereby generating nitric oxide, which can then be transferred to the wound and / or skin. In some embodiments, each of the layers (e.g., the nitrite-providing layer, the activator layer, and any other suitable layer) may be stored dry before use. These layers may be moistened with a suitable liquid such as saline before application to the skin or wound.

[0148] like Figure 11B As depicted, to maintain nitric oxide release, multiple layers containing dried sodium nitrite, such as a first nitrite-providing layer 13010 and a second nitrite-providing layer 13012, can be present. These layers are "activated" when wound fluid reaches and wets (multiple) layers, allowing the sodium nitrite to contact the acidic groups of the hydrogel or dry gel of the activator layer 13006, thereby generating nitric oxide. In some embodiments, two, three, four, five, six, or more layers containing dried sodium nitrite may be present. Figure 11B As shown, the masking layer 13004 can be used to prevent contact between the second nitrite providing layer 13012 and the activator layer 13006. In some embodiments, an additional collection and distribution layer and / or masking layer may be sandwiched with the activator layer to provide an additional nitric oxide source.

[0149] like Figures 11C-11D As depicted, in some embodiments, the activator layer 13006 may be located below the nitrite-providing layer, thereby relying on dressings (e.g., from wound exudate) to wet and activate the nitrite-providing layer 13010.

[0150] like Figure 11EAs depicted in the middle, in some embodiments, the wound dressing 13000 can have a cover layer 13002 as its uppermost layer as described herein. For example, the cover layer 13002 can include an IV 3000 top film and border. A masking or shield layer 13004 as described herein can be located beneath at least a portion of the cover layer 13002. For example, the masking layer 13004 can include a 17 gsm polypropylene mesh. An activator layer 13006 as described herein can be located beneath the masking layer 13004. For example, the activator layer 13006 can include DURAFIBER loaded with a hydrogel as described herein, such as a 50% AMPS sodium-based hydrogel with a bisacrylamide crosslinker and with sodium erythorbate as a reducing agent. A nitrite provision layer 13010 as described herein can be located beneath the activator layer 13006. The nitrite provision layer 13010 can be an integral part of the wound dressing 13000, or it can be provided as a separate component for use with the wound dressing 13000 (e.g., provided in a package separate from the wound dressing 13000).

[0151] Nitric oxide delivery hydrogel-based wound dressing formulations

[0152] As previously discussed, under normal atmospheric conditions, nitric oxide (NO) is a short-lived, unstable gaseous species. This instability is due to the unpaired electron of the nitrogen, and as an unstable species with an unpaired electron, nitric oxide can be described as a free radical. However, in contrast to typical free radicals with lifetimes on the order of milliseconds (e.g., hydroxyl radicals or superoxide), nitric oxide is relatively stable and generally converts to more stable chemical species within seconds of its generation. Thus, for example, if gaseous nitric oxide contacts air, it rapidly reacts with oxygen to form nitrogen dioxide, as follows:

[0153] 2NO + O2→ 2NO2+ N2O4

[0154] Further, while nitrogen dioxide (NO2) can exert antimicrobial properties, it does not have vasodilatory properties nor is it capable of activating cell proliferation. Thus, it is generally desirable to reduce the generation of nitrogen dioxide as much as possible in the acidification of nitrite, such as by removing oxygen from the hydrogel host in which the acidification of nitrite is occurring to reduce the oxidation of dissolved nitric oxide (NO).

[0155] Under certain conditions, such as when in a purely gaseous state, NO can be stored for very long periods of time without significant loss. NO is a very hydrophobic compound and as such has limited solubility in water. Under normal conditions, the maximum solubility of NO in water is approximately 1.7 mM, which is similar to that of oxygen. Dissolved oxygen in aqueous solutions oxidizes dissolved nitric oxide. However, given the rate constant and low concentrations of dissolved NO and O2, this reaction is much slower than in the gaseous state, where the concentration of oxygen is very high. In particular, some embodiments disclosed herein advantageously reduce the oxidation of dissolved nitric oxide (NO) by removing oxygen gas from the nitrite-acidifying hydrogel body in which it occurs.

[0156] Those skilled in the art will appreciate that the nitric oxide generating or nitrite providing layers described herein, particularly those described above and elsewhere in the specification with respect to Figures 1-5 , 11A-11E, 12, and 13, can include both a nitric oxide source element (such as a nitrite providing element as disclosed herein) and an activator (such as an acid providing element as disclosed herein), e.g., a nitrite providing layer such as a nitrite providing layer as disclosed herein and an activator layer such as an acid providing layer as disclosed herein. The interaction between the nitrite providing element and the acid providing element can result in the formation of nitric oxide, which is suitable for delivery to a wound via suitable means. Those skilled in the art will further appreciate that the following formulations can be used with any of the embodiments described herein, such as Figures 1-5 , the wound dressings and devices of 11A-11E, 12, and 13.

[0157] As those skilled in the art will understand, hydrogels can be composed of various polymers, such as polyethylene glycol (PEG), hydrophilic polyurethane, polyvinyl alcohol, polyvinylpyrrolidone, or other suitable polymers. Such hydrogels can be crosslinked via suitable multifunctional agents, condensation, polymerization, irradiation, physical crosslinking, or other suitable means. Those skilled in the art will understand that any suitable crosslinking molecule can be used, such as N,N'-methylenebisacrylamide in the case of polyethylene glycol hydrogels. As those skilled in the art will further understand, conventional crosslinking agents are used to provide the necessary mechanical stability and control the adhesive properties of the composition. In some embodiments, the crosslinking agent may include tripropylene glycol diacrylate, polyethylene 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 can be introduced into such hydrogel systems to generate nitric oxide. For example, suitable agents for introducing such functional groups may include silane coupling agents (such as those provided by Gelest). In some embodiments, these silane coupling agents may provide triethoxysilane or polysilanol end groups that react with abundant surface hydroxyl groups on a cellulose-based substrate to produce side-attached groups with carboxylate / carboxylic acid or sulfonate / sulfonic acid groups. Carboxylate / carboxylic acid and sulfonate / sulfonic acid groups will be described in more detail below.

[0158] In some embodiments, the acid-providing layer (such as a hydrogel-based wound dressing formulation) may comprise a copolymer, wherein the monomer is functionalized with covalently linked acidic functional groups having Formula I:

[0159]

[0160] Where R 1 Selected from the C that is arbitrarily replaced 1-4 Alkyl group, –CH2COOR 3 –CH2SO2R 3 and –CH2P(O)(OR 3 )2;R 2 Selected from the C that is arbitrarily replaced 1-4 Alkyl, –COOR 3 and –SO2R 3 ;–PO(OR 3 )2; and R 3 Selected from –H and optionally substituted C 1-4 Alkyl groups and cations.

[0161] In some embodiments of Formula I, R 3 It can be a cation, such as sodium ion, potassium ion, lithium ion, ammonium ion, trimethylammonium ion, or any other suitable cation.

[0162] In some embodiments of Formula I, the monomer can be crotonic acid, itaconic acid, fumaric acid, maleic acid, vinyl phosphonic acid, vinyl sulfonic acid, and salts thereof or any other suitable monomer.

[0163] As disclosed above and below, suitable monomers that present both unsaturation (i.e., moieties capable of incorporation into the acrylic copolymer via UV or free radical initiated polymerization) and sufficient acidity can result in efficient generation of nitric oxide from nitrite. Furthermore, these alternative monomers can provide advantages in terms of providing some examples of multifunctionality. In particular, the carboxylic acid monomers described herein can provide more than one carboxylic acid group per monomer unit, and thus can present more acidic functionality in an equivalent amount of material as compared to systems based on acrylic acid (AA) or 2-acrylamido 2-methylpropane sulfonic acid (AMPS). In some embodiments, such an arrangement can provide advantages in terms of yield of the desired NO product or other elements of controlling the profile of products generated upon activation with a nitrite source.

[0164] Those skilled in the art will appreciate that the polymerization of the hydrogels disclosed herein can be initiated using a suitable amount of any suitable initiator, for example: 2,2-dimethoxy-2-phenylacetophenone, ferrous sulfate heptahydrate, hydrogen peroxide, potassium bisulfite, potassium persulfate, thermal thiosulfate, or mixtures thereof. Additional details regarding initiators can be found in U.S. Patent No. US4581821, which is hereby incorporated by reference. Other examples of photoinitiators include 1-hydroxycyclohexyl phenyl ketone and 2-hydroxy-2-methylpropio- phenone. The energy source used to initiate polymerization can be any suitable source, such as described herein, for example: light (such as ultraviolet), radiation (such as gamma), heat, chemical, or any suitable energy source.

[0165] In certain embodiments, the hydrogel-based wound dressing formulation can comprise a copolymer, wherein the monomer is functionalized with a covalently linked reducing agent functional group having the formula II:

[0166]

[0167] wherein R 4 and R 5 are independently selected from the group consisting of -H, optionally substituted C 1-4 alkyl, optionally substituted C 6-10 aryl, and optionally substituted C 6-10 aralkyl; wherein X is selected from the group consisting of optionally substituted C 1-4alkyl, -CH2COO-, -COO-, -CH2SO2-, -SO-, -SO2-, -CH2CONH-, -CONH-, -P(O)(O)-, and -CH2P(O)(O)-; wherein Y is selected from the group consisting of optionally substituted C 1-4 alkyl, optionally substituted C 3-7 carbocyclyl, PEG chain, sugar unit, optionally substituted C 6-10 aryl, and optionally substituted C 6-10 aralkyl; R 6 is a reducing agent functional group selected from the group consisting of iodide anion, butylated hydroquinone, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene 2,3-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, beta-carotene, or any suitable group. In certain embodiments, m can be an integer from 1 to 2; and n can be an integer from 0 to 4. In some embodiments, m can range from 2 to 10 or more, while n can range from 4 to 10 or more. In certain instances, m or n can be any suitable integer.

[0168] In some embodiments of Formula II, the covalently linked reducing agent functional group of the monomer can include a 3,4-dihydroxyphenyl or 2,3-dihydroxyphenyl group or any suitable functional group.

[0169] As disclosed in the above embodiments and elsewhere herein, it can be advantageous from a safety / regulatory perspective to have a covalently linked functional group that can act as a reducing agent in the chemistry of NO generation while maintaining a suitable monomer attached to the hydrogel structure.

[0170] In certain embodiments, nitric oxide can be generated by the chemical reduction of nitrous acid. Many different reducing agents can be used to reduce nitrous acid, physiologically acceptable examples of such reducing agents include, but are not limited to: iodide anion, ascorbic acid, butylated quinone, tocopherol, or any suitable reducing agent. Nitrous acid is a weak acid with a pKa of 3.4, so at pH ~ 3.4, nitrous acid exists in an equimolar mixture of nitrous acid (HNO2) and nitrite (NO2 -1 ) anions. At higher pH values, the equilibrium shifts toward the nitrite anion; at lower pH values, the equilibrium shifts toward the nitrous acid. Since nitrous acid can be chemically reduced to nitric oxide, the efficiency of the conversion of nitrite to nitric oxide can increase as the pH decreases. Thus, in some embodiments, while the rate of such conversion can be negligible at pH ~ 6, it proceeds slowly at pH ~ 5 and very rapidly at pH < 4, especially at pH < 3.

[0171] In embodiments, hydrogel systems based primarily on AMPS sodium salts containing relatively small amounts of strong acidic AMPS acid and / or weakly acidic AA can provide an environment acidic enough. In addition, non-thiol reducing agents that are not acids with pKas between about 1 and 4 can be used as reducing agents in these systems. The reducing agent can be present in any suitable component of the wound dressing system. Examples of suitable reducing agents include, but are not limited to, iodide ions, butylated hydroquinone, hydroquinone, hydroquinone variants, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, ascorbate, ascorbate variants, erythorbate, erythorbate variants, and any other suitable reducing agent. The reducing agent is typically present in the dressing at a concentration 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 around 2% (w / w), based on the dressing. Inclusion of covalently linked reducing agents in the monomer as disclosed in the embodiments above can advantageously provide safety and regulatory benefits.

[0172] In some embodiments, the hydrogel-based wound dressing formulations such as described herein comprise monomers according to Formula I and / or Formula II. In certain embodiments, the hydrogel-based wound dressing formulations as described herein further comprise an oxygen scavenger, such oxygen scavengers can include glucose, glucose peroxidase, iron-based scavengers such as nano-iron particles, boron-based scavengers such as nano-boron particles, and electrolytes such as sodium chloride. The oxygen scavengers can be incorporated into the formulation via any suitable means, for example via dissolution, absorption, adsorption, and / or attachment to the polymer structure. Such oxygen scavengers can need to be protected from the aqueous environment such as any of the hydrogels disclosed herein, and thus can be sealed from the aqueous portion or incorporated into a polymer complex within the gel body. Such oxygen scavengers can also advantageously remove oxygen from the hydrogel during storage over a period of time, potentially improving the efficiency of nitric oxide production. In certain embodiments, the dressing can be manufactured in an inert environment to prevent oxygen ingress during the manufacturing process. Such a dressing can also be sealed such that oxygen ingress does not occur prior to application of the dressing.

[0173] Hydrogel-based wound dressing systems:

[0174] As Figure 12 and 13As depicted in FIG. 41, in some embodiments, the hydrogel-based wound dressing system 4100 can be placed over a wound and / or intact skin, such as in the area surrounding the wound, and can include a first acid-providing layer 4210 containing a copolymer of monomers having covalently attached multifunctional groups, wherein the monomers are functionalized with covalently attached acidic functional groups having the formula I, wherein R 1 may be -CH2SO2R 3 or -CH2P(O)(OR 3 )2 or any suitable group; R 2 may be -SO2R 3 or -PO(OR 3 )2 or any suitable group; and R 3 may be -H and optionally substituted C 1-4 alkyl or any suitable group.

[0175] In certain embodiments, a second acid-providing layer 4310 can be positioned over the first acid-providing layer and contain a copolymer of monomers having covalently attached multifunctional groups, wherein the monomers are functionalized with covalently attached acidic functional groups having the formula I, wherein R 1 may be optionally substituted C 1-4 alkyl, -CH2COOR 3 ; R 2 may be optionally substituted C 1-4 alkyl and -COOR 3 ; and R 3 may be -H and optionally substituted C 1-4 alkyl and a cation. Those skilled in the art will appreciate that the acid-providing layers can be in any order, such as the first layer over the second layer or the second layer over the first layer.

[0176] In some embodiments, the hydrogel-based wound formulation and dressing system can be free of water or substantially free of water. For example, the acid-providing layers described in the embodiments herein can be in the form of a dry gel (allowing the hydrogel to change its dimensions in a process of slow removal / reduction of water content) or an aerogel (the structure of the hydrogel is almost unaffected due to the fast removal of water via supercritical or freeze-drying, etc.). In some embodiments, the hydrogel-based wound formulation and dressing system can 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%.

[0177] In certain embodiments, the acidic component in the wound dressing system in the form of a xerogel / aerogel can provide a reduction in the weight of the dressing system, which can be advantageous for wound dressing products (lighter, more compact products). The physical properties of the system can also be advantageous (e.g., different rates of absorption can also reflect unique NO production profiles). As explained above, in certain embodiments, the hydrogel-based wound dressing system 4100 can include a first acid-providing layer 4210 containing a copolymer of monomers having covalently attached polyfunctional groups; and a second acid-providing layer 4310 containing a copolymer of monomers having covalently attached polyfunctional groups above the first acid-providing layer. In particular, embodiments of the present disclosure allow for a blend or combination of two acidic monomers. For example, such embodiments can be achieved by formulating a single gel layer or via construction of gel layers consisting of a “stack” or patterning, whereby different layers / regions consist of different acid property types. Such a stacked arrangement can include 2, 3, 4, 5, or more different acid-providing layers. The stack can include 2, 3, 4, 5, 6, or more acid-providing layers. In certain embodiments, one or more layers can be non-acidic, e.g., 1, 2, 3, 4, 5, or 6 or more non-acidic layers.

[0178] In embodiments, the release profile can be controlled by creating a hydrogel-based wound dressing system consisting of both a moderate amount of strong acid and weak acid attached to a polymeric structure. In certain embodiments, the hydrogel can be composed of layers or patterned regions containing strong and / or weak acids. Thus, different strengths of acid can be distributed hierarchically or patterned across the entire profile of the finished hydrogel sheet. For example, a strong acid environment can be located on the wound-facing side to provide very rapid NO release (highly efficient nitrite conversion), while a weaker acid as a subsequent other layer removed from the wound, which would provide slower conversion of nitrite to NO (and thus provide a more sustained element of the release profile as the provided nitrite solution is drawn through the hydrogel stack).

[0179] Returning to Figures 12-13, the hydrogel-based wound dressing system 4100 can include a nitrite providing layer 4410. As depicted in the figures, the nitrite providing layer can be above or below one or more acid providing layers. In some embodiments, the nitrite source can be a suitable material layer comprising an alkali metal nitrite and / or an alkaline earth metal nitrite. In certain embodiments, the nitrite salt can include: LiN02, NaN02, KN02, RbN02, CsN02, FrN02, Be(N02)2, Mg(N02)2, Ca(N02)2, Sr(N02)2, Ba(N02)2, Ra(N02)2, or any other suitable nitrite salt. In certain embodiments, the nitrite providing layer can contain sodium nitrite. In some embodiments, other sources of nitrite ions can be nitrate ions derived from alkali or alkaline earth metal salts that are capable of enzymatic conversion to nitrite. For example, LiN03, NaN03, KN03, RbN03, CsN03, FrN03, Be(N03)2, Mg(N03)2, Ca(N03)2, Sr(N03)2, Ba(N03)2, Ra(N03)2, or any other suitable molecule.

[0180] In certain embodiments, the acid providing layer as described above and elsewhere herein can contain covalently bound acidic functional groups and thus be capable of generating nitric oxide upon contact with a suitable source of nitrite such as an alkali metal nitrite. In embodiments, covalent functionalization, surface coating, or plasma functionalization of a suitable polymeric wound dressing material can impart the property of the dressing material being suitably acidic to efficiently convert nitrite to NO.

[0181] Hydrogels with various cross-linkers, with and without antioxidants and / or reducing agents

[0182] Figure 14 A hydrogel production process 5000 according to some embodiments is shown. The activator layer of a wound dressing as described herein can comprise a hydrogel produced by process 5000. While Figure 14 A number of process steps are shown in FIG. 5, but it should be understood that not all process steps are necessary, and that some process steps can be optional. Further, it should be understood that Figure 14The order in which the process steps of the process 5000 occur can be modified or rearranged, and additional process steps not shown can be added at any suitable step in the process. As shown, the process 5000 for producing a hydrogel can include a step 5002 of providing a stirred AMPS sodium solution to create a mixture, a step 5004 of adding an acid to the mixture, a step 5006 of adding a humectant to the mixture, a step 5008 of adding an antioxidant and / or reducing agent to the mixture, a step 5010 of adding a crosslinking agent to the mixture, a step 5012 of adding an initiator to the mixture, a step 5014 of transferring the mixture to a mold, a step 5016 of curing the mixture in the mold to produce a hydrogel, and a step 5018 of packaging the hydrogel.

[0183] As shown in Figure 14 As shown in As further shown in

[0184] As further shown in Figure 14 As further shown in As further shown in

[0185] As further shown in Figure 14 As further shown in As further shown in

[0186] As further shown in Figure 14As further shown, the process 5000 of producing a hydrogel can additionally include a step 5008 of adding an antioxidant and / or reducing agent to the mixture. The antioxidant and / or reducing agent can include sodium erythorbate, iodide anion, butylated hydroquinone, hydroquinone, hydroquinone variants, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, ascorbic acid, potassium iodide, ascorbate, ascorbate variants, erythorbate, erythorbate variants, any other suitable reducing agent, and / or any antioxidant and / or reducing agent described herein. The antioxidant and / or reducing agent can be present at a concentration 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 can 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 between about 1:2 and about 1:0.3. In some embodiments, the step 5008 of adding an antioxidant and / or reducing agent can be omitted. In some embodiments, the step 5008 of adding an antioxidant and / or reducing agent to the mixture can be performed near the end of the process 5000, such as after the step 5010 of adding a crosslinking agent to the mixture or after the step 5012 of adding an initiator to the mixture and before the step 5014 of transferring the mixture to a mold. In such embodiments, the addition of the antioxidant and / or reducing agent can advantageously prevent or reduce pre-gelling of the mixture.

[0187] As Figure 14Further shown therein, the process 5000 of producing a hydrogel can additionally include a step 5010 of adding a crosslinker to the mixture. In some embodiments, the crosslinker can include an acrylate, a dimethacrylate, and / or an acrylamide crosslinker. In some embodiments, the acrylate crosslinker can include PEG diacrylate Mn 575. In some embodiments, the dimethacrylate crosslinker can include PEG dimethacrylate Mn 550. In some embodiments, the acrylamide crosslinker can include Piperazine diacrylamide. In some embodiments, the crosslinker can include tripropyleneglycol diacrylate, ethyleneglycol dimethacrylate, alkoxylated triacrylate, polyethyleneglycol diacrylate (PEG 400 or PEG 600), and / or methylene bisacrylamide. In some embodiments, the crosslinker can include any of the crosslinkers described herein and / or any combination of the crosslinkers described herein. In some embodiments, the crosslinker can reduce and / or prevent hydrolysis of the hydrogel. For example, the dimethacrylate and / or acrylamide crosslinker can reduce and / or prevent hydrolysis of the hydrogel comprising the one or more crosslinkers. In some embodiments, the crosslinker that reduces and / or prevents hydrolysis of the hydrogel can improve the mechanical stability of the hydrogel.

[0188] As Figure 14 Further shown therein, the process 5000 of producing a hydrogel can additionally include a step 5012 of adding an initiator to the mixture. The initiator can include a photoinitiator, a thermal initiator, any of the initiators described herein, or any initiator configured to induce polymerization. In some embodiments, the initiator can include 2-hydroxy-2-methylpropionphenone, 2,2-dimethoxy-2-phenylacetophenone, ferrous sulfate heptahydrate, hydrogen peroxide, potassium bisulfite, potassium persulfate, thermal method thiosulfate, and / or mixtures thereof. Further details regarding initiators can be found in U.S. Patent No. US4581821, which is hereby incorporated by reference. Other examples of photoinitiators include 1-hydroxycyclohexyl phenyl ketone and 2-hydroxy-2-methylpropionphenone.

[0189] As Figure 14 Further shown therein, the process 5000 of producing a hydrogel can additionally include a step 5014 of transferring the mixture to a mold. The process 5000 can additionally include a step 5016 of curing the mixture in the mold to produce a hydrogel. The mold can include a Teflon-coated aluminum mold or any suitable mold for releasably detaching the hydrogel after the hydrogel is formed. The energy source for initiating polymerization / curing can be any suitable source, such as described herein, for example: light (such as ultraviolet), radiation (such as gamma), heat, chemical, or any suitable energy source.

[0190] As Figure 14Further shown, the process 5000 of producing a hydrogel can additionally include a step 5018 of packaging the hydrogel. In some embodiments, packaging the hydrogel can include packaging a wound dressing comprising the hydrogel. In some embodiments, packaging the hydrogel can be performed in the absence of oxygen and / or in a low oxygen environment. In some embodiments, packaging the hydrogel can be performed under reduced pressure and / or vacuum. In some embodiments, packaging the hydrogel can be performed 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 can be airtight and / or can prevent oxygen external to 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 can exclude oxygen. In some embodiments, oxygen-scrubbing can be employed to remove oxygen from the packaging. In some embodiments, the packaging can include foil packaging. In some embodiments, the packaging can comprise an oxygen scavenger packaged with the hydrogel and / or wound dressing comprising the hydrogel. Once sealed in the packaging, the oxygen scavenger can remove oxygen from the wound dressing and / or components thereof such as the hydrogel / activator layer and nitrite-providing layer. In some embodiments, once sealed, the oxygen scavenger can remove oxygen from within the packaging. In some embodiments, the sodium erythorbate in the hydrogel comprising sodium erythorbate can scavenge oxygen and / or reduce the oxygen content of the wound dressing and / or components thereof such as the nitrite-providing layer and / or activator layer. In some embodiments, the sodium erythorbate in the hydrogel comprising sodium erythorbate can scavenge residual oxygen content within the packaging. In some embodiments, the hydrogel comprising sodium erythorbate can comprise a sacrificial amount of sodium erythorbate to scavenge and / or reduce oxygen in and / or around the wound dressing and components thereof, as described herein.

[0191] In some embodiments, the process 5000 of producing a hydrogel can additionally include a step of adding an oxygen scavenger to the mixture prior to transferring the mixture to a mold as in step 5014. The oxygen scavenger can 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 can include an antioxidant as described herein, such as sodium erythorbate.

[0192] In some embodiments, one or more steps of process 5000 can be performed 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 can be performed in the absence of oxygen and / or in a low oxygen environment. In some embodiments, one or more steps of process 5000 can be performed under reduced pressure and / or vacuum. In some embodiments, one or more steps of process 5000 can be performed in an inert environment and / or in the presence of an inert gas, such as argon and / or nitrogen. In some embodiments, the hydrogel produced after process 5000 can be degassed and / or subjected to a reduced pressure cycle / vacuuming. In some embodiments, the nitrite-providing layer and / or components thereof (e.g., the sodium nitrite solution that saturates the mesh of the nitrite-providing layer) as described herein can be degassed and / or subjected to a reduced pressure cycle / vacuuming. In some embodiments, the wound dressing as described herein can be degassed and / or subjected to a reduced pressure cycle / vacuuming. In some embodiments, one or more steps of process 5000 can be performed in a low light environment and / or an environment that minimizes curing of the mixture, until step 5016 of process 5000. In some embodiments, the hydrogel produced by process 5000 can comprise a dissolved oxygen content of less than about 200 ppb, about 250 ppb, about 300 ppb, about 400 ppb, about 500 ppb, or about 1000 ppb. In some embodiments, a wound dressing comprising a hydrogel produced by process 5000 with minimized oxygen exposure / content and packaged can increase the nitric oxide production capacity of the wound dressing. In some embodiments, a wound dressing comprising a hydrogel produced by process 5000 with minimized oxygen exposure / content and packaged can increase the ratio of nitric oxide to nitrogen dioxide produced by the wound dressing (e.g., when the wound dressing is placed over a wound).

[0193] In some embodiments, the hydrogel produced by process 5000 can have a Tan D value at about 0.35, about 0.45, about 0.55, about 0.65, and / or about any Tan D value that provides optimal hydrogel properties, as evaluated by rheometry. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 can have a Tan D value at about 0.35, about 0.45, about 0.55, about 0.65, and / or about any Tan D value that provides optimal wound dressing properties, as evaluated by rheometry. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 can have a Tan D value that remains at about 0.35, about 0.45, about 0.55, about 0.65, and / or about any Tan D value that provides optimal wound dressing properties, as evaluated by rheometry, when packaged in packaging and until the packaging is opened. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 can remain substantially colorless when packaged in packaging until the packaging is opened.

[0194] The hydrogel produced by process 5000 can be used in any of the wound dressings described herein. In some embodiments, an activator layer (and / or acid providing layer) as described herein can comprise the hydrogel produced by process 5000. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 can additionally comprise a nitrite providing layer as described herein. In some embodiments, the hydrogel produced by process 5000 can be configured to provide protons to a nitrite providing layer to produce nitric oxide as described herein. In some embodiments, the nitrite providing layer can comprise sodium nitrite. In some embodiments, the nitrite providing layer can comprise a mesh. In some embodiments, the nitrite providing layer can comprise a saturated polypropylene mesh. In some embodiments, a wound dressing comprising the hydrogel produced by process 5000 can additionally comprise any other layer and / or aspect of a wound dressing described herein, such as a collection distribution layer, a cover layer, and / or a masking layer.

[0195] As will be appreciated by one of skill in the art, any amount of the aspects / ingredients as described in the process 5000 of producing a hydrogel can be used to produce a hydrogel having desired properties. For example, in some embodiments, a standard amount or twice, three times, or four times the desired amount of a crosslinking agent can be used in the process 5000. As another example, in some embodiments, a standard amount or twice the desired amount of an initiator can be used in the process 5000. As another example, in some embodiments, a standard amount or twice, three times, or any excess amount of an antioxidant and / or reducing agent can be used in the process 5000. Further, the hydrogel produced by the process 5000 can have any thickness, length, and width as desired. In some embodiments, the hydrogel can include one, two, three, or more layers, which can be prepared by continuously transferring the mixture to a mold and solidifying one layer on top of another, or by placing the produced hydrogel one on top of another. In some embodiments, each layer of a hydrogel including multiple layers can contain the same or different formulation.

[0196] In some embodiments and as described in the process 5000 of producing a hydrogel, the hydrogel can include an antioxidant and / or reducing agent. The antioxidant and / or reducing agent can facilitate the wound dressing including the hydrogel to generate nitric oxide. In some embodiments, a wound dressing including a hydrogel with an antioxidant and / or reducing agent can generate an amount of nitric oxide that is greater than that produced by a wound dressing including a hydrogel without an antioxidant and / or reducing agent. In some embodiments, a wound dressing including a hydrogel with an antioxidant and / or reducing agent can generate an amount of nitric oxide that is 2, 5, 10, or 20 times that of a hydrogel without an antioxidant and / or reducing agent. In some embodiments, a wound dressing including a hydrogel with an antioxidant and / or reducing agent can generate a nitric oxide to nitrogen dioxide ratio that is greater than that produced by a wound dressing including a hydrogel without an antioxidant and / or reducing agent. In some embodiments, a wound dressing including a hydrogel with an antioxidant and / or reducing agent can generate a nitric oxide to nitrogen dioxide ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, or 5: 1. As described herein, a wound dressing that produces more nitric oxide than nitrogen dioxide can be desirable.

[0197] One of skill in the art will appreciate that the hydrogels produced and / or packaged as described above can be used with any of the wound dressings and devices described herein, such as Figure 1-5 , 11A-11E, 12, and 13.

[0198] Examples of hydrogels with various cross-linkers, without antioxidants and / or reducing agents

[0199] Figure 15Data showing nitric oxide and nitrogen dioxide production over time from hydrogels without the reducing agent sodium erythorbate. An example process for preparing hydrogels used to generate Figure 15 data is described below.

[0200] Method

[0201] Into a suitable size beaker equipped with an overhead propeller type stirrer and surrounded by a water bath controlled at 15°C, 50% aqueous solution of 2-acrylamido-2-methyl-1 -propanesulfonic acid sodium salt (Na AMPS) was added. Under stirring forming a clear vortex without entraining air, the following components were added: pre-milled 2-acrylamido-2-methyl-1 -propanesulfonic acid (AMPS acid) and glycerol (added slowly) after the AMPS acid had dissolved. Then the selected crosslinker (listed in the Materials section) was added followed by the 2-hydroxy-2-methylpropiophenone photoinitiator. To facilitate dissolution of the less soluble piperazine-diacrylamide within a reasonable time period, the crosslinker was added prior to the AMPS acid and glycerol, while the AMPS acid and glycerol were added after the crosslinker had dissolved. The mixture was allowed to stir for 10-20 minutes. All hydrogel mixtures used the standard 0.5SA formulation.

[0202] The pre-polymer mixture was formed into a 3 mm thick hydrogel sheet by transferring 41.2 ml (53.4 g) of the prepared pre-polymer mixture via a 50 ml Eppendorf pipette into an 11 x 11 x 3 cm Teflon-coated aluminum mold. The mold was first placed onto a horizontal shelf in a UVC cabinet, then the pre-polymer mixture was transferred into the mold, which was then exposed to a UVC flood lamp (UVC output: ~1.4 mW / cm2) for 60 seconds. The cured sheet was removed from the mold, placed between silicone release papers inside a sealed bag, and assigned a batch reference number.

[0203] The hydrogel sheet was cut into 2.5 cm discs for rheometry or 3 x 3 cm squares for Nox determination (for NO and NO2 data as shown in Figure 15 The gel discs or squares were packaged in foil packages in triplicate and sealed under vacuum, atmospheric air, or nitrogen as indicated. The vacuum, nitrogen, and air sealed bags were either gamma sterilized or not and stored at 25°C / 60% RH or 40°C / 75% RH. At various time points, the gels were removed from storage and evaluated in triplicate for rheometry and Nox output determination.

[0204] Chemiluminescent Nox production results: hydrogels with / without sodium erythorbate

[0205] Figure 15Chemiluminescent NO / NO2 production is shown for a representative acidic AMPS-based hydrogel without sodium erythorbate in contact with a polypropylene mesh saturated in a 1 M aqueous solution of sodium nitrite (NaN0 2(aq) ) in contact with a saturated mesh.

[0206] As shown in Figure 15 , the hydrogel without sodium erythorbate produced more nitric oxide (NO) than nitrogen dioxide (N02) in contact with the saturated mesh. More specifically, the hydrogel without sodium erythorbate produced a peak of about 83,000 ppb of nitrogen dioxide and a peak of about 27,000 ppb of nitric acid, both of which occurred at about the same time after contact with the saturated mesh (as shown, at about 3 minutes after contact). Quantified, the ratio of nitric oxide to nitrogen dioxide production at the peaks was about 1 :3. As shown in Figure 15 , after the peaks of nitrogen dioxide and nitric acid production, their respective production decreased over time, with nitrogen dioxide production decreasing at a slightly faster rate than nitric acid, but its production remained higher than that of nitric oxide.

[0207] Chemiluminescence NO / NO2 generation results: sodium nitrite and sodium erythorbate dispersed in PEG 400

[0208] Figure 16 Examples of chemiluminescent NO / NO2 production over a period of 79 minutes are shown for an example acidic hydrogel with 1.0 SA in contact with a suspension generated by dispersing 0.1 g of NaN02 and 0.1 g of NaISO (sodium erythorbate) in 2 g of polyethylene glycol (PEG) 400. As will be appreciated by those skilled in the art, Figures 16-18D The materials / constructions of

[0209] As shown in Figure 16 , more nitric oxide (NO) than nitrogen dioxide (N02) was produced during the 46-73 minute period corresponding to the application of the PEG 400 / NO2 / NaISO suspension to the hydrogel. These results indicate that PEG 400 is suitable as a water-free, water-miscible carrier for the mixture of NaN02 and NaISO, and confirm that contact between the PEG 400 / NO2 / NaISO suspension and the acidic hydrogel is capable of generating nitric oxide. Additionally, the time points of about 22-34 minutes corresponding to the measurement of nitric oxide generated by the PEG 400 / NO2 / NaISO suspension indicate that the PEG 400 / NO2 / NaISO suspension did not generate detectable nitric oxide prior to contact with the acidic hydrogel.

[0210] Antimicrobial activity results: sodium nitrite and sodium erythorbate dispersed in PEG 400

[0211] Figures 17A-17CAn example of evaluating the antimicrobial activity of an example dressing composed of IV3000 top layer, hydrogel / DURAFIBER composite with 1.0 SA or 0.7 SA, and polypropylene (pp) mesh embedded with PEG400 / NO2 / NaISO suspension is shown. The 1.0 SA gel can be made from the following components (parts by weight for a 100 g batch): 63.32 g AMPS sodium; 0.0323 g Piperazine dipropylamide; 5.436 g AMPS (H+); 31.19 g glycerol and 0.01629 g 2-hydroxy-2-methylpropiophenone. The 0.7 SA gel can be made from the following components (parts by weight for a 100 g batch): 65.28 g AMPS sodium; 0.0317 g Piperazine dipropylamide; 3.923 g AMPS (H+); 30.74 g glycerol and 0.01756 g 2-hydroxy-2-methylpropiophenone.

[0212] Figure 17A The placement of layers of a dressing evaluated in a direct inoculation seal test model is shown. Insert plates containing 1 / 5 Tryptic Soy Agar (TSA) or 1 / 5 Sabouraud Dextrose Agar (SDA) and an additional 3.3% Bovine Serum Albumin (BSA) were prepared. Overnight cultures of test organisms Pseudomonas aeruginosa (PA) and Candida albicans (CA) were adjusted to yield 4 x 108CFU / ml inoculum. A 25 mm x 25 mm 17PP mesh (blank) was placed centrally on the plate and dosed with 1M NaNO2 and 1:1 W / W NaISO or 1:0.5 NaISO suspended in PEG400. 5 μΐ of the appropriate inoculum (total ~2 x 106CFU) was added directly to the composite / mixed dressing, which was sized 50 mm x 50 mm and loaded with 6 g of 1.0 SA or 0.7 SA gel. A 75 mm x 75 mm IV3000 top film was placed directly over the mesh to cover the steel insert and create a seal within 1-3 minutes of the dressing being applied. Incubation of the treatment was for 24 and 72 hour time points at 32°C. To assess microbial growth, the composite / IV3000 / pp mesh was added to 40 ml of neutralizer (D / E broth), stomached for 2 minutes at high setting to recover, serially diluted, and counted on pour plates / Petrifilm. All dressing elements were prepared on the day of the experiment, were not gamma sterilized, and no inert atmosphere was used.

[0213] Figure 17B An antimicrobial activity evaluation of an assembled dressing when viewed from above is shown, and the dimensions of the layers are indicated. Figure 17A

[0214] Figure 17C ​The results of the microbial evaluation are summarized as the average Logio reduction compared to the inoculum control. The DURAFIBER control condition, without the loaded hydrogel, failed to inhibit the proliferation of any of the test organisms and was therefore determined to be inactive. The conditions including the PP mesh embedded with 1 M NaNO2suspended in PEG 400 and 1 : 1 W / W sodium erythorbate or 1 :0.5 NaISO showed results equivalent to the previously studied conditions where NaNO2and NaISO were not localized. The conditions including 1.0 SA and the hydrogel showed higher than expected intrinsic activity against Candida, but did not decrease to the limit of detection, indicating that the NaNO2 / NaISO mixture achieved the target level of activity in this model. Therefore, it is feasible to migrate the NaISO from the hydrogel to the mesh where it will be co-localized with the NaNO2and maintain the reduction in microbial growth.

[0215] Considering the results of the microbial activity evaluation, the agar area remained clear when the ratio of NaNO2:NaISO on the mesh (w / w) was 1 : 1, however, this was less evident when the ratio was reduced to 1 :0.5.

[0216] Chemiluminescence NO / NO2 generation results: sodium nitrite and sodium erythorbate dispersed in various anhydrous water-miscible carriers Figures 18A-18D

[0217] Figure 18A Example chemiluminescent NO / NO2production is shown when a 3 x 3 cm DURAFIBER composite loaded with ~6 g of 1.0 SA acidic hydrogel is contacted with a 2.5 x 2.5 PP mesh embedded with 50 uL of a suspension generated by dispersing 0.1 g of NaNO2and 0.1 g of NaISO in various anhydrous water miscible carriers.

[0218] Figure 18B Nitric oxide production is shown where PEG 400 is used as the anhydrous water miscible carrier, Figure 18C Results are shown when PEG 600 is used as the anhydrous water miscible carrier, Figure 18D Results are shown when a 50 / 50 w / w blend of PEG 300 and PEG 1500 (FLEX) is used as the anhydrous water miscible carrier, Figure 18E Results are shown when a 41 / 1 w / w blend of PEG 400 and PEG 4000 (SORB) is used as the anhydrous water miscible carrier, and Figures 18A-18D Results are combined on a single graph. TERMINOLOGY Results are combined on a single graph.

[0219] Exemplary wound dressing configurations and formulations

[0220] Exemplary wound dressings can include a mesh component that contains co-located nitrite and antioxidant / reducing components. Exemplary wound dressings can include a mesh component that contains co-located embedded sodium nitrite and sodium erythorbate. Exemplary wound dressings can contain sodium erythorbate monohydrate. Exemplary wound dressings can contain anhydrous sodium erythorbate. The mesh component can have any amount of sodium nitrite dosage between about 0.5M to about 2.5M. Exemplary embodiments can include a 2.5 x 2.5 cm mesh loaded with any amount between 1-5 mg of each of the suspended sodium nitrite and antioxidant / reducing agent in a suitable carrier. Exemplary wound dressings can include a mesh component that has embedded a 1:1 W / W suspension of sodium nitrite to sodium erythorbate. Exemplary wound dressings can include a mesh component that has embedded a 1:0.5 W / W suspension of sodium nitrite to sodium erythorbate. Exemplary wound dressings can include a mesh component that has embedded a 1:0.25 W / W suspension of sodium nitrite to sodium erythorbate. Exemplary wound dressings can include a mesh component that has embedded a suspension of sodium nitrite to sodium erythorbate, where the sodium nitrite and sodium erythorbate are present in any ratio ranging from 1:0.1-1:4 W / W of sodium nitrite / sodium erythorbate. Exemplary wound dressings can include a mesh component where the embedded suspension is a paste. Exemplary wound dressings can include a mesh component where the embedded suspension contains a water soluble / water miscible carrier. In some embodiments, the embedded suspension can be a paste. Exemplary wound dressings can include a mesh component where the embedded liquid / carrier is PEG 200, PEG 400, PEG 600, or any blend of PEGs, triacetin, or glycerol. Exemplary wound dressings can include a mesh component where the embedded carrier is dried by using molecular sieves and other techniques known in the art. Exemplary wound dressings can provide higher stability of the reducing agent due to the embedded reducing agent and nitrite providing component mesh component storage under dry conditions. Exemplary wound dressings can include a reduction of undesirable colored species by storing the embedded reducing agent and nitrite providing component mesh component under dry conditions. In exemplary wound dressings, the nitrite providing layer can be provided as a separate layer in packaging separate from the packaging of the wound dressing. Exemplary wound dressings can provide more consistent nitric oxide generation than wound dressings where the reducing agent such as sodium erythorbate, ferric sulfate, or derivatives of Vitamin C are stored under aqueous conditions and subjected to higher levels of degradation. Exemplary wound dressings that maintain the reducing agent under dry conditions prior to combination with the activation layer can have a reduction of degradation induced by the action of free radicals generated when irradiating aqueous solutions.In comparison to wound dressings in which the reducing agent is stored under aqueous conditions, exemplary wound dressings can have advantageous stability after sterilization. Exemplary wound dressings can include a cover layer, a collection distribution layer, and / or a masking layer. Exemplary wound dressings can include an IV3000 top film and border as a cover layer, and a 17 gsm polypropylene mesh component. The polypropylene mesh can be any mesh in the range of 5 gsm to 200 gsm. Exemplary wound dressings can employ other mesh materials besides polypropylene, including polyethylene and fluorinated materials such as polyvinylidene fluoride (PVDF). The cover layer can be configured to form a seal around a wound, where the cover layer can be moisture vapor permeable. In some embodiments, the wound dressing is vacuum packaged. In some embodiments, the wound dressing can contain a surfactant.

[0221] An exemplary wound dressing can include an activation layer comprising an acidic hydrogel. An exemplary wound dressing can include an activation layer comprising a composite further comprising a gelling fiber substrate loaded with an acidic hydrogel. An exemplary wound dressing can include a substrate such as DURAFIBER or OPSITE POST-OP pad material. An exemplary wound dressing can contain a 2-acrylamido-2-methyl-l-propanesulfonic acid sodium salt aqueous solution and 2-acrylamido-2-methyl-l-propanesulfonic acid (SA). An exemplary wound dressing can include any number of hydrogels with an acid content ranging from 2.0 SA to 0.5 SA. A 1.0 SA gel can be made from the following components (weight parts for a 100 g batch): 63.32 g AMPS sodium; 0.0323 g Piperazine diacrylamide; 5.436 g AMPS (H+); 31.19 g Glycerol and 0.01629 g 2-hydroxy-2-methylpropyl phenone. A 0.7 SA gel can be made from the following components (weight parts for a 100 g batch): 65.28 g AMPS sodium; 0.0317 g Piperazine diacrylamide; 3.923 g AMPS (H+); 30.74 g Glycerol and 0.01756 g 2-hydroxy-2-methylpropyl phenone. An exemplary wound dressing can include an activator layer configured to provide protons to a nitrite-providing layer to generate nitric oxide. An exemplary wound dressing including a nitrite-providing layer comprising co-located sodium nitrite and sodium erythorbate can be configured to generate a higher nitric oxide to nitrous oxide ratio than a wound dressing including a nitrite-providing layer in which sodium nitrite and sodium erythorbate are not co-located. An exemplary wound dressing can include activation of a nitric oxide chemical reaction by fluid in the wound exudate, water provided by the aqueous hydrogel, and / or a separate ampoule of aqueous reagent. An exemplary wound dressing can include an application method in which an anhydrous suspension can be loaded into a region of the dressing so as to contact an acidic gel and initiate generation of nitric oxide. An exemplary wound dressing can include an application method in which an anhydrous suspension and an acidic gel are held apart from one another by a removable handle, and after removal of the handle, the dressing can be manipulated so as to contact the anhydrous suspension and the acidic gel, thereby initiating generation of nitric oxide. An exemplary wound dressing can include a pocket comprising a composite layer loaded with an acidic hydrogel, in which an anhydrous suspension can be loaded into the pocket so as to initiate generation of nitric oxide. The anhydrous suspension can be loaded into the pocket as part of a mesh component, or applied directly to the pocket in the absence of a mesh component.

[0222] An exemplary wound dressing can include milling sodium nitrite and sodium erythorbate powders to increase the surface area of the solid particles in the solvated dispersion, making it more available for reaction and also inhibiting its settling out of the suspension. An exemplary wound dressing can include use of a dispersant / surfactant, etc.

[0223] ​

[0224] Any patents, applications and other references noted above (including any literature references listed in any of the applications filed herewith) are incorporated herein by reference. Aspects of the disclosure can be modified, if necessary, to employ the systems, functions, and concepts of the various references described herein to provide yet further implementations.

[0225] Features, materials, characteristics or groups described in conjunction with a particular aspect, embodiment, or example are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features (including any accompanying claims, abstract and drawings) disclosed in the specification, or any method or process described herein, can be combined in any combination, provided that such features or steps are not mutually inconsistent. Protection is not limited to the specific embodiments described herein. Protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0226] While certain embodiments have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of protection. Indeed, the novel methods and systems described herein can be embodied in a variety of other forms. Furthermore, various omissions, substitutions and changes in the form of the methods and systems described herein can be made without departing from the spirit of the disclosure. Those skilled in the art will appreciate that the specific illustrative process steps disclosed in some embodiments can be modified in various ways without departing from the application. Certain steps can be omitted, others can be added, the order of steps can be altered, and / or some steps can be performed concurrently without departing from the application. For example, the actual process steps taken to accomplish a process disclosed can differ from those described in the figures. Certain steps can be omitted, others can be added, the order of steps can be altered, and / or some steps can be performed concurrently without departing from the application. Moreover, features and attributes of the specific embodiments disclosed above can be combined in different ways to form additional embodiments, all of which fall within the scope of the present disclosure.

[0227] While the present disclosure includes certain embodiments, examples, and applications, it will be appreciated that the present disclosure is not limited to those explicit embodiments, examples, and applications, but extends to other alternative embodiments and uses and obvious modifications and equivalents thereof, including embodiments which provide not all of the features and advantages summarized above. Accordingly, no limitation is placed on the scope of the present disclosure by the specific embodiments, examples, and applications described herein, and it is the intent that all variations and modifications not specifically described are to be considered within the scope of the present disclosure as set forth in the claims or claims that follow from the principles expressed herein.

[0228] Conditional language, such as "can," "could," "might," or "may," unless specifically stated otherwise, or otherwise understood within the context as used, generally are intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements, or steps. Thus, such conditional language is not generally intended to imply that one or more embodiments are required to include a feature, element or step. The terms "comprising," "including," "containing," etc. are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated in the specification as if it were individually recited herein. The terms "first," "second," "third," etc. are used herein to describe various elements, steps, etc. and are not intended to be a permanent or absolute nomenclature. The use of "first," "second," "third," etc. is interchangeable, unless otherwise stated, and does not denote a particular order or hierarchy. The terms "and / or" and "or" are used herein in their inclusive sense, unless otherwise indicated herein. Additionally, the term "each" as used herein, unless otherwise indicated, can mean any subset of a set of elements to which the term "each" applies. Further, the words "herein," "above," "below," and words of similar import refer to this application as a whole and not to any particular portion of this application, unless otherwise dictated by the context.

[0229] Unless specifically stated otherwise, connective language, such as the phrase "at least one of," is generally construed to use the inclusive or, i.e., the phrase "at least one of A and B" (or, equivalently, the phrase "at least one of A or B") means that A or B individually are each an acceptable choice in instances of the phrase.

[0230] As used herein, degree language such as the terms "substantially," "about," "approximately," and "essentially" are used to describe values, amounts, or characteristics that are close to, but not necessarily exactly, the stated value, amount, or characteristic. For example, the terms "substantially," "about," "approximately," and "essentially" can refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the specified amount. As another example, in certain embodiments, the terms "substantially parallel" and "approximately parallel" refer to values, amounts, or characteristics that are within less than or equal to 15 degrees, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degrees of exact parallel.

[0231] Any of the embodiments described herein can be used with or without a canister. Any of the dressing embodiments described herein can absorb and store wound exudate.

[0232] The scope of the disclosure is not intended to be limited to the description of certain embodiments thereof, but is instead defined by the claims. The language of the claims will be broadly interpreted as consistent with the language employed in the claims and the specification, and will not be limited to examples described in the specification or in presentations made during the prosecution of the application, which examples are to be construed as non-exclusive.

[0233] Various modifications to the embodiments described in this disclosure can be apparent to those of ordinary skill in the art, and the general principles defined herein can be applied to other embodiments without departing from the spirit or scope of the disclosure. Accordingly, the disclosure is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and features disclosed herein. Certain embodiments of the disclosure are encompassed in the claims presented below or in other claims presented in the future.

[0234] Certain embodiments of the disclosure are encompassed in the claims presented at the end of this specification, or in other claims presented at a later date.

Claims

1. A wound treatment device for treating wounds, the wound treatment device comprising: Wound dressing, the wound dressing comprising: The nitrite-providing layer includes a mesh component, wherein the mesh component comprises co-located nitrites and antioxidants / reducing agents. Includes the activator layer of the hydrogel; The activator layer is configured to provide protons to the nitrite-providing 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 device according to claim 2, wherein the nitrite and antioxidant / reducing agent are dissolved and / or suspended in an anhydrous carrier before being embedded in the mesh component, wherein the anhydrous carrier is soluble or miscible in water.

4. The wound treatment device according to claim 3, wherein the anhydrous water-miscible carrier is selected from polyethylene glycol (PEG) 200, PEG 400, PEG 600, blends of PEGs with 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, methyl diethanolamine, methyl isocyanate, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propionic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol.

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

6. The wound treatment device according to any one of claims 1-5, wherein the antioxidant / reducing agent co-located with the nitrite in the mesh component of the nitrite providing layer has higher stability compared to an antioxidant / reducing agent not stored in a dry state.

7. The wound treatment device according to any one of claims 1-6, wherein the antioxidant / reducing agent exhibits higher stability after sterilization compared to the stability of the antioxidant / reducing agent in a sterilized wound treatment device not stored in a dry state.

8. The wound treatment device according to any one of claims 1-7, wherein the wound treatment device is configured to produce less color than the 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 1-8, wherein the mesh comprises a coated polypropylene mesh.

10. The wound treatment device according to any one of claims 1-9, wherein the activator layer comprises a complex comprising a gelling fiber substrate loaded with acidic hydrogel.

11. The wound treatment device of 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. The wound treatment device according to any one of claims 1-12, wherein the wound treatment device further comprises a collection and distribution layer.

13. The wound treatment device according to any one of claims 1-13, wherein the wound treatment device further comprises a covering layer configured to form a seal around the wound.

14. The wound treatment device of claim 14, wherein the covering layer is moisture-permeable.

15. The wound treatment device according to any one of claims 1-15, wherein the wound treatment device further comprises a masking layer configured to at least partially restrict the visualization of the wound.

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

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

18. The wound treatment device according to any one of claims 1-17, wherein the wound treatment device further comprises a surfactant.

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

20. A method for treating a wound, the method comprising: Apply a wound dressing to the wound, the wound dressing comprising: The nitrite-providing layer includes a mesh component, wherein the mesh component comprises co-located nitrite and an antioxidant / reducing agent; and The activator layer includes a hydrogel, which is configured to provide protons to the nitrite-providing layer to generate nitric oxide.

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

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

23. The method according to claim 22, wherein the anhydrous water-miscible carrier is selected from polyethylene glycol (PEG) 200, PEG 400, PEG 600, blends of PEGs with 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, methyl diethanolamine, methyl isocyanate, N-methyl-2-pyrrolidone, 1-propanediol, 1,3-propanediol, 1,5-pentanediol, 1-propanol, 2-propanol, propionic acid, propylene glycol, pyridine, tetrahydrofuran, and triethylene glycol.

24. The method according to any one of claims 20-23, wherein the mesh component of the nitrite-providing layer is stored in a dry state.

25. The method according to any one of claims 20-24, wherein the antioxidant / reducing agent co-located with the nitrite in the mesh component of the nitrite providing layer has higher stability compared to an antioxidant / reducing agent not stored in a dry state.

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

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

28. The method according to any one of claims 20-27, wherein the mesh comprises a coated polypropylene mesh.

29. The method according to any one of claims 20-28, wherein the activator layer comprises a complex comprising a gelling fiber substrate loaded with acidic hydrogel.

30. The method of 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 20-30, wherein the wound dressing further comprises a collection and distribution layer.

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

33. The method of claim 32, wherein the covering layer is moisture-permeable.

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

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

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

37. The wound treatment device according to any one of claims 20-36, wherein the wound treatment device further comprises a surfactant.

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

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