Patent Publication Number: US-2023136007-A1

Title: Wound dressing

Description:
BACKGROUND 
     Technical Field 
     Disclosed herein are materials, devices, methods, and systems, such as therapeutic compositions, wound care materials, their uses, and methods of treatment therewith. In some examples, the materials, devices, and systems described herein comprise a wound dressing configured for nitric oxide (NO) delivery and/or the delivery of other actives. 
     Description of the Related Art 
     Nitric oxide (NO) is a well-known molecule with multiple biological functions. For example, nitric oxide influences blood vessel vasodilation, stimulates angiogenesis, influences the host immune response, and demonstrates potent, broad spectrum antimicrobial activity and anti-biofilm activity. Due to these multiple roles, NO demonstrates a potent effect on tissue and increased amounts of NO may support the acceleration of healing in wounds, particularly chronic wounds. 
     Additionally, diabetic patients often have lower levels of nitric oxide as compared to healthy patients, and diminished supply of nitric oxide in diabetic patients is a compounding factor in a healing chronic ulcer. Diminished supply of nitric oxide may lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage may also lead to decreased blood flow to the extremities, thereby potentially causing the diabetic patient to be more likely to develop neuropathy and non-healing ulcers, and to be at a greater risk for lower limb amputation. 
     Consequently, there is a need for improved mechanisms of delivering an effective dose of nitric oxide to a wound. Under normal conditions, nitric oxide (NO), a free radical, is short-lived and converted to a more stable chemical species within seconds of production. Thus, for example, if gaseous nitric oxide contacts air, the gaseous nitric oxide will be rapidly oxidized to generate nitrogen dioxide (NO 2 ). Accordingly, it may be difficult to maintain high concentrations of nitric oxide within a wound dressing or other similar structure for a prolonged period of time. Therefore, a device or a wound dressing having one or more layers containing more stable compositions may effectively generate nitric oxide over time upon activation, for the stable and sustained delivery of nitric oxide to biological tissues. Of particular interest are mechanisms of delivering nitric oxide in combination with use of a wound dressing, particularly a negative pressure wound dressing and/or while undergoing negative pressure wound therapy and/or other appropriate therapies. 
     SUMMARY 
     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. It will be understood by one of skill in the art that application of the materials, devices, methods, and systems described herein are not limited to a particular tissue, particular location on the body, or a particular injury. 
     In some configurations, a wound dressing for treating a wound includes a one or more nitric oxide generating layers and an acquisition distribution layer configured to horizontally and/or vertically wick fluid. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The wound dressing can further include a cover layer configured to form a seal around the wound. The one or more nitric oxide generator layers can include a nitric oxide source layer. The one or more nitric oxide generating layers can include an activator layer. The acquisition distribution layer can be positioned directly below the activator layer. The acquisition distribution layer can be attached to the activator layer. The acquisition distribution layer can be attached to the acid providing layer by adhesive, stitching or heat welding. The wound dressing can further include a second acquisition distribution layer, wherein the activator layer is sandwiched between the two acquisition distribution layers. The activator layer can be fully enclosed within the two acquisition distribution layers. The acquisition distribution layer can include a plurality of fibers, and a majority of the plurality of fibers extend horizontally, or substantially horizontally. The acquisition distribution layer can include a plurality of fibers, and 80% to 90% of the plurality of fibers extend horizontally, or substantially horizontally. The cover layer can be moisture vapor permeable. The cover layer can have an outer perimeter larger than an outer perimeter of the activator layer, thereby defining a border region between the outer perimeter of the cover layer and the outer perimeter of the activator layer. At least a portion of the border region of the cover layer can be configured to be sealed to the skin around the wound. The nitric oxide source layer can include an aqueous solution of the nitrite salt. The nitric oxide source layer can include a dry nitrite salt. The nitrite salt can be selected from a group consisting of ammonium nitrite, calcium nitrite, sodium nitrite, potassium nitrate. The nitric oxide source layer can include a mesh. The activator layer can include xerogel or hydrogel. The activator layer can include a foam. The activator can include a plurality of perforations. The wound dressing can further include an obscuring layer. 
     In some configurations, a wound dressing for treating a wound includes one or more nitric oxide generating layers; and a masking element configured to at least partially prevent visualization of the layer there below. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The wound dressing can further include a cover layer, wherein the masking element is positioned below the cover layer. The wound dressing can further include a cover layer, wherein the masking element is positioned above the cover layer. The wound dressing can further include a cover layer, wherein the cover layer is the masking element. The masking element can include one or more viewing windows. The wound dressing can further include an acquisition distribution layer. The acquisition distribution layer can include a plurality of fibers, and a majority of the plurality of fibers extend horizontally, or substantially horizontally. The wound dressing can further include a cover layer, wherein the cover layer has an outer perimeter larger than an outer perimeter of the acid providing layer, thereby defining a border region between the outer perimeter of the cover layer and the outer perimeter of the acid providing layer. At least a portion of the border region of the cover layer can be configured to be sealed to the skin around the wound. The nitric oxide generating layers can include a nitrite providing layer comprising a nitrite salt. The nitrite providing layer can include an aqueous solution of the nitrite salt. The nitrite providing layer can include a dry nitrite salt. The nitrite salt can be selected from a group consisting of ammonium nitrite, calcium nitrite, sodium nitrite, and potassium nitrate. The nitrite providing layer can include a mesh. The nitric oxide generating layers can include an acid providing layer comprising acidic groups. The acid providing layer can include Xerogel or hydrogel. The acid providing layer can include a foam. The acid providing layer can include a plurality of perforations. The wound dressing can include an indicating layer configured to change indication in contact with nitric oxide. The masking element can include a material which changes indication in contact with nitric oxide. 
     In some configurations, a method for treating a wound includes applying a wound dressing to the wound. The wound dressing includes one or more nitric oxide generating layers; and a masking layer configured to at least partially prevent visualization of the layer there below. 
     The method of the preceding paragraph can include one or more of the following features. The method can further include generating nitric oxide. The method can further include allowing nitrite ions to contact an acid. 
     In some configurations, a wound dressing for treating a wound includes a cover layer, a nitrite providing layer, and an acid providing layer. The cover layer is configured to form a seal around the wound. The nitrite providing layer includes a nitrite salt. The acid providing layer is positioned below the cover layer and includes acidic groups. Visualization of the acid providing layer and/or the nitrite providing layer is prevented from above the cover layer. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The cover layer can be at least partially opaque, such that the cover layer prevents visualization of the acid providing layer and/or the nitrite providing layer below the cover layer. The wound dressing can further include an acquisition distribution layer. The acquisition distribution layer can include a plurality of fibers, and a majority of the plurality of fibers extend horizontally, or substantially horizontally. The cover layer can be moisture vapor permeable. The cover layer can have an outer perimeter larger than an outer perimeter of the acid providing layer, thereby defining a border region between the outer perimeter of the cover layer and the outer perimeter of the acid providing layer. At least a portion of the border region of the cover layer can be configured to be sealed to the skin around the wound. The nitrite providing layer can include an aqueous solution of the nitrite salt. The nitrite providing layer can include a dry nitrite salt. The nitrite salt can be selected from a group consisting of ammonium nitrite, calcium nitrite, sodium nitrite, and potassium nitrite. The nitrite providing layer can include a mesh. The acid providing layer can include Xerogel or hydrogel. The acid providing layer can include a foam. The acid providing layer can include a plurality of perforations. The wound dressing can further include an indicating layer configured to change indication in contact with nitric oxide. The cover layer can include a material which changes indication in contact with nitric oxide. 
     In some configurations, a method for treating a wound includes applying a wound dressing to the wound. The wound dressing includes one or more nitric oxide generating layers and an acquisition distribution layer configured to horizontally and/or vertically wick fluid. 
     The method of the preceding paragraph can include one or more of the following features. The method can further include generating nitric oxide. The method can further include allowing a nitric oxide source to contact an activator layer. The acquisition distribution layer can be pre-attached to an one of the one or more nitric oxide generating layers before applying the wound dressing to the wound. The wound dressing can further include a cover layer, wherein the cover layer has an outer perimeter larger than an outer perimeter of the acid providing layer, thereby defining a border region between the outer perimeter of the cover layer and the outer perimeter of the acid providing layer, and sealing at least a portion of the border region of the cover layer to the skin around the wound. The wound dressing can further include an obscuring layer positioned between the acid providing layer and the cover layer. 
     In some configurations, a wound dressing for treating a wound includes a cover layer, a nitrite providing layer, and an acid providing layer. The cover layer is configured to form a seal around the wound. The nitrite providing layer includes a nitrite salt. The acid providing layer includes acidic groups, wherein the acid providing layer further includes one or more holes through the thickness of the acid proving layer. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The cover layer can be moisture vapor permeable. The cover layer can have an outer perimeter larger than an outer perimeter of the acid providing layer, thereby defining a border region between the outer perimeter of the cover layer and the outer perimeter of the acid providing layer. At least a portion of the border region of the cover layer can be configured to be sealed to the skin around the wound. The nitrite providing layer can include an aqueous solution of the nitrite salt. The nitrite providing layer can include a dry nitrite salt. The nitrite salt can he selected from a group consisting of ammonium nitrite, calcium nitrite, sodium nitrite, potassium nitrite. The nitrite providing layer can include a mesh. The acid providing layer can include Xerogel or hydrogel. The acid providing layer can include a foam. The wound dressing can include an obscuring layer positioned between the acid providing layer and the cover layer. 
     In some configurations, a wound dressing includes a nitric oxide source layer comprising a plurality of through-holes through the thickness of the acid proving layer; and an acquisition distribution layer. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The wound dressing can further include a cover layer configured to form a seal around the wound. The cover layer can be moisture vapor permeable. The nitric oxide source layer can include an aqueous solution of the nitrite salt. The nitric oxide source layer can include a dry nitrite salt. The nitrite salt can be selected from a group consisting of ammonium nitrite, calcium nitrite, sodium nitrite, potassium nitrate. The nitric oxide source layer can include a mesh. The wound dressing can further include an obscuring layer. 
     In some configurations, a method for producing a wound dressing includes producing an acid providing gel layer. Producing the acid providing gel layer includes positioning a template on a mold, adding a gel prepolymer above the template on the mold, allowing the gel prepolymer to be absent at a plurality of locations above the template to define a plurality of perforations, and curing the gel prepolymer. 
     The method of the preceding paragraph can include one or more of the following features. The template can include a plurality of perforations. The template can have higher surface energy than the mold. Producing the acid providing gel layer can further include flipping the acid providing gel layer after curing the gel prepolymer on the mold, positioning another template above the cured gel prepolymer, adding an additional portion of the gel prepolymer above the cured gel prepolymer, and curing the additional portion of the gel prepolymer. The template can include a plurality of pillars. The template can include woven or non-woven material. The template can include polypropylene, polyethylene, or a combination thereof. 
     In some configurations, a method for producing a wound dressing includes producing an acid providing gel layer. Producing the acid providing gel layer includes positioning a material layer on a mold, adding a gel prepolymer above the material layer on the mold, and curing the gel prepolymer. 
     The method of the preceding paragraph can include one or more of the following features. Producing an acid providing gel layer can further include allowing the material layer to float above the gel prepolymer before curing the gel prepolymer. Producing an acid providing gel layer can further include adding an additional portion of the gel prepolymer above the material layer after curing the gel prepolymer; and curing the additional portion of the gel prepolymer. Producing the acid providing gel layer can further include flipping the acid providing gel layer after curing the gel prepolymer on the mold, positioning another material layer above the cured gel prepolymer; adding an additional portion of the gel prepolymer above the cured gel prepolymer; and curing the additional portion of the gel prepolymer. The material layer can include woven or non-woven material. The material layer can include a mesh. The material layer can include polypropylene, polyethylene, or a combination thereof. The material layer can be pretreated with a wetting agent. The gel prepolymer can include a prepolymer for hydrogel or Xerogel. 
     In some configurations, a method for treating a wound includes applying a wound dressing to the wound. The wound dressing includes a cover layer, a nitrite providing layer, and an acid providing layer positioned below the cover layer. The cover layer is configured to form a seal around the wound. The nitrite providing layer includes a nitrite salt. The acid providing layer includes acid groups, and further includes one or more material layers. 
     The method of the preceding paragraph can include one or more of the following features. The method can further include generating nitric oxide. The method can further include allowing nitrite ions of the nitrite salt to contact the acid providing layer. 
     In some configurations, a wound dressing for treating a wound include a cover layer, a nitrite providing layer, and an acid providing layer. The cover layer is configured to form a seal around the wound. The nitrite providing layer includes a nitrite salt. The acid providing layer is positioned below the cover layer and includes acidic groups. The acid providing layer includes one or more material layer immobilized therein. 
     The wound dressing of the preceding paragraph can include one or more of the following features. The one or more material layers can include woven or non-woven material. The one or more material layers can include a mesh. The one or more material layers can include polypropylene, polyethylene, or a combination thereof. The acid providing layer can include one material layer, wherein the material layer covers a lower wound-facing side of the acid providing layer. The acid providing layer can include one material layer, wherein the material layer covers an upper side of the acid providing layer opposite a wound facing side. The acid providing layer can be sandwiched between the one or more material layers. The acid providing layer can be encapsulated by the one or more material layers. The one or more material layers can be embedded within the acid providing layer. The acid providing layer can include xerogel or hydrogel. The material layers can be immobilized to the acid providing layer without an adhesive. The acid providing layer can include a plurality of perforations. 
     Alternative or additional embodiments described herein provide a composition comprising one or more of the features of the foregoing description or of any description elsewhere herein. 
     Alternative or additional embodiments described herein provide a wound contact layer comprising one or more of the features of the foregoing description or of any description elsewhere herein. 
     Alternative or additional embodiments described herein provide a wound dressing comprising one or more of the features of the foregoing description or of any description elsewhere herein. 
     Alternative or additional embodiments described herein provide a wound treatment system comprising one or more of the features of the foregoing description or of any description elsewhere herein. 
     Alternative or additional embodiments described herein provide a method of treating a wound comprising one or more of the features of the foregoing description or of any description elsewhere herein. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a schematic diagram of an example of a negative pressure wound therapy system; 
         FIG.  2 A  illustrates an embodiment of a negative pressure wound treatment system employing a pump, a flexible fluidic connector and a wound dressing capable of absorbing and storing wound exudate; 
         FIG.  2 B  illustrates an embodiment of a negative pressure wound treatment system employing a flexible fluidic connector and a wound dressing capable of absorbing and storing wound exudate; 
         FIG.  2 C  illustrates a cross section of an embodiment of a fluidic connector connected to a wound dressing; 
         FIG.  2 D  illustrates a cross-section of an embodiment of a wound dressing; 
         FIGS.  3 A- 3 D  illustrate embodiments of wound dressings capable of absorbing and storing wound exudate to be used without negative pressure; 
         FIG.  3 E  illustrates a cross section of an embodiment of a wound dressing capable of absorbing and storing wound exudate to be used without negative pressure; 
         FIG.  4    is an exploded view of an embodiment of a wound dressing which can generate nitric oxide; 
         FIG.  5    is a cross sectional view of the wound dressing of  FIG.  4    (12); 
         FIG.  6    illustrates an example of a chemiluminescence experimental protocol equipment setup; 
         FIGS.  7 A-B  illustrates a negative pressure and nitric oxide delivery experiment; 
         FIG.  8 A  depicts an example of chemiluminescence experimental results for a sodium nitrate mesh; 
         FIG.  8 B  depicts an example of chemiluminescence experimental results for a full dressing design with a pull-out tab and self-sealing borders; 
         FIG.  8 C  depicts an example of chemiluminescence experimental results for a dressing containing a degradable film; 
         FIG.  9    depicts an example of a graph displaying peak NO and NO 2  outputs for acrylic adhesive containing hydrogels; 
         FIGS.  10 A-D  depict examples of chemiluminescence experimental results for nitric oxide dressing; 
         FIG.  11    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  12    is a cross sectional view of the wound dressing of  FIG.  11   ; 
         FIG.  13    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  14    is a cross sectional view of the wound dressing of  FIG.  13   ; 
         FIG.  15    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  16    is a cross sectional view of the wound dressing of  FIG.  15   ; 
         FIG.  17    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  18    is a cross sectional view of the wound dressing of  FIG.  17   ; 
         FIG.  19    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  20    is a cross sectional view of the wound dressing of  FIG.  19   ; 
         FIG.  21    is a cross sectional view of a hydrogel layer according to one embodiment; 
         FIG.  22    is a cross sectional view of a hydrogel layer according to one embodiment; 
         FIG.  23    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  24    is a cross sectional view of the wound dressing of  FIG.  23   ; 
         FIG.  25    illustrates a process for producing a layer for a wound dressing; 
         FIG.  26    illustrates a process for producing a layer for a wound dressing; 
         FIG.  27    is an exploded view of an embodiment of a wound dressing which generates nitric oxide; 
         FIG.  28    is a cross sectional view of the wound dressing of  FIG.  27   ; 
     
    
    
     DETAILED DESCRIPTION 
     Overview 
     Embodiments described herein relate to materials, apparatuses, methods, and systems that incorporate, or comprise, or utilize one or more compositions and/or materials that effectively generate gases (e.g. nitric oxide) over time upon activation. Embodiments herein may be directed toward a device and/or a wound dressing having one or more layers containing compositions and/or materials that effectively generate nitric oxide over time upon activation. For example, one or more nitric oxide generating layers may include a nitrite delivery layer which contains nitrite salts and can release nitrite ions, such that the nitrite ions can generate nitric oxide upon reaction with acids. In some embodiments, the one or more nitric oxide generating layers can further include an acidic-group-providing layer in addition to the nitrite delivery layer. The one or more nitric oxide generating layers may be utilized as a stand-alone component for separately positioning at a wound site, or may be incorporated into any number of multi-layer wound dressings and wound treatment apparatuses, such as described herein below with respect to  FIGS.  1  through  11   . Embodiments of the present disclosure are generally applicable to use under ambient conditions, in negative pressure or reduced pressure therapy systems, or in compression therapy systems. 
     Some of the preferred embodiments described herein incorporate, or comprise, or utilize one or more nitric oxide generating layers. Such one or more nitric oxide generating layers may possess one or more of the following functional features: inflammation-related activities, blood flow-related activities, antimicrobial, anti-planktonic and anti-biofilm activities, ease of application or/and removal as one piece, cuttability/tearability, conformability to the three-dimensional contour of a wound surface, durability to wear, compatibility with negative pressure wound therapy or/and compression wound therapy, exudate management, capability of facilitating autolytic debridement of wounds, capability of promoting wound healing, and self-indication of compositional or functional changes. The antimicrobial activities, such as in vitro antimicrobial activities, can include one or more of the following: broad-spectrum antimicrobial activity, anti-biofilm activity, rapid speed of kill against microorganisms, sustained kill against microorganisms; and the microorganisms can include one or more of the following: Gram-negative bacteria, Gram-positive bacteria, fungi, yeasts, viruses, algae, archaea and protozoa. 
     Certain preferred embodiments described herein provide a wound treatment system. Such a wound treatment system may comprise nitric oxide generating layers, configured to be sized for positioning over a wound and/or the periwound area. One of skill in the art will understand that when an apparatus/dressing/layer is described as being placed on or over a wound, such an apparatus/dressing/layer may extend over and treat the periwound area. In some instances, stimulation of the periwound area and/or the wound edge may play a role in initiating the wound healing process, and the wound healing process can be activated through the delivery of nitric oxide to the periwound area and/or the wound edge. The delivery of nitric oxide to the periwound area and/or the wound edge may target, for example epithelial cell activity to promote migration of epithelial tongue; vasodilation of the microcirculation in the skin surrounding the wound to promote profusion by providing oxygen and nutrients; and neo-angiogenesis to promote granulation tissue formation. The wound treatment systems described herein may further comprise a secondary wound dressing configured to be separately positioned over the nitric oxide generating layers. The nitric oxide generating layers may have an adhesive adhered to the lower surface; and the adhesive can be configured such that the nitric oxide generating layers may be placed in proximity to the wound. The secondary wound dressing, if used, may adhere to skin surrounding the wound and may have the same size or may be larger than the nitric oxide generating layers, such that the nitric oxide generating layers will touch or be placed in proximity to the wound and/or the periwound area. The secondary wound dressing can be alternatively or additionally configured to form a seal to skin surrounding the wound so that the nitric oxide generating layers will touch or be placed in proximity to the wound. The wound treatment system may further comprise a source of negative pressure configured to supply negative pressure through the secondary wound dressing and through the wound contact layer to the wound. 
     Certain other preferred embodiments described herein provide a multi-layered wound dressing, such as described herein the specification with respect to  FIGS.  1  through  11   . Such a multi-layered wound dressing may incorporate the one or more nitric oxide generating layers as component layers thereof or, alternatively, may comprise a composite or laminate including the one or more nitric oxide generating layers as part of one of the component layers thereof. The multi-layered wound dressing may comprise: nitric oxide generating layers as described above or described elsewhere herein; a transmission layer and/or 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 transmission layer and/or absorbent layer. The wound dressing may further comprise a negative pressure port positioned on or above the cover layer. The one or more nitric oxide generating layers may 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 may have a perimeter shape that is smaller than a perimeter shape of the cover layer. 
     One of skill in the art will understand that nitric oxide generating compositions, such as any disclosed herein this “Overview” section or elsewhere in the specification, may be loaded within the 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 powder form. One of skill in the art will further understand that reactive compositions, such as any disclosed herein this section or elsewhere in the specification may be incorporated into any suitable absorbent layer disclosed herein this section or elsewhere in the specification by any suitable means, and/or any suitable transmission layer disclosed herein this section or elsewhere in the specification, and/or any foam layer disclosed herein this section or elsewhere in the specification. 
     In certain embodiments, the wound treatment systems and multi-layered wound dressings disclosed above or disclosed elsewhere herein the specification may incorporate or comprise nitric oxide generating layers. As described herein this section or elsewhere in the specification, particularly below, the nitric oxide generating layers may be configured to be activated to release nitric oxide. At least a portion of the released nitric oxide may be released, for example by diffusion. To facilitate release and diffusion of nitric oxide, the nitric oxide generating layers may be placed proximate to the wound. 
     Some preferred embodiments described herein the specification provide a method to treat a wound, intact tissue, or other suitable location. Such a method may include placing nitric oxide generating layers, either separately or by placing a multi-layered wound dressing having nitric oxide generating layers, over the wound. The method may comprise adhering the separate nitric oxide generating layers and/or the multi-layer wound dressing having nitric oxide generating layers to healthy skin around the wound. Such a method may further comprise one or more of the following steps: A further wound dressing can be placed over the separate nitric oxide generating layers or multi-layered wound dressing having the nitric oxide generating layers that is placed over the wound. Wound exudate, or any moist or aqueous medium other than wound exudate, may be provided to reach and/or touch the nitric oxide generating layers. Wound exudate, or any moist or aqueous medium other than wound exudate may be diffused or wicked into the wound dressing incorporating the nitric oxide generating layers or into a wound dressing provided over the nitric oxide generating layers. Negative pressure may be applied to the separate nitric oxide generating layers or multi-layered wound dressing having the nitric oxide generating layers, such that wound exudate is suctioned into the nitric oxide generating layers directly, or into the wound dressing incorporating the nitric oxide generating layers, or into a wound dressing provided over the nitric oxide generating layers. 
     One of skill in the art will understand that wound dressings, devices and systems disclosed herein this “Overview” section or elsewhere in the specification may include one or more layers, compositions, materials or components that generate gases other than nitric oxide in addition to or in place of the nitric oxide generating layers, compositions or materials. For example, a wound dressing or a device can include one or more layers that effectively generate vasodilatory agents, such as carbon monoxide or hydrogen sulfide, over time upon activation. 
     One of skill in the art will further understand that carbon monoxide and/or hydrogen sulfide may be used in place of a nitric oxide delivery element (such as a layer) or in combination with a nitric oxide delivery element (such as a layer) where suitable. Further details regarding generation and delivery of carbon monoxide and/or hydrogen sulfide may be found in chapter six of the text Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells, ISBN 978-0-12-803814-7, which is hereby incorporated by reference. For example, hydrogen sulfide may be generated from elements/layers that contain cleavable/releasable hydrogen sulfide, diallyl thiosulfinate, GYY4137, S-Mesalamine ATB-429, S-Naproxen ATB-346, S-Diclofenac ATB-337/ACS-15. For example, carbon monoxide may be generated from elements/layers that provide of complexes of carbon monoxide bound to suitable metals such as chromium, molybdenum, tungsten, manganese, rhenium, iron, ruthenium, cobalt, rhodium, and iridium. Such complexes may be enzymatically triggered to release carbon monoxide, photo-cleavable, and/or responsive to interaction with a suitable ligand to induce release of carbon monoxide. 
     Method of Treating a Wound 
     Some preferred embodiments described herein the specification provide a method of treating a wound, intact tissue, or other suitable location. Such a method may include placing one or more nitric oxide generating layers, either separately or by placing a multi-layered wound dressing having one or more nitric oxide generating layers over the wound. The method may comprise adhering the separate one or more nitric oxide generating layers and/or the multi-layer wound dressing having one or more nitric oxide generating layers to healthy skin around the wound, such as the periwound area. The method may further comprise one or more of the following steps: A further wound dressing can be placed over the separate one or more nitric oxide generating layers or multi-layered wound dressing having the one or more nitric oxide generating layers that is placed over the wound. Wound exudate, or any moist or aqueous medium other than wound exudate, may be provided to reach and/or touch the one or more nitric oxide generating layers. Wound exudate, or any moist or aqueous medium other than wound exudate may be diffused or wicked into the wound dressing incorporating the one or more nitric oxide generating layers or into a wound dressing provided over the one or more nitric oxide generating layers. Negative pressure may be applied to the separate one or more nitric oxide generating layers or multi-layered wound dressing having the one or more nitric oxide generating layers, as described in the following “Negative Pressure Wound Therapy (NPWT) Systems” section or described elsewhere herein the specification, such that wound exudate is suctioned into the one or more nitric oxide generating layers directly, or into the wound dressing incorporating the one or more nitric oxide generating layers, or into a wound dressing provided over the one or more nitric oxide generating layers. 
     The method of treating a wound, intact tissue, or other suitable location as described above or described elsewhere herein may further comprise delivering negative pressure through the wound contact layer to the wound, as described in the following “Negative Pressure Wound Therapy (NPWT) Systems” section or described elsewhere herein the specification. The wound contact layer may substantially maintain the negative pressure delivered for at least about 24 hours, or for at least about 48 hours, or for at least about 72 hours. Alternatively, the method of treating a wound, intact tissue, or other suitable location may comprise applying compression (positive) pressure through the wound contact layer to the wound. Alternatively, the method may comprise altering ambient pressure, negative pressure and compression pressure in a programmable manner through the wound contact layer to the wound. 
     In embodiments, the method of treating a wound, intact tissue, or other suitable location may comprise using the wound contact layer, or the wound treatment system or wound dressing that comprises the wound contact layer, under ambient conditions not in connection with a negative pressure wound therapy system as described above, or described elsewhere herein. 
     In some embodiments, a method of treating a wound, intact tissue, or other suitable location may reduce the wound bioburden, for example, at least in vitro, by reducing the numbers (CFU/sample) of viable microorganisms within the first 4 hours after the application wound contact layer. In some examples, the numbers of viable microorganisms may be reduced by four log or more, 48 to 72 hours after positioning the wound dressing in contact with the microorganisms. 
     Negative Pressure Wound Therapy (NPWT) Systems 
     It will be understood that embodiments of the present disclosure are generally applicable to, but not limited to, use in topical negative pressure (“TNP”) therapy systems. Briefly, negative pressure wound therapy assists in the closure and healing of many forms of “hard to heal” wounds by reducing tissue oedema; encouraging blood flow and granular tissue formation; removing excess exudate and may reduce bacterial load (and thus infection risk). In addition, the therapy allows for less disturbance of a wound leading to more rapid healing. TNP therapy systems may also assist on the healing of surgically closed wounds by removing fluid and by helping to stabilize the tissue in the apposed position of closure. A further beneficial use of TNP therapy can be found in grafts and flaps where removal of excess fluid is important and close proximity of the graft to tissue is required in order to ensure tissue viability. 
     As is used herein, reduced or negative pressure levels, such as -X mmHg, represent pressure levels 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.). Accordingly, a negative pressure value of -X mmHg reflects absolute pressure that is X mmHg below 760 mmHg or, in other words, an absolute pressure of (760-X) mmHg. In addition, negative pressure that is “less” or “smaller” than X mmHg corresponds to pressure that is closer to atmospheric pressure (e.g., -40 mmHg is less than -60 mmHg). Negative pressure that is “more” or “greater” than -X mmHg corresponds to pressure that is further from atmospheric pressure (e.g., -80 mmHg is more than -60 mmHg). In some embodiments, local ambient atmospheric pressure is used as a reference point, and such local atmospheric pressure may not necessarily be, for example, 760 mmHg. 
     The negative pressure range for some embodiments of the present disclosure can be approximately -80 mmHg, or between about -20 mmHg and -200 mmHg. Note that these pressures are relative to normal ambient atmospheric pressure, which can be 760 mmHg. Thus, -200 mmHg would be about 560 mmHg in practical terms. In some embodiments, the pressure range can be between about -40 mmHg and -150 mmHg. Alternatively, a pressure range of up to -75 mmHg, up to -80 mmHg or over -80 mmHg can be used. Also in other embodiments a pressure range of below -75 mmHg can be used. Alternatively, a pressure range of over approximately -100 mmHg, or even -150 mmHg, can be supplied by the negative pressure apparatus. 
     In some embodiments of wound closure devices described herein, increased wound contraction can lead to increased tissue expansion in the surrounding wound tissue. This effect may be increased by varying the force applied to the tissue, for example by varying the negative pressure applied to the wound over time, possibly in conjunction with increased tensile forces applied to the wound via embodiments of the wound closure devices. In some embodiments, negative pressure may be varied over time for example using a sinusoidal wave, square wave, or in synchronization with one or more patient physiological indices (e.g., heartbeat). Examples of such applications where additional disclosure relating to the preceding may be found include U.S. Pat. No. 8,235,955, titled “Wound treatment apparatus and method,” issued on Aug. 7, 2012; and U.S. Pat. No. 7,753,894, titled “Wound cleansing apparatus with stress,” issued Jul. 13, 2010. The disclosures of both of these patents are hereby incorporated by reference in their entirety. 
     Embodiments of the wound dressings, wound dressing components, wound treatment apparatuses and methods described herein may also be used in combination or in addition to those described in International Application No. PCT/IB2013/001469, filed May 22, 2013, published as WO 2013/175306 A2 on Nov. 28, 2013, titled “APPARATUSES AND METHODS FOR NEGATIVE PRESSURE WOUND THERAPY,” International Application No. PCT/IB2013/002060, filed on Jul. 31, 2013, published as WO2014/020440, entitled “WOUND DRESSING,” the disclosures of which are hereby incorporated by reference in their entireties. Embodiments of the wound dressings, wound treatment apparatuses and methods described herein may also be used in combination or in addition to those described in U.S. Pat. No. 9,061,095, titled “WOUND DRESSING AND METHOD OF USE,” issued on Jun. 23, 2015; and U.S. Application Publication No. 2016/0339158, titled “FLUIDIC CONNECTOR FOR NEGATIVE PRESSURE WOUND THERAPY,” published on Nov. 24, 2016, the disclosures of which are hereby incorporated by reference in its entirety, including further details relating to embodiments of wound dressings, the wound dressing components and principles, and the materials used for the wound dressings. 
     Additionally, some embodiments related to TNP wound treatment comprising a wound dressing in combination with a pump or associated electronics described herein may also be used in combination or in addition to those described in International Publication No. WO 2016/174048 A1, entitled “REDUCED PRESSURE APPARATUSES”, published on Nov. 3, 2016, the entirety of which is hereby incorporated by reference. In some of these embodiments, the pump or associate electronic components may be integrated into the wound dressing to provide a single article to be applied to the wound. 
     Multi-Layered Wound Dressings for NPWT 
       FIG.  1    illustrates an example of a negative pressure wound therapy system  700 . 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 so that negative pressure can be maintained in the wound cavity. For example, a film layer of the wound dressing  720  can provide substantially fluid impermeable seal over the wound cavity  710 . In some embodiments, a wound filler, such as a layer of foam or gauze, may be utilized to pack the wound. The wound filler may include one or more nitric oxide generating layers (e.g. a nitrite delivery layer, an acidic-group providing layer) as described herein this section or elsewhere in the specification. For example, in a traditional negative pressure wound therapy system utilizing foam or gauze, such as the Smith &amp; Nephew RENASYS Negative Pressure Wound Therapy System utilizing foam (RENASYS-F) or gauze (RENASYS-G), the foam or gauze may be supplemented with nitric oxide generating layers as described above. When supplementing a foam or gauze layer or other wound packing material, the one or more nitric oxide generating layers may either be separately inserted into the wound or may be pre-attached with the wound packing material for insertion into the wound. 
     A single or multi lumen tube or conduit  740  connects the wound dressing  720  with a negative pressure device  750  configured to supply reduced pressure. The negative pressure device  750  includes a negative pressure source. The negative pressure device  750  can be a canisterless device (meaning that exudate is collected in the wound dressing and/or is transferred via the tube  740  for collection to 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 fully or partially embedded in, mounted to, or supported by the wound dressing  720 . 
     The conduit  740  can be any suitable article configured to provide at least a substantially sealed fluid flow path or pathway between the negative pressure device  750  and the wound cavity  710  so as to supply 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, a port can include a hole in the 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 reduced pressure to the wound cavity  710  so as to maintain a desired level of reduced pressure in the wound cavity. In some embodiments, at least a part of the conduit  740  is integral with or attached to the wound dressing  720 . 
       FIG.  2 A  illustrates an embodiment of a negative pressure wound treatment system  10  employing a wound dressing  100  in conjunction with a fluidic connector  110 . Additional examples related to negative pressure wound treatment comprising a wound dressing in combination with a pump as described herein may also be used in combination or in addition to those described in U.S. Pat. No. 9,061,095, which is incorporated by reference in its entirety. Here, the fluidic connector  110  may comprise an elongate conduit, more preferably a bridge  120  having a proximal end  130  and a distal end  140 , and an applicator  180  at the distal end  140  of the bridge  120 . The system  10  may include a source of negative pressure such as a pump or negative pressure unit  150  capable of supplying negative pressure. The pump may comprise a canister or other container for the storage of wound exudates and other fluids that may be removed from the wound. A canister or container may also be provided separate from the pump. In some embodiments, the pump  150  can be a canisterless pump such as the PICO™ pump, as sold by Smith &amp; Nephew. The pump  150  may be connected to the bridge  120  via a tube, or the pump  150  may be connected directly to the bridge  120 . In use, the dressing  100  is placed over a suitably-prepared wound, which may in some cases be filled with a wound packing material such as foam or gauze as described above. The applicator  180  of the fluidic connector  110  has a sealing surface that is placed over an aperture in the dressing  100  and is sealed to the top surface of the dressing  100 . Either before, during, or after connection of the fluidic connector  110  to the dressing  100 , the pump  150  is connected via the tube to the coupling  160 , or is connected directly to the bridge  120 . The pump is then activated, thereby supplying negative pressure to the wound. Application of negative pressure may be applied until a desired level of healing of the wound is achieved. 
     As shown in  FIG.  2 B , the fluidic connector  110  preferably comprises an enlarged distal end, or head  140  that is in fluidic communication with the dressing  100  as will be described in further detail below. In one embodiment, the enlarged distal end has a round or circular shape. The head  140  is illustrated here as being positioned near an edge of the dressing  100 , but may also be positioned at any location on the dressing. For example, some embodiments may provide for a centrally or off-centered location not on or near an edge or corner of the dressing  100 . In some embodiments, the dressing  10  may comprise two or more fluidic connectors  110 , each comprising one or more heads  140 , in fluidic communication therewith. In a preferred embodiment, the head  140  may measure 30 mm along its widest edge. The head  140  forms at least in part the applicator  180 , described above, that is configured to seal against a top surface of the wound dressing. 
       FIG.  2 C  illustrates a cross-section through a wound dressing  100  similar to the wound dressing  10  as described in International Patent Publication WO2013175306 A2, which is incorporated by reference in its entirety, along with fluidic connector  110 . The wound dressing  100 , which can alternatively be any wound dressing embodiment disclosed herein or any combination of features of any number of wound dressing embodiments disclosed herein, can be located over a wound site to be treated. The dressing  100  may be placed as to form a sealed cavity over the wound site. In a preferred embodiment, the dressing  100  comprises a top or cover layer, or backing layer  220  attached to an optional wound contact layer  222 , both of which are described in greater detail below. These two layers  220 ,  222  are preferably joined or sealed together so as to define an interior space or chamber. This interior space or chamber may comprise additional structures that may be adapted to distribute or transmit negative pressure, store wound exudate and other fluids removed from the wound, and other functions which will be explained in greater detail below. Examples of such structures, described below, include a transmission layer  226  and an absorbent layer  221 . 
     As used herein the upper layer, top layer, or layer above refers to a layer furthest from the surface of the skin or wound while the dressing is in use and positioned over the wound. Accordingly, the lower surface, lower layer, bottom layer, or layer below refers to the layer that is closest to the surface of the skin or wound while the dressing is in use and positioned over the wound. 
     As illustrated in  FIG.  2 C , the wound contact layer  222  can be a polyurethane layer or polyethylene layer or other flexible layer which is perforated, for example via a hot pin process, laser ablation process, ultrasound process or in some other way or otherwise made permeable to liquid and gas. The wound contact layer  222  has a lower surface  224  and an upper surface  223 . The perforations  225  preferably comprise through holes in the wound contact layer  222  which enable fluid to flow through the layer  222 . The wound contact layer  222  helps prevent tissue ingrowth into the other material of the wound dressing. Preferably, the perforations are small enough to meet this requirement while still allowing fluid to flow therethrough. For example, perforations formed as slits or holes having a size ranging from 0.025 mm to 1.2 mm are considered small enough to help prevent tissue ingrowth 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 air tight seal around the absorbent pad in order to maintain negative pressure at the wound. 
     Some embodiments of the wound contact layer  222  may also act as a carrier for an optional lower and upper adhesive layer (not shown). For example, a lower pressure sensitive adhesive may be provided on the lower surface  224  of the wound dressing  100  whilst an upper pressure sensitive adhesive layer may be provided on the upper surface  223  of the wound contact layer. The pressure sensitive adhesive, which may be a silicone, hot melt, hydrocolloid or acrylic based adhesive or other such adhesives, may be formed on both sides or optionally on a selected one or none of the sides of the wound contact layer. When a lower pressure sensitive adhesive layer is utilized may be helpful to adhere the wound dressing  100  to the skin around a wound site. In some embodiments, the wound contact layer may comprise perforated polyurethane film. The lower surface of the film may be provided with a silicone pressure sensitive adhesive and the upper surface may be provided with an acrylic pressure sensitive adhesive, which may help the dressing maintain its integrity. In some embodiments, a polyurethane film layer may be provided with an adhesive layer on both its upper surface and lower surface, and all three layers may be perforated together. 
     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 transmission of fluid including liquid and gas away from a wound site into upper layers of the wound dressing. In particular, the transmission layer  226  preferably ensures that an open-air channel can be maintained to communicate negative pressure over the wound area even when the absorbent layer has absorbed substantial amounts of exudates. The layer  226  should preferably remain open under the typical pressures that will be applied during negative pressure wound therapy as described above, so that the whole wound site sees an equalized negative pressure. The layer  226  may be formed of a material having a three-dimensional structure. For example, a knitted or woven spacer fabric (for example Baltex 7970 weft knitted polyester) or a non-woven fabric could be used. The three-dimensional material can comprise a 3D spacer fabric material similar to the material described in International Publication WO 2013/175306 A2 and International Publication WO2014/020440, the disclosures of which are incorporated by reference in their entireties. 
     In certain embodiments, the wound dressing  100  may incorporate or comprise one or more nitric oxide generating layers (e.g. a nitrite delivery layer, an acidic-group providing layer) as described herein this section or elsewhere in the specification. One of skill in the art will understand that the wound dressing  100  may incorporate any of the one or more nitric oxide generating layers disclosed herein this section or elsewhere in the specification. One of skill in the art will also understand that the one or more nitric oxide generating layers may be incorporated as a whole component layer or a part of a component layer. In some embodiments, the one or more nitric oxide generating layers may be provided below the transmission layer  226 . In some embodiments, the one or more nitric oxide generating layers may be provided above the wound contact layer  222 . In certain embodiments, the one or more nitric oxide generating layers may replace the transmission layer  226 , such that the one or more nitric oxide generating layers are provided between an 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 the wound contact layer  222 , and the one or more nitric oxide generating layers may be the lowermost layer of the wound dressing  100 . The one or more nitric oxide generating layers may have same or substantially similar size and shape with the transmission layer  226  and/or the absorbent layer  221 . 
     The one or more nitric oxide generating layers may be constructed to be flexible but stiff enough to withstand negative pressure, such that the one or more nitric oxide generating layers is not collapsed excessively and thereby may transmit negative pressure sufficiently to the wound when negative pressure is supplied to the wound dressing  100 . The one or more nitric oxide generating layers may be constructed to include sufficient number or size of pores to enable transmission of negative pressure. The one or more nitric oxide generating layer may include an aperture or hole, for example, under the port, to transmit negative pressure and/or wound fluid. Further, the one or more nitric oxide generating layers may have suitable thickness(es) to transmit suitable negative pressure to the wound. For example, the one or more nitric oxide generating layers may have a thickness of about 1 mm to 10 mm, or 1 mm to 7 mm, or 1.5 mm to 7 mm, or 1.5 mm to 4 mm, or 2 mm to 3 mm. In some embodiments, the one or more nitric oxide generating layers may have a thickness of approximately 2 mm. 
     In some embodiments, the layer  221  of absorbent material is provided above the transmission layer  226 . The absorbent material, which can comprise a foam or non-woven natural or synthetic material, and which may optionally comprise a super-absorbent material, forms a reservoir for fluid, particularly liquid, removed from the wound site. In some embodiments, the layer  221  may also aid in drawing fluids towards the backing layer  220 . 
     The material of the absorbent layer  221  may also prevent liquid collected in the wound dressing  100  from flowing freely within the dressing, and preferably acts so as to contain any liquid collected within the dressing. The absorbent layer  221  also helps distribute fluid throughout the layer via a wicking action so that fluid is drawn from the wound site and stored throughout the absorbent layer. This helps prevent agglomeration in areas of the absorbent layer. The capacity of the absorbent material must be sufficient to manage the exudates flow rate of a wound when negative pressure is applied. Since in use the absorbent layer experiences negative pressures the material of the absorbent layer is chosen to absorb liquid under such circumstances. A number of materials exist that are able to absorb liquid when under negative pressure, for example superabsorber material. The absorbent layer  221  may typically be manufactured from ALLEVYN™ foam, Freudenberg 114-224-4 or Chem-Posite™1 1C-450. In some embodiments, the absorbent layer  221  may comprise a composite comprising superabsorbent powder, fibrous material such as cellulose, and bonding fibers. In a preferred embodiment, the composite is an air-laid, thermally-bonded composite. 
     In some embodiments, the absorbent layer  221  is a layer of non-woven cellulose fibers having super-absorbent material in the form of dry particles dispersed throughout. Use of the cellulose fibers introduces fast wicking elements which help quickly and evenly distribute liquid taken up by the dressing. The juxtaposition of multiple strand-like fibers leads to strong capillary action in the fibrous pad which helps distribute liquid. In this way, the super-absorbent material is efficiently supplied with liquid. The wicking action also assists in bringing liquid into contact with the upper cover layer to aid increase transpiration rates of the dressing. 
     An aperture, hole, or orifice  227  is preferably provided in the backing layer  220  to allow a negative pressure to be applied to the dressing  100 . The fluidic connector  110  is preferably attached or sealed to the top of the backing layer  220  over the orifice  227  made into the dressing  100 , and communicates negative pressure through the orifice  227 . A length of tubing may be coupled at a first end to the fluidic connector  110  and at a second end to a pump unit (not shown) to allow fluids to be pumped out of the dressing. Where the fluidic connector is adhered to the top layer of the wound dressing, a length of tubing may be coupled at a first end of the fluidic connector such that the tubing, or conduit, extends away from the fluidic connector parallel or substantially to the top surface of the dressing. The fluidic connector  110  may 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 fluidic connector  110  may be formed from a soft polymer, for example a polyethylene, a polyvinyl chloride, a silicone or polyurethane having a hardness of 30 to 90 on the Shore A scale. In some embodiments, the fluidic connector  110  may be made from a soft or conformable material. 
     Optionally, the absorbent layer  221  includes at least one through hole  228  located so as to underlie the fluidic connector  110 . The through hole  228  may in some embodiments be the same size as the opening  227  in the backing layer, or may be bigger or smaller. As illustrated in  FIG.  2 C  a single through hole can be used to produce an opening underlying the fluidic connector  110 . It will be appreciated that multiple openings could alternatively be utilized. Additionally, should more than one port be utilized according to certain embodiments of the present disclosure one or multiple openings may be made in the absorbent layer in registration with each respective fluidic connector. Although not essential to certain embodiments of the present disclosure the use of through holes in the super-absorbent layer may provide a fluid flow pathway which remains unblocked in particular when the absorbent layer is near saturation. 
     The aperture or through-hole  228  is preferably provided in the absorbent layer  221  beneath the orifice  227  such that the orifice is connected directly to the transmission layer  226  as illustrated in  FIG.  2 C . This allows the negative pressure applied to the fluidic connector  110  to be communicated to the transmission layer  226  without passing through the absorbent layer  221 . This ensures that the negative pressure applied to the wound site is not inhibited by the absorbent layer as it absorbs wound exudates. In other embodiments, no aperture may be provided in the absorbent layer  221 , or alternatively a plurality of apertures underlying the orifice  227  may be provided. In further alternative embodiments, additional layers such as another transmission layer or an obscuring layer such as described with in International Patent Publication WO2014/020440, the entirety of which is hereby incorporated by reference, may be provided over the absorbent layer  221  and beneath the backing layer  220 . 
     The backing layer  220  is preferably gas impermeable, but moisture vapor permeable, and can extend across the width of the wound dressing  100 . The backing layer  220 , which may for example be a polyurethane film (for example, Elastollan SP9109) having a pressure sensitive adhesive on one side, is impermeable to gas and this layer thus operates to cover the wound and to seal a wound cavity over which the wound dressing is placed. In this way, an effective chamber is made between the backing layer  220  and a wound site where a negative pressure can be established. The backing layer  220  is preferably sealed to the wound contact layer  222  in a border region around the circumference of the dressing, ensuring that no air is drawn in through the border area, for example via adhesive or welding techniques. The backing layer  220  protects the wound from external bacterial contamination (bacterial barrier) and allows liquid from wound exudates to be transferred through the layer and evaporated from the film outer surface. The backing layer  220  preferably comprises two layers; a polyurethane film and an adhesive pattern spread onto the film. The polyurethane film is preferably moisture vapor permeable and may be manufactured from a material that has an increased water transmission rate when wet. In some embodiments, the moisture vapor permeability of the backing layer increases when the backing layer becomes wet. The moisture vapor permeability of the wet backing layer may be up to about ten times more than the moisture vapor permeability of the dry backing layer. 
     The absorbent layer  221  may be of a greater area than the transmission layer  226 , such that the absorbent layer overlaps the edges of the transmission layer  226 , thereby ensuring that the transmission layer does not contact the backing layer  220 . This provides an outer channel of the absorbent layer  221  that is in direct contact with the wound contact layer  222 , which aids more rapid absorption of exudates to the absorbent layer. Furthermore, this outer channel ensures that no liquid is able to pool around the circumference of the wound cavity, which may otherwise seep through the seal around the perimeter of the dressing leading to the formation of leaks. As illustrated in  FIG.  2 C , the absorbent layer  221  may define a smaller perimeter than that of the backing layer  220 , such that a boundary or border region is defined between the edge of the absorbent layer  221  and the edge of the backing layer  220 . 
     As shown in  FIG.  2 C , one embodiment of the wound dressing  100  comprises an aperture  228  in the absorbent layer  221  situated underneath the fluidic connector  110 . In use, for example when negative pressure is applied to the dressing  100 , a wound facing portion of the fluidic connector may thus come into contact with the transmission layer  226 , which can thus aid in transmitting negative pressure to the wound site even when the absorbent layer  221  is filled with wound fluids. Some embodiments may have the backing layer  220  be at least partly adhered to the transmission layer  226 . In some embodiments, the aperture  228  is at least 1-2 mm larger than the diameter of the wound facing portion of the fluidic connector 11, or the orifice  227 . 
     In particular for embodiments with a single fluidic connector  110  and through hole, it may be preferable for the fluidic connector  110  and through hole to be located in an off-center position as illustrated in  FIG.  2 B . Such a location may permit the dressing  100  to be positioned onto a patient such that the fluidic connector  110  is raised in relation to the remainder of the dressing  100 . So positioned, the fluidic connector  110  and the filter  214  may be less likely to come into contact with wound fluids that could prematurely occlude the filter  214  so as to impair the transmission of negative pressure to the wound site. 
     Similar to the embodiments of wound dressings described above, some wound dressings comprise a perforated wound contact layer with silicone adhesive on the skin-contact face and acrylic adhesive on the reverse. In some embodiments, the wound contact layer may be constructed from polyurethane, polyethylene or polyester. Above this bordered layer sits a transmission layer. Above the transmission layer, sits an absorbent layer. The absorbent layer can include a superabsorbent non-woven (NW) pad. The absorbent layer can over-border the transmission layer by approximately 5 mm at the perimeter. The absorbent layer can have an aperture or through-hole toward one end. The aperture can be about 10 mm in diameter. Over the transmission layer and absorbent layer lies a backing layer. The backing layer can be a high moisture vapor transmission rate (MVTR) film, pattern coated with acrylic adhesive. The high MVTR film and wound contact layer encapsulate the transmission layer and absorbent layer, creating a perimeter border of approximately 20 mm. The backing layer can have a 10 mm aperture that overlies the aperture in the absorbent layer. Above the hole can be bonded a fluidic connector that comprises a liquid-impermeable, gas-permeable semi-permeable membrane (SPM) or filter that overlies the aforementioned apertures. 
       FIG.  2 D  depicts an embodiment of a wound dressing, similar to the wound dressings of  FIGS.  2 A- 2 C . With reference to  FIG.  2 D , a masking or obscuring layer  2107  can be positioned beneath 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 of any of the other embodiments of the obscuring layers disclosed herein, including but not limited to having any viewing windows or holes. Examples of wound dressings with obscuring layers and viewing windows are described in International Patent Publication WO2014/020440, 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 dressing layer desired. In some embodiments, the obscuring layer  2107  can be adhered to 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 overlay it. As such, in these embodiments the obscuring layer  2107  will be of a smaller area than the backing layer  2140 . 
     Preferably the absorbent layer  2110  and the obscuring layer  2107  include at least one through hole  2145  located so as to underlie the port  2150 . Of course, the respective holes through these various layers  2107 ,  2140 , and  2110  may be of different sizes with respect to each other. As illustrated in  FIG.  2 D  a single through hole can be used to produce an opening underlying the port  2150 . In certain embodiments, the port may be replaced with or used in combination with a fluidic connector such as depicted in  FIG.  2 C . It will be appreciated that multiple openings could alternatively be utilized. Additionally, should more than one port be utilized according to certain embodiments of the present disclosure one or multiple openings may be made in the absorbent layer and the obscuring layer in registration with each respective port. Although not essential to certain embodiments of the present disclosure the use of through holes in the super-absorbent layer may provide a fluid flow pathway which remains unblocked in particular when the absorbent layer  2110  is near saturation. 
     The aperture or through-hole  2144  may be provided in the absorbent layer  2110  and the obscuring layer  2107  beneath the orifice  2144  such that the orifice is connected directly to the transmission layer  2105 . This allows the negative pressure applied to the port  2150  to be communicated to the transmission layer  2105  without passing through the absorbent layer  2110 . This ensures that the negative pressure applied to the wound site is not inhibited by the absorbent layer as it absorbs wound exudates. In other embodiments, no aperture may be provided in the absorbent layer  2110  and/or the obscuring layer  2107 , or alternatively a plurality of apertures underlying the orifice  2144  may be provided. 
     In some embodiments, the obscuring layer  1404  can help to reduce the unsightly appearance of a dressing during use, by using materials that impart partial obscuring or masking of the dressing surface. The obscuring layer  1404  in one embodiment only partially obscures the dressing, to allow clinicians to access the information they require by observing the spread of exudate across the dressing surface. The partial masking nature of this embodiment of the obscuring layer enables a skilled clinician to perceive a different color caused by exudate, blood, by-products etc. in the dressing allowing for a visual assessment and monitoring of the extent of spread across the dressing. However, since the change in color of the dressing from its clean state to a state containing exudate is only a slight change, the patient is unlikely to notice any aesthetic difference. Reducing or eliminating a visual indicator of wound exudate from a patient’s wound is likely to have a positive effect on their health, reducing stress for example. 
     In some embodiments, the obscuring layer can be formed from a non-woven fabric (for example, polypropylene), and may 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 may provide added moisture vapor permeability. In some embodiments, however, hydrophobic obscuring layers may still provide sufficient moisture vapor permeability (i.e., through appropriate material selection, thickness of the obscuring layer), while also permitting better retention of dye or color in the obscuring layer. As such, dye or color may be trapped beneath the obscuring layer. In some embodiments, this may permit the obscuring layer to be colored in lighter colors or in white. In the preferred embodiment, the obscuring layer is hydrophobic. In some embodiments, the obscuring layer material can be sterilizable using ethylene oxide. Other embodiments may be sterilized using gamma irradiation, an electron beam, steam or other alternative sterilization methods. Additionally, in various embodiments the obscuring layer can colored or pigmented, e.g., in medical blue. The obscuring layer may also be constructed from multiple layers, including a colored layer laminated or fused to a stronger uncolored layer. Preferably, the obscuring layer is odorless and exhibits minimal shedding of fibers. 
     Multi-Layered Dressing for Use Without Negative Pressure 
       FIGS.  3 A- 3 D  illustrates various embodiments of a wound dressing  500  that can be used for healing a wound without negative pressure.  FIG.  3 E  illustrates a cross-section of the wound dressing in  FIGS.  3 A- 3 D . As shown in the dressings of  FIGS.  3 A- 3 E , the wound dressings can have multiple layers similar to the dressings described with reference to  FIGS.  2 A- 2 D  except the dressings of  FIGS.  3 A-E  do not include a port or fluidic connector. The wound dressings of  FIGS.  3 A-E  can include a cover layer  501  and an optional wound contact layer  505  as described herein. In some embodiments, the cover layer  501  may be permeable to moisture and/or air. The wound dressing can include various layers positioned between the wound contact layer  505  and 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  FIGS.  2 A- 2 C . 
     As shown in  FIGS.  3 A- 3 E , the dressing  500  may include a perforated wound contact layer  505  and a top film  501 . Further components of the wound dressing  500  include a foam layer  504 , such as a layer of polyurethane hydrocellular foam, of a suitable size to cover the recommended dimension of wounds corresponding to the particular dressing size chosen. An optional layer of activated charcoal cloth (not shown) of similar or slightly smaller dimensions than layer  504  may be provided to allow for odour control. An absorbent layer  502 , such as a layer of superabsorbent air-laid material containing cellulose fibres and a superabsorbent polyacrylate particulates, is provided over layer  504 , of dimensions slightly larger than layer  504 , and allows for an overlap of superabsorbent material and acts as leak prevention. A masking or obscuring layer  503 , such as a layer of three-dimensional knitted spacer fabric, is provided over layer  502 , providing protection from pressure, while allowing partial masking of the top surface of the superabsorber where coloured exudate would remain. In this embodiment this is of smaller dimension (in plan view) than the layer  502 , to allow for visibility of the edge of the absorbent layer, which can be used by clinicians to assess whether the dressing needs to be changed. 
     The wound dressing  500  may incorporate or comprise one or more nitric oxide generating layers (e.g. a nitrite delivery layer, an acidic-group providing layer) as described herein this section or elsewhere. One of skill in the art will understand that the wound dressing  500  may incorporate any of the one or more nitric oxide generating layers disclosed herein this section or elsewhere in the specification. One of skill in the art will also understand that the one or more nitric oxide generating layers may be incorporated as a whole component layer or a part of a component layer. In some embodiments, the nitric oxide generating layers may be provided below the cover layer  501 . In some embodiments, the nitric oxide generating layers may be provided above the wound contact layer  505 . In certain embodiments, the dressing  500  may not include the wound contact layer  505 , such that one of the nitric oxide generating layers may be the lowermost layer and be configured to touch the wound surface. In some embodiments, the nitric oxide generating layers may be provided below the foam layer  504 . In embodiments, the nitric oxide generating layers may replace the foam layer  504 . In some embodiments, the dressing  500  may include only the cover layer  501  and the one or more nitric oxide generating layers. 
     As described previously herein, the one or more nitric oxide generating layers, may be incorporated into or used with commercially available dressings, such as ALLEVYN™ foam, ALLEVYN™ Life, ALLEVYN™ Adhesive, ALLEVYN™ Gentle Border, ALLEVYN™ Gentle, ALLEVYN™ Ag Gentle Border, ALLEVYN™ Ag Gentle, Opsite Post-Op Visible. In some embodiments, the wound dressing  500  may include the cover layer  501 , the wound contact layer  505  and the nitric oxide generating layers sandwiched therebetween. In some embodiments, the wound dressing  500  may include the cover layer  501 , the absorbent layer  502 , the nitric oxide generating layers below the absorbent layer  502 , and the wound contact layer  505 . 
     Further details regarding wound dressings that may be combined with or be used in addition to the embodiments described herein, are found in U.S. Pat. No. 9,877,872, issued on Jan. 30, 2018, titled “WOUND DRESSING AND METHOD OF TREATMENT,” the disclosure of which are hereby incorporated by reference in its entirety, including further details relating to embodiments of wound dressings, the wound dressing components and principles, and the materials used for the wound dressings. 
     Multilayered Wound Dressing With an Integrated Source of Negative Pressure 
     In some embodiments, a source of negative pressure (such as a pump) and some or all other components of the TNP system, such as power source(s), sensor(s), connector(s), user interface component(s) (such as button(s), switch(es), speaker(s), screen(s), etc.) and the like, can be integral with the wound dressing, such as the dressings described above in relation to  FIG.  1   -3D. Additionally, some embodiments related to wound treatment comprising a wound dressing described herein may also be used in combination or in addition to those described in International Application WO 2016/174048 and International Patent Application PCT/EP2017/055225, filed on Mar. 6, 2017, entitled “WOUND TREATMENT APPARATUSES AND METHODS WITH NEGATIVE PRESSURE SOURCE INTEGRATED INTO THE WOUND DRESSING,” the disclosure of which is hereby incorporated by reference in its entirety herein, including further details relating to embodiments of wound dressings, the wound dressing components and principles, and the materials used for the wound dressings and wound dressing components. 
     In some embodiments, the pump and/or other electronic components can be configured to be positioned adjacent to or next to the absorbent and/or transmission layers in the wound dressing so that the pump and/or other electronic components are still part of a single apparatus to be applied to a patient with the pump and/or other electronics positioned away from the wound site. 
     Nitric Oxide Generating Layers 
       FIGS.  4 - 5    illustrate a wound dressing  12000  including nitric oxide generating layers according to some embodiments. In the illustrated embodiments, the wound dressing  12000  may include a cover layer  12200 , an activator layer  12400 , and a nitric oxide source layer  12600 . In some embodiments, the wound dressing  12000  may include additional layers, as further described herein. One of skill in the art will understand that although the various sections of the dressing may be referred to as “layers,” such sections may be in other suitable shapes or configurations. 
     The cover layer  12200  may be gas impermeable, but moisture vapor permeable, and can extend across the width of the wound dressing  12000 . The cover layer  12200 , which may for example be a polyurethane film (for example, Elastollan SP9109 or Elastollan SP806) having a pressure sensitive adhesive on one side, may be impermeable to gas and this layer may thus operate to cover the wound and to seal a wound cavity over which the wound dressing is placed. Therefore, a chamber or a sealed wound space is made between the cover layer  12200  and the wound site. In some embodiments, negative pressure can be established within the chamber or the sealed wound space made 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 wound exudates to be transferred through the layer and evaporated from the film outer surface. The cover layer  12200  may include two or more layers, for example, a polyurethane film and an adhesive pattern spread onto the film. In certain examples, the polyurethane film may be moisture vapor permeable and may be manufactured from a material that has an increased water transmission rate when wet. In some embodiments, the moisture vapor permeability of the cover layer increases when the cover layer becomes wet. The moisture vapor permeability of the wet cover layer may be up to about ten times more than the moisture vapor permeability of the dry cover layer. In some embodiments, the cover layer  12200  may be replaced or supplemented with an additional wound dressings described elsewhere herein, such that the additional wound dressings are positioned above the nitric oxide generating layers. The cover layer may also be shower proof, such that a dressing incorporating such a cover layer may be used in the shower. The cover layer may 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 trapping nitric oxide against the tissue such that nitric oxide can interact with the body of a user. One of skill in the art will understand that the cover layer may be made to be both vapor permeable, but nitric oxide impermeable. 
     The nitric oxide source layer  12600  may provide one or more nitric oxide-releasing agents at the wound site. The nitric oxide-releasing agent can include any chemical entity that yields nitric oxide at the wound site when activated or otherwise stimulated to do so. In some embodiments, the nitric oxide-releasing agent can include nitrite ion, a nitrite salt, organic and inorganic nitrites, or any pharmacologically acceptable source of nitrite such that the nitrite ion can be reduced to produce nitric oxide at the wound site. For example, the nitric oxide source layer  12600  and/or element may include one or more of ammonium nitrite, lithium nitrite, calcium nitrite, sodium nitrite, potassium nitrite. In some embodiments, the nitric oxide source layer may be a suitable material layer or element that includes alkali metal nitrites and/or alkaline earth metal nitrites. In certain embodiments, the nitrites may include: LiNO 2 , NaNO 2 , KNO 2 , RbNO 2 , CsNO 2 , FrNO 2 , Be(NO 2 ) 2 , Mg(NO 2 ) 2 , Ca(NO 2 ) 2 , Sr(NO 2 ) 2 , Ba(NO 2 ) 2 , Ra(NO 2 ) 2  or any other suitable nitrite. In some embodiments, a precursor of nitrite ions, such as nitrous acid, nitrate ions, nitroprusside ions, or any pharmacologically acceptable salts thereof may be used as the source of the nitrite. In some embodiments, the nitric oxide-releasing agents may include nitrites such as nitro-functionalized compounds. For example, the nitric oxide-releasing agents may include nitroglycerine, isoamyl nitrite, isorbide mononitrate, N-(Ethoxycarbonyl)-3-(4-morpholinyl)sydnoneimine; 3-morpholinosydnonimine; 1,2,3,4-Oxatriazolium; 5-amino-3-(3,4-di-chlorophenyl)-chloride; 1,2,3,4-Oxatriazolium; 5-amino-3-(chloro-2-methyl-phenyl)chloride; 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[[cyanomethylamino]carbonyl]amino]-hydroxide inner salt; S-nitroso-N-acetyl-(D,L)-penicillamine; 1-[(4&#39;,5′-Bis(carboxymethoxy)-21-nitrophenyl)methoxy]-2-oxo-3,3,diethyl-l-triazene dipotassium salt; and [1-(4′, 5′-Bis(carboymethoxy)-2′-nitropheyl)methoxy]-2-oxo-3,3-diethyl-1-triazine diacetoxymethyl ester. 
     In some embodiments, the nitric oxide-releasing agent of the nitric oxide source layer  12600  can include diazeniumdiolates, including O-alkylated diazeniumdiolate, O-derivatized diazeniumdiolate, and non-O-derivatized diaziniumdiolate. 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 nitric oxide source layer  12600  can include S-nitrosothiols, such as S-nitro-gluthathione, S-nitroso-N-acetylcystein, S-nitroso-acetylpenicillamine. In some embodiments, the nitric oxide-releasing agent of the nitric oxide source layer  12600  may include silica, or silica nano-particles 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, polypropyleneimines, polybutyleneimines, polyurethanes or polyamides can be modified with nitric oxide to form diazeniumdiolate. In some embodiments, the nitric oxide source layer  12600  may be constructed from such polymers modified with nitric oxide. Further examples of the 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 herein incorporated by reference in their entireties. 
     In some embodiments, the nitric oxide source layer  12600  may include a nitric oxide-releasing agent (e.g. sodium nitrite) in an aqueous solution. For example, the nitric oxide source layer  12600  may include a material imbibed with the nitric oxide-releasing agent (e.g. sodium nitrite) solution. In some embodiments, the nitric oxide source layer  12600  may include a dry nitric oxide-releasing agent (e.g. sodium nitrite) in solid form. 
     The nitric oxide source layer  12600  may include a mesh, a foam, a gel or any other material suitable for containing the nitric oxide-releasing agent. For example, the nitric oxide source layer  12600  may include a mesh imbibed with the nitric oxide-releasing agent (e.g. sodium nitrite) solution. The mesh may be knitted, woven or non-woven. The mesh may be made of a polymeric material, for example, viscose, polyamide, polyester, polypropylene or a combination thereof. In some embodiments, the nitric oxide source layer  12600  may include polypropylene, polyester, polyurethane, polyvinyl chloride, polyamide, viscose, polyester, polypropylene and/or cellulose. As described herein, the nitric oxide source layer  12600  may be constructed from one or more polymers modified with nitric oxide. The nitric oxide source layer  12600  could also be made of a hydrogel without acidic groups to prevent reaction with nitrite ions to emit nitric oxide. In some embodiments, the nitric oxide source layer  12600  may be constructed from a colored material, such that the nitric oxide source layer  12600  can be visible to assist positioning of the wound dressing  12000  during application to the wound, and to reduce the risk of incomplete removal of the nitric oxide source layer  12600  from the wound after treatment. The nitric oxide source layer  12600  may be fully or semi-permeable to the diffusion of nitric oxide. 
     In some embodiments, the nitric oxide source layer  12600  is the lowermost layer of the dressing  12000 , such that the nitric oxide source layer  12600  may contact the wound. In some embodiments, the nitric oxide source layer  12600  may be positioned within and/or over the wound. The nitric oxide source layer may be constructed such that the nitric oxide source layer  12600  do not substantially adhere to the skin or wound, or cause da mage to the wound when in contact with the wound. In some embodiments, the dressing  12000  may include one or more layers, for example a wound contact layer, beneath the nitric oxide source layer  12600 . In some embodiments, the wound dressing  12000  may include two or more nitric oxide source layers. For example, the wound dressing  12000  may include 2, 3, 4, 5, 6, 7 or more nitric oxide source layers. 
     The activator layer  12400  may contain chemical agents, functional groups or moieties which can activate and/or facilitate release of nitric oxide from the nitric oxide-releasing agent. For example, protons or acidic environment promotes the reduction of nitrites to nitric oxide, and the activator layer  12400  may include acidic groups or moieties which may provide protons in aqueous environment, thereby lowering the pH at the site of application. In certain embodiments, the acidic groups or moieties are immobilized at the activator layer  12400 , for example on the surface of the activator layer  12400 . The acidic groups or moieties may be covalently bonded at the activator layer  12400 . In some embodiments, the activator layer  12400  may include an acidic solution. The activator layer  12400  may include a mesh, a foam, a gel or any other material suitable for containing acid groups or moieties. In embodiments, the activator layer  12400  is positioned above the nitric oxide source layer  12600  or the activator layer  12400  may be positioned below the nitric oxide source layer  12600 . In some embodiments, the activator layer  12400  may include proton sources such as water, methanol, ethanol, propanols, butanols, pentanols, hexanols, phenols, naphtols or polyols; aqueous acidic buffers such as phosphates, succinates, carbonates, acetates, formats, propionates, butyrates, fatty acids, amino acids, or ascorbic acids; or any suitable enzymatic or catalytic compounds. In some embodiments, body fluid such as blood, lymph, bile, or wound exudate may function as the activator, and can assist the activator layer  12400 . In some embodiments, the wound dressing  12000  may not include the activator layer  12400 , and wound fluid or wound exudate may function as the activator. Further examples of the activators for the 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 herein incorporated by reference in their entireties. 
     In some embodiments, the wound dressing  12000  may include two or more nitric oxide source layers and/or two or more activator layers. For example, the wound dressing  12000  may include 2, 3, 4, 5, 6, 7 or more nitric oxide source layers and/or activator layers. 
     In some embodiments, the activator layer  12400  includes hydrogel, such that the activator layer  12400  can absorb the wound exudate. In certain examples, the activator layer  12400  may be constructed of a xerogel. The activator layer  12400  may be constructed from any suitable materials disclosed herein. The gel of the activator layer  12400  may be presented in different physical formats. For example, the activator layer  12400  may be foamed during curing. The hydrogel may be poured into a foam and then cured in the foam. In some embodiments, the activator layer  12400  may be perforated through its thickness. The perforations may be sized to allow fluid absorption and for the desired therapeutic dose of nitric oxide to be released from the wound dressing. For example, the perforations may have a diameter sized approximately between 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 may have a circular shape, a square shape, a triangular shape, or any other suitable shape. The foamed construction and/or the perforations may contribute to fluid handling capabilities of the activator layer. 
     In some embodiments, an activator material for the activator layer may be provided as a dispensable composition, for example as a prepolymer solution or otherwise malleable form, instead of being provided as the activator layer such as the activator layer  12400 , such that it can be applied over the wound and/or around the wound more freely. For example, the activator material may be provided as gel prepolymer solution, such that it can be applied closely to or around a wound having an irregular shape size by a clinician. In some embodiments, the activator material, such as the gel prepolymer solution, may be provided in and/or applied with a syringe, and the gel prepolymer solution may have a viscosity suitable to be dispensed from the syringe. The activator material can be also formulated such that it can be rapidly cured and no longer flows once applied to or around the wound. The activator material may include an evaporative solvent, such as isopropanol. The activator material can have a suitable secondary curing mechanism, such as photoinitiated 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 may be provided to be mixed to result in polymer formation immediately before dispensing. In some embodiments, the first part and the second part may be oppositely charged flowable gels, such that they can interact on mixing to provide gels that do not flow substantially. In some embodiments, the activator material may include a material such as a gel which change in response to the change in environment. For example, the activator material may include a material such as certain pluronics, such that it can be cured once the temperature changes as being applied from the dispenser or syringe to the skin. The activator material may be applied such that it can interact with nitrite from the nitric oxide source layer  12600  (which may provide nitrite) to generate nitric oxide. Once the activator material is applied and cured or does not flow otherwise, the cover layer  18200  may be applied. 
     Once the dressing  12000  is activated, for example by placing the activator layer  12400  in contact with the nitric oxide source layer  12600 , nitric oxide-releasing agents from the nitric oxide source layers  12600  releases nitric oxide. For example, in some embodiments, nitrites can be reduced to nitric oxide in the presence of an acidic environment provided by the activator layer  12400  as shown below:  
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     The activator layer  12400  and the nitric oxide source layer  12600  may be positioned such that the nitric oxide-releasing agents can react to provide nitric oxide. For example, the activator layer  12400  and the nitric oxide source layer  12600  may be in contact with each other within the dressing  12000  when in use. In some embodiments, one or more additional layers may be positioned between the activator layer  12400  and the nitric oxide source layer  12600 . In some embodiments, the activator layer  12400  and the nitric oxide source layer  12600  may be fluidically isolated from each other before applying the dressing  12000  to the patient to prevent premature release of nitric oxide. For example, the nitric oxide source layer  12600  may be provided in a packaging separate from the rest of the dressing  12000 . Once the dressing  12000  is activated, the nitric oxide-releasing agents from the nitric oxide source layer  12600  may disperse within the dressing  12000 . In some embodiments, the nitric oxide-releasing agents may be dissolved in wound exudate and wound exudate may facilitate dispersal of the nitric oxide-releasing agents. At least a portion of the nitric oxide-releasing agents would react to release nitric oxide in the presence of the activators of the activator layer  12400 . The generated nitric oxide may diffuse into the wound or be delivered to the wound by any suitable mechanisms. In some embodiments, the generated nitric oxide may not be delivered immediately or at all and is instead held within the dressing, for example by a selectively permeable membrane, such that the nitric oxide may prevent growth of or kill microbes within the dressing. 
     In some embodiments, the wound dressing  12000  can include a reducing agent to facilitate reduction of the nitric oxide-releasing agent (e.g. nitrite ion) to nitric oxide. Physiologically acceptable examples of such reducing agents include but are not limited to: iodide anion, ascorbic acid, ascorbate (e.g. sodium ascorbate), isoascorbates (e.g. sodium isoascorbate), hydroquinone, butylated quinone, tocopherol. The reducing agent may be included in one or more layers of the wound dressing  12000 . For example, the reducing agent may be included in the cover layer  12200 , the activator layer  12400 , the nitric oxide source layer  12600 , the wound contact layer  12800 , and/or any suitable layers of nitric oxide generating wound dressings described herein. The reducing agent may be incorporated to the one or more layers, for example, by physical entrapment, physical blending, coating, covalent bonding, or any other suitable methods. The reducing agent may be incorporated into the dressing in a into the appropriate layer, such as a hydrogel activating layer, at a w/w% of 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%. For example, the w/w% may be about 0.03%, 1.2%, 1.4%, or 2.43%. Higher levels of reducing agent may lead to increased production of nitric oxide; however, very high levels of reducing agent may become toxic. 
     As described herein, the nitric oxide source layer may include nitrite and may be referred to as a nitrite delivery layer or a nitrite providing layer in this specification. As described herein, the activator layer may include acids and may be referred to as an acid providing layer or an acid delivery layer in this specification. The nitric oxide source layer/the nitrite delivery layer/the nitrite providing layer and the activator layer/the acid providing layer may be collectively or individually referred to as nitric oxide generating layer(s) in this specification. 
     Nitric Oxide Dressing Materials and Construction 
     As will be understood by one of skill in the art, the materials and dressing constructions described above in relation to the nitric oxide delivery dressings 1200 of  FIGS.  4 - 5    and elsewhere in the specification may include multiple suitable constructions and different types of materials. For example, the topmost layer furthest away from the wound may be a top or cover film layer, such as a top or cover layer disclosed herein, such as polyurethane materials. Such a top or cover film may be construction from materials used in the cover layer of the RENASYS drape, sold by Smith + Nephew. Below the top or cover film layer may be a masking or fabric layer, which may be constructed of any suitable material disclosed as a masking or fabric layer herein. The masking layer may be constructed from a stretch and non-stretch polyester, polyethylene, polypropylene, polypropylethylene, and nonwovens and suitable blends constructed thereof. Further suitable nonwovens and blend may also be utilized. In certain embodiments, the masking layer may be foam. Beneath the masking or fabric layer is an activator layer, similar to the activator layers described herein and throughout the specification. Such an activator layer may be constructed from a hydrogel adhesive, optionally containing a central polyester supporting mesh and/or supporting release liners. The activator layer may be constructed from any suitable hydrogel material disclosed herein such as an acrylic acid hydrogel and/or a sulfonic acid hydrogel. Below the activator layer may be an acquisition distribution layer, which may be constructed of any suitable acquisition distribution layer materials disclosed herein, such as in relation to  FIG.  2   . For example, the acquisition distribution layer may be constructed from 3-D knit, gauze and/or stretch polyester fibers woven into a net format, similar to the material used in Acticoat Flex by Smith + Nephew, although silver is optional. In some embodiments the acquisition distribution layer may be constructed from a pre-polymer solution with a mixture of water, surfactant, and polyethylene glycol such as foams used in Allevyn foam by Smith + Nephew. The masking layer and acquisition distribution layer may use the same materials and be interchangeable. In certain embodiments, the acquisition distribution layer may be pressed into the activator layer and/or cured into the activator layer. Curing the acquisition distribution layer into the activator layer may increase the rate of nitric oxide formation due to more rapid transport. Under the acquisition distribution layer, there may be a wound contact layer which may be constructed from any suitable material disclosed herein, such as in relation to  FIG.  2   . For example, the wound contact layer may include a silicone adhesive and perforated polyurethane film. The wound contact layer may include an acrylic adhesive. A nitric oxide source layer, such as a nitrite layer, constructed from any suitable materials disclosed herein, may be positioned beneath the wound contact layer such that the nitric oxide source layer is directly against a wound or other tissue. In some embodiments, the nitric oxide source layer may be in other positions, such as above the activator layer and/or elsewhere in the dressing. In certain, embodiments the ALLEVYN or PICO dressings disclosed in  FIGS.  2 - 3    may be placed directly over an activator layer and underlying nitric oxide source layer. Placing the nitric oxide source layer directly against the wound, periwound area, and/or other tissues may allow for increased release of nitric oxide directly into the tissue. 
     Chemiluminescence 
       FIG.  6    shows an example setup  600  for a chemiluminescence protocol for testing a nitric oxide delivery dressing such as disclosed above in relation to  FIGS.  4  and  5   . The protocol may include a sample  602 , desiccant  604 , an atmospheric air source  606 , a chemiluminescence detector  608 , a nitrogen supply  610 , an air pump  612 , a mass flow meter  614 , and T-piece connector  616 . In certain embodiments, a ThermoFisher 42i-HL detector may be used as a chemiluminescence detector  608 . After warming up the equipment with air flow under atmospheric pressure, the sample box  602  and nitrogen supply can be connected to the equipment. The nitrogen flow through the mass flow controller may be set to a suitable value, such as between about: 1 to 100, 10 to 90, 25 to 75, 40 to 60, or about 50 mL/min. After flushing the system (such as for about 1 to 60, 10 to 50, 20 to 40, or about 30 minutes), a nitric oxide source layer (such as a nitrite mesh) and activator layer (such as an acid providing hydrogel) may be placed in the sample chamber  602 . In embodiments, the nitrite mesh is smaller in total area than the activator layer. In particular embodiments, the nitric oxide source layer and/or the activator layer may have a length and/or a width of about .5 to 20, 1 to 10, 2 to 8, or about 4 to 6 centimeters. In certain embodiments, the nitric oxide source layer may be 2.5 cm x 2.5 cm while the activator layer is 3 cm ×3 cm. 
     NO/NO 2  release concentrations may be measured by the chemiluminescence detector at an appropriate rate, checking the concentrations in ppb or ppm and monitoring periodically, such as about every 1, 2, 5, 10, 30, 60 or 90 seconds. In certain embodiments, the NO/NO 2  concentration may be checked in ppm. 
     As will be understood by one of skill in the art, maximizing NO over NO 2  is desirable for the dressings disclosed herein, such as the dressings described in relation to  FIGS.  4 - 5   . While nitrogen dioxide (NO 2 ) may exert antimicrobial properties, NO 2  does not have the vasodilating properties nor the capability of activating cell proliferation of NO. It is therefore generally desirable to reduce the generation of NO 2  as far as possible in the acidification of nitrites such as by such means as reducing the oxidation of dissolved nitric oxide (NO) by removing the oxygen from the body of the hydrogel where the acidification of nitrite takes place. The nitric oxide delivery dressings disclosed herein may produce both NO and NO 2 . In some embodiments, the nitric oxide dressings disclosed herein may produce NO and NO 2  in a ratio of NO/ NO 2  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. For example, the ratio may 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. 
       FIGS.  7 A-B  show an example of an experimental set-up  700  and the subsequent results  750  demonstrating nitric oxide delivery from a combination of activator layer and nitric oxide source layer, similar to the dressings described in relation to  FIGS.  4  and  5   , while under negative pressure. As shown in  FIG.  7 A , a negative pressure wound therapy pump  702  is connected to a negative pressure wound therapy dressing  704  such as described herein in  FIGS.  2 A- 2 D . The dressing is sealed over a chamber  706  containing nitrite test solution  708  which changes color in the presence of NO.  FIG.  7 B  shows an example of results of the negative pressure nitric oxide experiment shown in  FIG.  7 A . Prior to applying negative pressure, the test solution did not change color  750 . After running negative pressure for a period of time to ensure that no background color change occurred as shown in  760 , an activator layer  710  such as described herein (such as an acid-providing hydrogel), was placed in the chamber and negative pressure was applied. Again, no color change occurred  770 . Lastly, a nitric oxide source layer  712  such as described herein (such as a sodium nitrite mesh) was placed onto the activator layer  780  without having the nitric oxide source layer touch the nitrite test solution, and negative pressure was applied. After 15 minutes of negative pressure, the indicator solution changed color  790 , thereby demonstrating that interaction between the activator layer and the nitric oxide layer can produce nitric oxide, even while under negative pressure. 
     As will be understood by one of skill in the art, negative pressure may be applied to any of the nitric oxide delivering dressings disclosed herein, such as the dressings described in  FIGS.  4 - 5    and elsewhere in the specification. A dressing, such as the dressings described in  FIGS.  2 A- 2 D  may be placed over an activator layer and nitric oxide source layer which are placed in a wound, thereby delivering nitric oxide to a wound while simultaneously applying negative pressure wound therapy. 
       FIGS.  8 A through  8 C  show examples of chemiluminescence experimental runs using a protocol similar to that described above. As will be understood by one of skill in the art, these measurements taken in these experimental runs are merely exemplary and the disclosures herein are not limited to such values.  FIG.  8 A  shows the experimental results when testing a dry sodium nitrate mesh embodiment with the arrangement shown in  FIG.  8 A , including a polyurethane cover layer overlying a stretch polyester ADL layer, positioned over a hydrogel activator layer sandwiched between another stretch polyester ADL layer over a dry sodium nitrite mesh as shown in the figure. In this experimental run, after the DI water was added, the dry sodium nitrate mesh released approximately 550 ppm NO and 75 ppm NO 2  at its peak at the 25 minute mark, slowly reducing in concentration to approximately 80 ppm NO and 10 ppm NO 2  at the 50 minute mark. 
       FIG.  8 B  shows the experimental results when testing a full dressing design with a pull-out tab and self-sealing borders. The pull out tab is used to initially separate the nitric oxide source layer from the activator layer, therefore when the tab is removed and the dressing becomes wet, the interaction between the nitric oxide source layer and the activator layer produces nitric oxide. In this experimental run, after the DI water was added, the full dressing design with the pull-out tab and self-sealing borders released approximately 84 ppm NO and 15 ppm NO 2  at its peak at the 17 minute mark, slowly reducing in concentration to approximately 25 ppm NO and 5 ppm NO 2  at the 50 minute mark. 
       FIG.  8 C  shows an example of the experimental results for a dressing containing a degradable film. Here, a degradable film was placed between the activator layer and the nitric oxide source layer, thereby generating nitric oxide once the degradable layer breaks down. In this experimental run, after the DI water was added, the dressing containing a degradable film released approximately 1000 ppm NO and 45 ppm NO 2  at its peak at the 25 minute mark, slowly reducing in concentration to approximately 225 ppm NO and 20 ppm NO 2  at the 50 minute mark. The experimental protocol was also utilized to test an activator layer containing sodium isoascorbate. In this experimental run, after the DI water was added, the activator layer containing sodium isoascorbate released approximately 52 ppm NO and 4 ppm NO 2  at its first peak at the 80 minute mark, 66 ppm NO and 5 ppm NO 2  at its second and maximum peak at the 110 minute mark slowly reducing in concentration to approximately 45 ppm NO and 2 ppm NO 2  at the 160 minute mark. 
       FIG.  9    shows an example of the relative peak output in ppm for activator hydrogels (acid providing) either with an acquisition distribution layer or without, including polypropylene, polypropylethylene, or stretch polyester acquisition distribution layers with various gsm (g/m 2 ). With no acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 55 ppm and 10 ppm respectively; however, one of skill in the art will understand that an acquisition distribution layer may allow for improved fluid distribution and handling throughout a larger area such as a dressing. With a 17 gsm polypropylene pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 20 ppm and 2 ppm respectively. With a 17 gsm polypropylene cured acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 40 ppm and 5 ppm respectively. As explained above, curing the acquisition distribution layer may allow for increased fluid transport and an increased rate of nitric oxide formation. With a polypropylene 30 g/m 2  pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 40 ppm and 5 ppm respectively. With a polypropylene 30 g/m 2  acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 40 ppm and 5 ppm respectively. With a polypropylene 40 g/m 2  pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 30 ppm and 2 ppm respectively. With a polypropylene 40 g/m 2  cured acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 38 ppm and 5 ppm respectively. With a polypropylethylene 30 g/m 2  pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 35 ppm and 3 ppm respectively. With a polypropylethylene 30 g/m 2  cured acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 35 ppm and 3 ppm respectively. With a stretch polyester pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 35 ppm and 3 ppm respectively. With a FLEX pressed acquisition distribution layer, the peak NO and NO 2  concentrations were approximately 55 ppm and 8 ppm respectively. 
       FIGS.  10 A through  10 D  show examples of the concentration of NO and NO 2  over time for several embodiments incorporating an activator layer and nitric oxide providing layer. As shown in  FIGS.  10 A-B , an activator layer containing approximately 2-3% sodium isoascorbate was tested with or without different acquisition distribution layers that were pressed or cured. The gel with no acquisition distribution layer produced (p indicating peak) pNO = 785 ppm and pNO2 = 78 ppm. The activator layer with a stretch polyester pressed into the gel produced pNO = 506 ppm and pNO2 = 24 ppm. For stretch polyester cured on the activator layer, pNO = 625 ppm; pNO2 = 50 ppm. For polypropylene pressed into the gel, the pNO = 508 ppm and pNO2 = 26 ppm. For polypropylene cured into the gel, the pNO = 624 ppm and pNO2 = 26 ppm. 
       FIGS.  10 C-D  show examples of the concentration of NO and NO 2  over time for an activator layer containing approximately 1-2% sodium isoascorbate with or without different acquisition distribution layers that were pressed or cured. The activator layer with no ADL produced pNO = 334 ppm; pNO2 = 40 ppm. For the stretch polyester acquisition distribution layer pressed into the activator layer, pNO = 211 ppm and pNO2 = 10 ppm. For the stretch polyester acquisition distribution layer cured into the activator layer, pNO = 247 ppm and pNO2 = 14 ppm. For the polypropylene acquisition distribution layer pressed into the activator layer, pNO = 112 ppm and pNO2 = 5 ppm. For the polypropylene acquisition distribution layer cured into the activator layer, pNO = 184 ppm and pNO2 = 8 ppm. As explained elsewhere in the specification, curing an acquisition distribution layer into an activator layer may improve fluid handling and nitric oxide production relative to nitrogen dioxide production. 
     Xerogels and Hydrogel Construction 
     Reference may be made throughout the specification to xerogels. A xerogel may be formed from a gel by drying with unhindered shrinkage. As will be understood by one of skill in the art, a xerogel is a gel that has very low free water content, so low that minimal reaction to form nitric oxide will occur without the addition of further water and/or liquid. For example, a xerogel may be substantially free of water in the dry state. Drying may be completed by any suitable means known in the art. 
     In certain examples, hydrogels (which may subsequently become xerogels after drying) may be generated with or without glycerol, and may contain a standard amount or double, triple, or quaruple the required amount of crosslinker PEG diacrylate as needed. A 2-Acrylamido-2-methyl-1-propanesulfonic acid sodium salt solution may be present in the xerogel. Hydrogels and xerogels may be created by converting acrylamido-2-methyl-1-propanesulphonic acid (SA), stabilised with MEHQ as supplied, to a sodium salt by dissolving into water, then neutralising with 50% NaOH to pH 7.0 with cooling from a 10C water bath to form a solution of the neutralised acid (NaAMPS). Hydrogel prepolymers may be prepared by predispersing 2-hydroxy-2-methylpropiophenone photoinitiator into PEG diacrylate under minimal light, then mixing for 10-20 mins with a mixture of 58% aqueous sodium 2-acrylamido-2-methyl-1-propanesulfonate solution (Na AMPS), (Sodium iso-ascorbate, pre-ground 2-Acrylamido-2-methyl-1-propanesulfonic acid (AMPS acid) and glycerol. The AMPS acid may be fully dissolved in the stirred Na AMPS solution prior to slowly adding the glycerol, and then the photoinitiator/diacrylate mixture in a water bath. In certain embodiments, hydrogels may also prepared with twice the normal amount of photoinitiator/crosslinker and/or the omission of glycerol and/or using triple the amounts of prepolymer mix in the moulds to form gels with three times the thickness. 
     Layers of Nitric Oxide Generating Dressings 
       FIGS.  11 - 12    illustrate a wound dressing  14000  having nitric oxide generating layers. The wound dressing  14000  may be similar to the wound dressing  12000 . The wound dressing  14000  may include a cover layer  14200 , an activator layer or acid providing layer  14400 , and a nitric oxide source layer or nitrite providing layer  14600 , each of which can be similar to the cover layer  12200 , the activator layer or acid providing layer  12400 , and the nitric oxide source layer or nitrite providing layer  12600 , respectively. 
     The cover layer  14200  may be similar to the cover layer  12200 . The cover layer  14200  may have a greater length and width than other layers  14400 ,  14600 ,  14800 , such that the cover layer  14200  defines a border region extending between outer perimeters of other layers and the outer perimeter of the cover layer  14200 . The border region of the cover layer  14200  may be attached to the skin around the wound, forming a seal, such that the wound exudate can be contained within the wound dressing  14000 . 
     In the illustrated embodiment, the wound dressing  14000  further includes an acquisition distribution layer  14800 . The acquisition distribution layer  14800  may be constructed so as to advantageously horizontally wick fluid, such as wound exudate, as it is absorbed through the layers of the dressing  14000 . Such lateral wicking of fluid may allow maximum distribution of the fluid through the acid providing layer  14400 , enabling the acid providing layer  14400  to reach its full holding capacity. Further, acquisition distribution layer  14800  may facilitate nitric oxide production, as nitrite ions dissolved in fluid may spread across the surface of the acid providing layer  14400  more quickly. Some embodiments of the acquisition distribution layer  14800  may comprise viscose, polyester, polypropylene, cellulose, or a combination of some or all of these, and the material may be needle-punched. Some embodiments of the acquisition distribution layer  14800  may comprise cellulose in the range of 1-220 grams per square meter (gsm) (or about 1 to about 220 gsm), 3-200 grams per square meter (gsm) (or about 3 to about 200 gsm), 5-190 gsm (or about 5 to about 190 gsm), 10-180 gsm (or about 10 to about 180 gsm), 20-170 gsm (or about 20 to about 170 gsm), or 40-160 gsm (or about 40 to about 160 gsm), for example 80 (or about 80) gsm. Some embodiments of the acquisition distribution layer  14800  may comprise polyethylene in the range of 3-200 gsm (or about 3 to about 200 gsm), 5-190 gsm (or about 5 to about 190 gsm), 10-180 gsm (or about 10 to about 180 gsm), 20-170 gsm (or about 20 to about 170 gsm), or 40-150 gsm. In some embodiments, the acquisition distribution layer  14800  may have a thickness of 1.2 mm or about 1.2 mm, or may have a thickness in the range of 0.07 mm to 7.0 mm, 0.1 mm to 5.0 mm, 0.5 mm to 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. The acquisition distribution layer  14800  may be constructed from a material which resists compression under the levels of negative pressure commonly applied during negative pressure therapy. 
     The acquisition distribution layer  14800  may include a plurality of loosely packed fibers, which may be arranged in a substantially horizontal fibrous network. In some embodiments, the acquisition distribution layer  14800  may consist of a mix of two or more fiber types. One may be a flat fiber which may be 20 µm to 50 µm in width, or approximately 20 µm to approximately 50 µm in width, and may comprise a cellulosic based material. The other fiber may be a two component fiber that has an inner core that is 8 µm to 10 µm in diameter, approximately is 8 µm to approximately 10 µm in diameter, 7 µm to 11 µm in diameter, 6 µm to 12 µm in diameter, or 5 µm to 13 µm in diameter and an outer layer with a thickness of 1 µm to 2 µm, approximately 1 µm to approximately 2 um, 1 µm to 2.3 µm, 0.8 µm to 2.5 µm, or 0.5 µm to 3 µm. The two component fiber may be a mix of a polyethylene (PE) type material, and polyethylene terephthalate (PET). In some embodiments the inner core of the two component fiber may be PET and the outer layer may be PE. The PE/PET fibers may have a smooth surface morphology, while the cellulosic fibers may have a relatively rougher surface morphology. In some embodiments the ADL material may comprise about 60% to about 90% cellulosic fibers, for example approximately 75% cellulosic fibers, and may comprise about 10% to about 40% PE/PET fibers, for example approximately 25% PE/PET fibers. In some embodiments, the acquisition distribution layer  14800  may include split microfibers. 
     A majority of the fiber volume may extend horizontally (that is, parallel to the plane of the top and bottom surfaces of the material), or substantially or generally horizontally. In another embodiment, 80%-90% (or approximately 80% to approximately 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, a majority, 80%-90% (or approximately 80% to approximately 90%) of the fibers or more, or even all or substantially all of the fibers, span a distance perpendicular to the thickness of the acquisition distribution layer  14800  (a horizontal or lateral distance) that is greater than the thickness of the acquisition distribution layer  14800 . In some embodiments, the horizontal or lateral distance spanned by such fibers is 2 times (or about 2 times) or more, 3 times (or about 3 times) or more, 4 times (or about 4 times) or more, 5 times (or about 5 times) or more, or 10 times (or about 10 times) or more the thickness of the acquisition distribution layer  14800 . The orientation of such fibers may promote lateral wicking of fluid through the acquisition distribution layer  14800 . This may more evenly distribute fluid such as wound exudate throughout the acquisition distribution layer  14800 . In some embodiments, the ratio of the amount of fluid wicked laterally across the acquisition distribution layer  14800  to the amount of fluid wicked vertically through the acquisition distribution layer  14800  under negative pressure may be 2:1 or more, or approximately 2:1 or more, or may be up to 10:1 or more, or approximately 10:1 or more, in some embodiments. 
     In some embodiments, at least some of the fiber volume of the acquisition distribution layer  14800  may extend vertically (that is, perpendicular to the plane of the top and bottom surfaces of the material), or substantially or generally vertically. In some embodiments, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%&lt; more than 80%, or more than 90% of the fiber volume may extend vertically, or substantially or generally vertically. The orientation of such fibers may promote vertical wicking of fluid through the acquisition distribution layer  14800 . In some embodiments, the ratio of the amount of fluid wicked vertically across the acquisition distribution layer  14800  to the amount of fluid wicked laterally through the acquisition distribution layer  14800  under negative pressure may be 2:1 or more, or approximately 2:1 or more, or may be up to 10:1 or more, or approximately 10:1 or more, in some embodiments. 
     In some embodiments, the acquisition distribution layer  14800  may be positioned below the acid providing layer  14400  as shown in  FIGS.  11 - 12   . In some embodiments, the acquisition distribution layer  14800  may be positioned above the acid providing layer  14400 . 
     In some embodiments, a wound dressing having nitric oxide generating layers may include two or more acquisition distribution layers.  FIGS.  13 - 14    illustrate a wound dressing  16000  having two acquisition distribution layers, a first acquisition distribution layer  16820  and a second acquisition distribution layer  16840 . The wound dressing  16000  further includes a cover layer  16200 , an acid providing layer  16400 , and a nitrite providing layer  16600 , which are similar with the cover layer  14200 , the acid providing layer  14400 , and the nitrite providing layer  14600 , respectively. The first acquisition distribution layer  16820  and the second acquisition distribution layer  16840  are similar with the acquisition distribution  14800  of the wound dressing  14000 . 
     As illustrated in  FIGS.  13 - 14   , the acid providing layer  16400  may be sandwiched between the first fluid distribution layer  16820  and the second fluid distribution layer  16840 . In some embodiments, both of the first and second distribution layers may be positioned above the acid providing layer  16400  or below the acid providing layer  16400 . 
     In some embodiments, one or more layers of a nitric oxide generating wound dressing can be transparent. For example, a cover layer, such that the cover layer  12200 , the cover layer  14200  and the cover layer  16200 , may be transparent. Further, an acid providing layer, such as the acid providing layer  12400 , the acid providing layer  14400 , and the acid providing layer  16400 , can be translucent when the hydrogel material becomes wet, for example from contacting wound exudate. In some embodiments, a masking layer may be positioned within the wound dressing to prevent visualization of the wound or the wound exudate through the cover layer or the acid providing layer. 
       FIGS.  15 - 16    illustrate a wound dressing  18000  including a cover layer  18200 , an acid providing layer  18400 , a nitrite providing layer  18600  and an acquisition distribution layer  18800 . The wound dressing  18000  may be similar with the dressings  14000 ,  16000 , and layers of the wound dressing  18000  may be similar with the corresponding layers of the wound dressings  14000  and  16000  except for as described herein. 
     The wound dressing  18000  may include a masking or obscuring layer  18900  to prevent visualization of the wound or the wound exudate through the cover layer  18200  or the acid providing layer  18400 . The masking or obscuring layer  18900  can be positioned beneath at least a portion of the cover layer  18200 . In some embodiments, the obscuring layer  18900  can have any of the same features, materials, or other details of any of the other embodiments of the obscuring layers disclosed herein, including but not limited to having any viewing windows or holes. Examples of wound dressings with obscuring layers and viewing windows are described in International Patent Publications WO2013/007973 and WO2014/020440, the entireties of which are incorporated by reference. Additionally, the obscuring layer  18900  can be positioned directly below the cover layer  18200 , or can be positioned adjacent to any other dressing layer desired. In the illustrated embodiment, the obscuring layer  18900  is positioned between the cover layer  18200  and the acid providing layer  18400 . In some embodiments, the obscuring layer  18900  can be adhered to or integrally formed with the cover layer  18200 . The obscuring layer  18900  can be configured to have approximately the same size and shape as the acid providing layer  18400  so as to overlay it. As such, in these embodiments the obscuring layer  18900  will be of a smaller area than the cover layer  18200 . In some embodiments, an acquisition distribution layer, such as the acquisition distribution layers described elsewhere herein may be opaque, and function as a masking or obscuring layer. 
     Construction of Nitric Oxide Generating Dressings 
     In some embodiments, at least some of the layers of the wound dressings  12000 ,  14000 ,  16000 ,  18000  may be attached to one another, preventing delamination of the layers. In some embodiments, one or more layers of the wound dressings  12000 ,  14000 ,  16000 ,  18000  may include adhesive coating for attachment. In some embodiments, one or more layers of the wound dressings  12000 ,  14000 ,  16000 ,  18000  may be tacky or have adhesiveness even without additional adhesive coating, such that they can be attached to the adjacent layers. For example, the layers  12400 ,  14400 ,  16400 ,  18400  have adhesive properties, and can be attached to other layers. However, when the layers absorb moisture or wound exudate, the adhesive properties of the layers can be lost or weakened, which can result in delamination of the layers. Accordingly, additional means to secure the layers of the wound dressing are desired. 
       FIGS.  17 - 18    illustrate a wound dressing  20000 . The wound dressing  20000  is similar to the wound dressing  16000 , and includes a cover layer  16200 , a first acquisition distribution layer  16820 , an acid providing layer  16400 , a second acquisition distribution layer  16840  and a nitrite providing layer  16600 . The layers of the wound dressing  20000  may be similar with the corresponding layers of the wound dressing  16000  except for as described herein. The wound dressing  20000  further includes a frame layer  20100 . The frame layer  20100  may be positioned at a wound facing side or a bottom side of the dressing  20000  and cover at least a border region of the wound dressing  20000 . The frame layer  20100  can be a polyurethane layer or polyethylene layer or another flexible layer. The frame layer  20100  has a lower surface and an upper surface. In some embodiments, at least a portion of the upper surface of the frame layer  20100  is attached to the cover layer  20200 . In some embodiments, at least a portion of the lower surface of the frame layer  20100  can be attached to the skin around the wound. In some embodiments, the frame layer  20100  includes a window  20110 , such that fluid communication between the nitrite providing layer  20600  and other layers of the wound dressing  20000  is permitted. In some embodiments, the window  20110  has a same or larger size than the nitrite providing layer  20600 , such that the nitrite providing layer  20600  is positioned within the window  20110 . In some embodiments, the frame layer  20100  is positioned below the second acquisition distribution layer  20840  and/or the acid providing layer  20400 . In some embodiments, the acquisition distribution layers  20820  and  20840  and/or the acid providing layer  20400  are fully enclosed by the cover layer  20200  and the frame layer  20100  except for the window  20110 . In some configurations, the frame layer  20100  may help maintain the integrity of the entire wound dressing  20000  while also creating a fluid tight seal around the wound. As shown in  FIGS.  19 - 20   , in some embodiments, the frame layer  20100  may be a wound contact layer  20900 , such as the wound contact layers described elsewhere in the specification, and may not include the window  20110 . The wound contact layer  20900  may be shaped and/or sized to allow fluid communication from the nitrite providing layer  20600  to other layers, such as the acquisition distribution layers  20820  and  20840  or the acid providing layer  20400 . The wound contact layer  20900  may include perforations to facilitate fluid communication through the wound contact layer  20900 . The one or both sides of the wound contact layer  20900  may be coated with adhesives. 
     In some embodiments, delamination of layers of a wound dressing may be prevented by physically joining the layers, such as by adhesives, welding, or stitching.  FIG.  21    illustrates a cross-sectional view of a hydrogel layer  22400  encapsulated within a first acquisition distribution layer  22820  and a second acquisition distribution layer  22840 . As illustrated in  FIG.  21   , the outer edges of the first and second acquisition layers  22820  and  22840  may be attached around the hydrogel layer  22400 , such that the first and second acquisition layers  22820  and  22840  and the hydrogel layer  22400  are assembled in a single piece. The first and second acquisition layers  22820  and  22840  may be attached to each other at outer edges by adhesive, heat-welding, stitching or any other suitable means. In some embodiments, the first and second acquisition distribution layers  22820  and  22840  are formed as a single layer, and the hydrogel layer  22400  may be wrapped around and/or encapsulated by the single layer of the acquisition distribution layers. In some embodiments, the first acquisition distribution layer  22820  and/or the second acquisition distribution layer  22840  may be an obscuring layer such as the obscuring layer  18900  or any other layers described elsewhere herein. 
       FIG.  22    illustrates a cross-sectional view of a hydrogel layer  23400  sandwiched between a first acquisition distribution layer  23820  and a second acquisition distribution layer  23840 . As illustrated in  FIG.  25   , the first acquisition distribution layer  23820  and the second acquisition distribution layer  23840  are joined to each other and to the hydrogel layer  23400  by stitching  23900  through the hydrogel layer  23400  at one or more points. In some embodiments, the first and second acquisition distribution layers  23820  and 23  840  may be spot welded at multiple points through the hydrogel layer  23400 . As described elsewhere herein, the hydrogel layer  23400  may be perforated, and the first and the second distribution layers  23820  and  23840  may be jointed through the perforations of the hydrogel layer  23400 . In some embodiments, the first acquisition distribution layer  22820  and/or the second acquisition distribution layer  22840  may be an obscuring layer such as the obscuring layer  18900  or any other layers described elsewhere herein. 
     As shown in  FIGS.  23 - 24   , the wound dressing  14001  may further include a masking element, masking layer or obscuring layer  14901  to prevent visualization of the wound or the wound exudate through the cover layer  14201  or the acid providing layer  14401 . The masking layer or obscuring layer  14901  can be positioned beneath at least a portion of the cover layer  14201 . In some embodiments the masking layer or obscuring layer  14901  can be positioned above the cover layer  14201 . In some embodiments, the obscuring layer  14901  can have any of the same features, materials, or other details of any of the other embodiments of the obscuring layers disclosed herein, including but not limited to having any viewing windows or holes. Examples of wound dressings with obscuring layers and viewing windows are described in International Patent Publications WO2013/007973 and WO2014/020440, the entireties of which are incorporated by reference. Additionally, the obscuring layer  14901  can be positioned directly below or above the cover layer, or can be positioned adjacent to any other dressing layer desired. In the illustrated embodiment, the obscuring layer  14901  is positioned between the cover layer  14201  and the acid providing layer  14401 . In some embodiments, the obscuring layer  14901  can be adhered to or integrally formed with the cover layer  14201 . The obscuring layer  14901  can be configured to have approximately the same size and shape as the acid providing layer  14401  so as to overlay it. As such, in these embodiments the obscuring layer  14901  will be of a same or smaller area than the cover layer  14201 . In some embodiments, the masking or obscuring layer  14901  can horizontally and/or vertically wick fluid and may function as an acquisition distribution layer as well. In some embodiments, the cover layer  14201  can by partially or completely opaque or colored, such that the cover layer  14201  can function as a masking or obscuring layer and prevent visualization of the wound or the wound exudate through the cover layer  14201 , and/or prevent visualization of the layers below the cover layer  14201 . 
     The masking layer or obscuring layer  14901  may be constructed from one or more polymers, such as polypropylene, polyester, polyurethane, polyvinyl chloride, polyamide, viscose, polyester, polypropylene, cellulose, or any copolymers thereof. In some embodiments, The masking layer or obscuring layer  14901  may include a foam, mesh or any other suitable type of material. In some embodiments, the masking layer or obscuring layer  14901  may be at least partially coated with a hydrophobic coating, such that excessive soaking by wound exudate is prevented. The hydrophobic coating may be applied to either of a wound facing lower side or an opposite upper side of the masking layer  14901 , or both sides. In some embodiments, the masking layer or obscuring layer  14901  may include a hydrophilic coating to facilitate the transportation of wound exudate toward the cover layer  14201  to be evaporated. The hydrophilic coating may be applied to either of a wound facing lower side or an opposite upper side of the masking layer  14901 , or both sides. In some embodiments, the masking layer  14901  may contain a reducing agent which facilitates reduction of nitrite ions to nitric oxide. For example, the masking layer  14901  may contain hydroquinone, ascorbic acid, potassium iodide, erythrobate or sodium erythorbate or sodium D-isoascorbate monohydrate, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, butylated hydroquinone, beta-carotene, lipoic acid and/or uric acid. Further examples of the reducing agent is described in International Patent Publication WO2009/019498, the entirety of which is incorporated by reference. 
     In some embodiments, the masking layer  14901  may be colored, such that visualization of the wound fluid in layers beneath is prevented even when the layers are saturated with wound fluid. For example, the masking layer  14901  may be blue, pink, red, orange or green. In some embodiments, the masking layer  14901  may be white, such that the wound exudate may be visible when the layers below the masking layer  14901  are saturated. In such embodiments, clinical judgment of the exudate spread can be made by observing the spread of exudate through the masking layer  14901 . 
     In some embodiments, the masking layer  14901  has a size similar or greater than the acid providing layer  14401 , the acquisition distribution layer  14801 , the nitrite providing layer  14601  and/or any other fluid absorbing layers, such that the visualization of the wound exudate or layers below the masking layer  14901  may be completely blocked. In some embodiments, the masking layer  14901  have a smaller size than the acid providing layer  14401 , the acquisition distribution layer  14801 , the nitrite providing layer  14601  and/or any other fluid absorbing layers, such that one or more layers below the masking layer  14901  may be visible around the edge of the masking layer  14901 . For example, the acid providing layer  14901  may be constructed from a hydrogel, and when the acid providing layer  14401  is saturated and turns transparent or changes color, such change will be visible from above around the edge of the masking layer  14901 , such that a clinician or a patient may be notified of a change in wound status, thereby triggering a wound dressing change or other suitable action. The masking layer  14901  may cover about 50% or more, 60% or more, 70% or more, 80% or more, 90% or more of the area of the layer directly below the masking layer  14901  (e.g. the acid providing layer  14401 ). 
     In some embodiments, the masking layer  14901  may include one or more viewing windows, which can permit visualization of the layers below the masking layer  14901  through them. For example, the masking layer  14901  may include holes extending through the thickness of the masking layer  14901 . The holes may have any suitable shape, such as: circle, crescent, star, triangle, square, diamond, or any other suitable shape. The holes or viewing windows may constitute 5% or more, 10% or more, 20% or more, 30% or more, 50% or more, 70% or more, 90% or more of the area of the masking layer  14901 . In some embodiments, the holes or viewing windows are spaced evenly or substantially evenly at the masking layer  14901 . 
     In some embodiments, the wound dressing  14001  may include indicating layers for indicating therapeutic delivery of nitric oxide. For example, the indicating layers may include polyurethane which changes color in contact with nitric oxide or nitrogen dioxide. Such change in color may be used to indicate that nitric oxide is being produced and delivered to the wound. In some embodiments, the indicating layers may include any other polymers with chemical groups (e.g. aromatic groups) that exhibits a color change when exposed to nitric oxide. In some embodiments, other layers described elsewhere herein, such as the masking layer  14901  and/or the acquisition distribution layer  14801  may include materials which change color in contact with nitric oxide or nitrogen dioxide, such that the masking layer  14901  or the acquisition distribution layer  14801  may indicate that nitric oxide is being produced and delivered to the wound. The indicating layer may be visible from above the wound dressing, through the cover layer  14200  or any other layers. 
     In some embodiments, the wound dressing  14001  may include one or more layers having color changing indicators which change color when exposed to nitrite. The color change indicators may be Griess reagents. Such color change indicators may indicate presence of nitrite ion within the wound dressing  14001 . 
     Material Layer With Hydro Gel Layer 
     As described elsewhere herein, the acid providing layers  12400  and  14401  may be constructed from a gel, such as a hydrogel. In embodiments, hydrogels can have a tacky surface having adhesion properties, and in some configurations, it may be desirable to reduce the tack of the hydrogel of the acid providing layer, such as the acid-providing layers described above and further herein, to improve and ease of handling the acid providing hydrogel layer. 
     Continuing with  FIGS.  23 - 24   , in some embodiments, an acid providing hydrogel layer  14401  may include one or more material layer  14421  as shielding layers to mask at least some of the hydrogel’s adhesion properties. The material layer or layers  14421  may be applied to at least a portion of a wound facing lower side of the acid providing hydrogel layer  14401  and/or an upper, non-wound facing side of the hydrogel layer  14401 . In some embodiments, the hydrogel layer may be completely encapsulated by the material layers. In some embodiments, the material layer may cover the entire upper side and/or lower side of the hydrogel layer. In some embodiments, the material layer may partially cover the upper side and/or lower side of the hydrogel layer. For example, the material layer may cover about: 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more of the area of the upper side and/or lower side of the hydrogel layer. The partial covering of the hydrogel layer by the material layer(s) may allow a limited level of adhesion by partial masking. 
     In some embodiments, the material layers may be constructed from suitable nets, mesh, knitted, woven or non-woven materials. In some embodiments, the material layer may be constructed from polypropylene, polyester or a combination/copolymer thereof. The material layer may be permeable to fluid, such as water or wound exudate, such that the acid providing hydrogel layer may absorb wound exudate, and/or the acid group of the acid providing hydrogel layer may react with nitrite ions to produce nitric oxide. 
     Although hydrogels have adhesive properties, in embodiments the material layers may not be attached to the hydrogel layer solely by their adhesive properties. In certain hydrogel examples, the adhesiveness of the hydrogel may be reduced or lost when the hydrogel absorbs fluid, such as wound exudate. Accordingly, the material layers may need to be immobilized to the hydrogel layer via additional suitable means. For example, the material layers may be immobilized to the hydrogel layer through the use of flexible ties, staples or by sewing the material layers to the hydrogel. In some embodiments, the hydrogel layer may be encapsulated within a bag formed with the material layers. 
     In some embodiments, the material layers may be physically implanted or immobilized to the hydrogel layer during the formation and/or curing of the hydrogel layer.  FIG.  25    illustrates a process to physically implant or adhere a material layer within or onto a hydrogel layer during the formation of the hydrogel layer according to some embodiments. As illustrated in  FIG.  25   , a material layer  16201  may be positioned at a mold  16401  for curing a hydrogel layer, for example, at a bottom of the mold  16401 . Before being positioned at the mold  16401 , the material layer  16201  may be pretreated, for example with a wetting agent to make it hydrophilic, such that the affinity with hydrogel prepolymer is increased. 
     After the material layer  16201  is positioned at the bottom of the mold  16401 , a first portion of a hydrogel prepolymer may be added. When the first portion of the hydrogel prepolymer is added, the pretreated material layer  16201  may be substantially wetted out with the first portion of the hydrogel prepolymer. The pretreated material layer  16201  positioned at the bottom of the mold  16401  may further facilitate the lateral spread of the hydrogel prepolymer and cause the bottom of the mold  16401  to also become substantially wetted with a continuous layer of the first portion of the hydrogel prepolymer. After the first portion of the hydrogel prepolymer is added, the material layer  16201  may rise from the bottom of the mold  16401  to the top of the hydrogel prepolymer. In some embodiments, the material layer  16201  may rise to the top of the hydrogel prepolymer in 10 minutes or less, 7 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, or more than 10 minutes. After the material layer  16201  rises, the first portion of the hydrogel prepolymer may be cured to form a first hydrogel layer  16501 , and the material layer  16201  may be fixed on the top of the first hydrogel layer  16501 , thereby masking the top side of the cured hydrogel. The first portion of the hydrogel prepolymer may be UV from top side, bottom side, or both sides, or any other suitable methods known in the art, or any other suitable methods known in the art. 
     In some embodiments, after the first hydrogel layer  16501  is formed, a second portion of the hydrogel prepolymer may be added to the mold, over first hydrogel layer  16501  and the material layer  16201 . After the second portion of the hydrogel prepolymer is added, the material layer  16201  may be encapsulated by the second portion of the hydrogel prepolymer and the first hydrogel layer  16501 . The material layer  16201  may not rise or float, because it is immobilized to the first hydrogel layer  16501 . Then the second portion of the hydrogel prepolymer may be cured to form a second hydrogel layer  16701 , and the material layer  16201  may be encapsulated by the hydrogel layers  16501  and  16701  which may be integrated into a single layer. The material layer  16201  implanted embedded within the integrated hydrogel layer formed with hydrogel layers  16501  and  16701  may increase the structural integrity of the hydrogel layer. For example, when the hydrogel layer absorbs water, it may swell, and the material layer be act as a reinforcing layer preventing the hydrogel from stretching and falling apart. In some embodiments, the refractive index of the material layer and the hydrogel layer may be similar such that the material layer is completely invisible and the hydrogel layer appears as a single sheet of clear/transparent material. As will be understood by one of skill in the art and reiterated later in the specification, the aforementioned description of a method for addition of a material layer to a hydrogel is not limiting and may be performed in any suitable order and may involve the addition or removal of certain steps.  FIG.  26    illustrates a process to physically implant a material layer onto both upper and lower sides of a hydrogel layer during the formation of the hydrogel layer according to some embodiments. However, one of skill in the art will understand that material layers may be added to one side only. As illustrated in  FIG.  26   , after the first hydrogel layer  16501  having the material layer  16201  is formed as described in relation to  FIG.  25   , it may be taken out from the mold  16401 , flipped, and placed back into the mold  16401 , such that the side of the hydrogel layer  16501  having the material layer  16201  faces the bottom of the mold  16401 . Then, another material layer  16801  is positioned over the hydrogel layer  16501 , and subsequently a second portion of the hydrogel prepolymer is added above the hydrogel layer  16501  and the material layer  16801 . The material layer  16801  may float and rise to the top of the second portion of the hydrogel prepolymer in a similar manner to the material layer  16201  being floated during the formation of the hydrogel layer  16501  as described with regard to  FIG.  25   . After the material layer  16801  rises to the top of the second portion of the hydrogel prepolymer, the second portion of the hydrogel prepolymer may be cured to form a hydrogel layer  16901  with the hydrogel layer  16501 , and the material layer  16801  may be fixed on the top of the hydrogel layer  16901 , thereby masking the top side of the hydrogel layer  16901 . The second portion of the hydrogel prepolymer may be cured by UV from top side, bottom side, or both sides, or any other suitable methods known in the art. As a result, the hydrogel layer  16901  may be sandwiched between the material layers  16201  and  16801 , which are immobilized to the hydrogel layer  16901 . 
     Perforated Hydrogel Layer 
     The acid providing layer (e.g. hydrogel layer) may include a plurality of perforations that extend through the thickness of the acid providing layer, as described elsewhere herein. The plurality of perforations may allow or facilitate passage of wound exudate through the acid providing layer, such that wound exudate below or around the acid providing layer can be transported to one or more additional absorbing layers and/or an evaporative layer or layers (e.g. cover layer) above the acid providing layer, thus preventing excessive buildup of wound exudate below the acid providing layer. Additionally, the plurality of perforations may provide increased surface area of the acid providing layer, thereby increasing the absorption rate of the acid providing layer. 
     In some embodiments, the plurality of perforations may be formed after the acid providing layer is cured. For example, the perforations may be formed by punching holes out of the acid providing layer, via ultrasonic perforation, via flame perforation, or any other suitable methods. 
     In some embodiments, the plurality of perforations may be formed during the formation of the acid providing layer. For example, the plurality of perforations may be formed during curing of the acid providing gel layer. The perforations may be formed by guiding the location of the hydrogel prepolymer solution being applied onto a mold bottom or release sheet, such that there are small portions without the hydrogel prepolymer solution applied. In some embodiments, a template having high surface energy (i.e. wettable) may be used in conjunction with a lower surface energy surface, such as a mold bottom or a release sheet. The template may be perforated, and the hydrogel prepolymer solution may preferentially wet out the template except at the perforations, and the hydrogel prepolymer solution may not be positioned above the perforations of the template. Such distributed hydrogel prepolymer solution may form a perforated hydrogel layer once cured. The hydrogel prepolymer may be cured by UV, or any other suitable methods known in the art. 
     In some embodiments, the template may be hydrophilic, or pretreated with a wetting agent to be hydrophilic. In certain embodiments, the template may also be constructed to be hydrophobic. The template may be constructed from polypropylene or polyethylene or any other suitable material. The template may be constructed from woven or non-woven material or any other suitable material. In some embodiments, the template may be constructed from a spun-bonded material. The perforations of the template may have a diameter of about: approximately between 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. 
     In some embodiments, the template may rise from the bottom of the mold to the top of the hydrogel prepolymer before curing. After the template rises, the hydrogel prepolymer may be cured to form the perforated hydrogel layer, and the template may be fixed on the top of the perforated hydrogel layer. Then a second portion of the hydrogel prepolymer may be added to the mold, over the perforated hydrogel layer and the template. After the second portion of the hydrogel prepolymer is added, the template may be encapsulated by the second portion of the hydrogel prepolymer and the perforated hydrogel layer. The template may not rise or float, because it is immobilized to the perforated hydrogel layer. Then the second portion of the hydrogel prepolymer may be cured to form a second perforated hydrogel layer, and the template may be encapsulated within the perforated hydrogel layer and the second perforated hydrogel layer. In some embodiments, the hydrogel layer may be formed from two or more hydrogel layers. 
     In some embodiments, the shielding layers such as the shieling layers  16200  and  16800  may be perforated and also function as the template for the perforated hydrogel layer. Such perforated hydrogel layer may be prepared according to methods similar to the method described with regard to  FIGS.  25  and  26   . 
     In some embodiments, a template for the hydrogel layer may include a plurality of pillars, and a hydrogel prepolymer may be poured and cured around the pillars to form a hydrogel layer with perforations. In some embodiments, perforations or other patterns may be formed at a hydrogel layer by screen printing or laying down “fibers” of hydrogel using a die, spinneret or electrospun process and then curing. A hydrogel prepolymer for these processes may include a viscosity modifier (e.g. thixotropic agent) and/or be positioned on a hydrophobic release paper to limit spreading of the laid down prepolymer prior to curing. 
     Nitric Oxide Generating Wound Dressing for Treating Peri-Wound 
     In some instances, stimulation of the peri-wound (skin surrounding the wound) and the wound edge may play a role in initiating the wound healing process. In certain embodiments, the wound healing process can be activated through the delivery of nitric oxide to the peri-wound and/or the wound edge. The delivery of nitric oxide to the peri-wound and/or the wound edge may target, for example epithelial cell activity to promote migration of epithelial tongue; vasodilation of the microcirculation in the skin surrounding the wound to promote perfusion by providing oxygen and nutrients; and neo-angiogenesis to promote granulation tissue formation. 
       FIGS.  27 - 28    illustrate a wound dressing  18001  for the delivery of nitric oxide to the peri-wound and/or the wound edge according to some embodiments. The wound dressing  18001  is similar to the wound dressing  14001  of  FIG.  25   , and may include a cover layer  18201 , an acid providing layer  18401 , an acquisition distribution layer  18801  and a nitrite providing layer  18601 . The layers of the wound dressing  18001  may be similar to the corresponding layers of the wound dressing  14001 . 
     In the illustrated embodiment, the acid providing layer  18401  is provided at a border region, encompassing a central absorbent material  18451 . The acid providing layer  18401  and the central absorbent material  18451  may be attached to each other, or may not be attached to each other. In some embodiments, the acid providing layer  18401  and the central absorbent material  18451  may be provided as an integral component. The acid providing layer  18401  may define a window at the center, and the central absorbent material  18451  may be shaped and/or sized to fit the window of the acid providing layer  18401 . 
     The acid providing layer  18401  may be constructed from materials similar to acid providing layers  12400  and  14400 . For example, the acid providing layer  18401  may be constructed from hydrogel or Xerogel and contain acid groups or moieties. In some embodiments, the acid providing layer  18401  may be constructed from a mesh, a foam, a gel or any other material suitable for containing acid groups or moieties. The acid providing layer  18401  may provide an acidic environment at the border region of the wound dressing  18001 , thereby generating nitric oxide from the border region of the dressing  18001  for delivery to the peri-wound or wound border. As illustrated in  FIG.  28   , the acid providing layer  18401  may be sized and/or positioned such that the acid providing layer  18401  is positioned at least partially above a peri-wound  18921 . The acid providing layer  18401  may include a plurality of perforations or one or more material layers such as material layers  16201  and  16801  described elsewhere herein. 
     In the illustrated embodiment, the acid providing layer  18401  is frame-shaped. However, the acid providing layer  18401  may have any other suitable shape or configuration. In some embodiments, the acid providing layer  18401  may be provided as a plurality of acid providing strips instead of as a frame-shaped layer, such that the acid providing strips can be separately applied at a border region closer to the immediate peri-wound area. Each of the acid providing strips may be positioned at a side of the wound to create an acid providing layer  18401  that fits closer to the peri-wound. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more acid providing strips may be provided and/or applied around the wound. The acid providing strips may be constructed from the same material with the acid providing layers described herein. 
     The central absorbent material  18451  may be positioned above the wound to absorb wound exudate. For example, as illustrated in  FIG.  28   , the central absorbent material  18451  may be sized and/or positioned such that the central absorbent material  18451  is positioned at least partially above a wound  18911 . In some embodiments, the central absorbent material  18451  may be same or larger than the wound, such that the central absorbent material  18451  entirely covers the wound. In some embodiments, the central absorbent material  18451  may be smaller than the wound, such that the acid providing layer  18401  can be positioned closer to the wound edge. 
     The central absorbent material  18451  may include a foam or non-woven natural or synthetic material, and which may optionally comprise a super-absorbent material, and form a reservoir for fluid, particularly liquid, removed from the wound site. In some embodiments, the central absorbent material  18451  may also aid in drawing fluids towards the cover layer  18200 . The material of the central absorbent material  18451  may also prevent liquid collected in the wound dressing  18001  from flowing freely within the dressing, and preferably acts so as to contain any liquid collected within the dressing. The capacity of the absorbent material may be sufficient to manage the exudate flow rate of a wound when negative pressure is applied. In some embodiments, the central absorbent material  18451  may be chosen to absorb liquid under negative pressure. A number of materials exist that are able to absorb liquid when under negative pressure, for example superabsorber material. The central absorbent material  18451  may be manufactured from ALLEVYN™ foam, Freudenberg 114-224-4 or Chem-Posite™11C-450. In some embodiments, the central absorbent material  18451  may include a composite comprising superabsorbent powder, fibrous material such as cellulose, and bonding fibers. In embodiment, the composite is an air-laid, thermally-bonded composite. In some embodiments, the central absorbent material  18451  is a layer of non-woven cellulose fibers having super-absorbent material in the form of dry particles dispersed throughout. Use of the cellulose fibers may introduce fast wicking elements which help quickly and evenly distribute liquid taken up by the dressing. The juxtaposition of multiple strand-like fibers may lead to strong capillary action in the fibrous pad which helps distribute liquid. In this way, the super-absorbent material may be more efficiently supplied with liquid. In certain embodiments, the wicking action may also assist in bringing liquid into contact with the upper cover layer to aid increase transpiration rates of the dressing. 
     The wound dressing  18001  further includes a frame layer  18101 , which may further support the acid providing layer  18401 . The frame layer  18101  may be positioned at a wound facing side or a bottom side of the dressing  18001  and cover at least a border region of the wound dressing  18001 . The frame layer  18101  can be a polyurethane layer or polyethylene layer or another suitable flexible layer. The frame layer  18101  has a lower surface and an upper surface. In some embodiments, at least a portion of the upper surface of the frame layer  18101  is attached to the cover layer  18201 . In some embodiments, at least a portion of the lower surface of the frame layer  18101  can be attached to the skin around the wound. In some embodiments, the frame layer  18101  includes a window  18111 , such that fluid communication between the nitrite providing layer  18601  and other layers of the wound dressing  18001  is permitted. In some embodiments, the window  18111  has a same or larger size than the nitrite providing layer  18601 , such that the nitrite providing layer  18601  is positioned within the window  18111 . In some embodiments, the frame layer  18101  is positioned below the acquisition distribution layer  18801  and/or the acid providing layer  18401 . In some embodiments, the acquisition distribution layers  18801  and/or the acid providing layer  18401  are fully enclosed by the cover layer  18201  and the frame layer  18101  except for the window  18111 . In some configurations, the frame layer  18101  may help maintain the integrity of the entire wound dressing  18001  while also creating a fluid tight seal around the wound. 
     In some embodiments, an acid providing material may be provided as a dispensable composition, for example as a prepolymer solution or otherwise malleable form, instead of being provided as the acid providing layer  18401 , such that it can be applied around the wound more freely. For example, the acid providing material may be provided as gel prepolymer solution, such that it can be applied closely around a wound having an irregular shape size by a clinician. In some embodiments, the acid providing material, such as the gel prepolymer solution, may be provided in and/or applied with a syringe, and the gel prepolymer solution may have a viscosity suitable to be dispensed from the syringe. The acid providing material can be also formulated such that it can be rapidly cured and no longer flows once applied around the wound. The acid providing material may include an evaporative solvent, such as isopropanol. The acid providing material can have a suitable secondary curing mechanism, such as photoinitiated acrylate functionality. In some embodiments, the acid providing material may include a material which may be swell and bind together when in contact with wound fluid or moisture, for example methacrylate. In some embodiments, the acid providing material can be provided as a reactive two-part system. For example, a first part including isocyanate and a second part including water or polyol may be provided to be mixed to result in urethane formation immediately before dispensing. In some embodiments, the first part and the second part may be oppositely charged flowable gels, such that they can interact on mixing to provide gels that do not flow substantially. In some embodiments, the acid providing material may include a material such as a gel which changes in response to the change in environment. For example, the acid providing material may include a material such as certain pluronics, such that it can be cured once the temperature changes as it is being applied from the dispenser or syringe to the skin. The acid providing material may be applied such that it can interact with nitrite from the nitrite providing layer  18601  to generate nitric oxide. Once the acid providing material is applied and cured or does not flow otherwise, the cover layer  18200  may be applied. 
     In some embodiments, the nitrite ion or nitrite salt may be provided as a dispensable composition, alternatively or in addition to the nitrite providing layer  18601 , in similar manner with the acid providing material described herein. In some embodiments, both the acid providing material and the nitrite ion or salt may be provided as one or more dispensable compositions, such that they can be applied around the wound more freely. For example, in a two part system, a first part may include the acid providing material, such as the gel prepolymer solution, and a second part may include nitrite ion or salt, and the first and second parts may be mixed and cooperatively dispensed around the wound, thereby generating nitric oxide. In some embodiments, a static mixer such as a double-barreled syringe with a mixing head may be used. The first and second parts may have a viscosity suitable to be dispensed from the syringe. The first and second parts can be also formulated such that it can be rapidly cured and no longer flows once applied around the wound. Either or both of the first and second parts may include an evaporative solvent, such as isopropanol. Either or both of the first and second parts can have a suitable secondary curing mechanism, such as photoinitiated acrylate functionality. In some embodiments, the acid providing material may include a material which may be swell and bind together when in contact with wound fluid or moisture, for example methacrylate. In some embodiments, the first and second parts may be provided as a reactive two-part system. For example, a first part including isocyanate and a second part including water or polyol may be provided to be mixed to result in urethane formation immediately before dispensing. In some embodiments, the first part and the second part may be oppositely charged flowable gels, such that they can interact on mixing to provide gels that do not flow substantially. In some embodiments, the first and/or second part may include a material such as a gel which changes in response to the change in environment. For example, the first and/or second part may include a material such as certain pluronics, such that it can be cured once the temperature changes as it is being applied from the dispenser or syringe to the skin. Once the first and second parts are mixed, applied and cured or does not flow otherwise, the cover layer  18200  may be applied. 
     Terminology 
     Any patents and applications and other references noted above, including any that may be listed in accompanying filing papers, 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. 
     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 of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features or steps are mutually exclusive. The protection is not restricted to the details of any foregoing embodiments. The 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. 
     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 may be embodied in a variety of other forms. Furthermore, various omissions, substitutions and changes in the form of the methods and systems described herein may be made. Those skilled in the art will appreciate that in some embodiments, the actual steps taken in the processes illustrated or disclosed may differ from those shown in the figures. Depending on the embodiment, certain of the steps described above may be removed, others may be added. For example, the actual steps or order of steps taken in the disclosed processes may differ from those shown in the figure. Depending on the embodiment, certain of the steps described above may be removed, others may be added. Furthermore, the features and attributes of the specific embodiments disclosed above may be combined in different ways to form additional embodiments, all of which fall within the scope of the present disclosure. 
     Although the present disclosure includes certain embodiments, examples and applications, it will be understood by those skilled in the art that the present disclosure extends beyond the specifically disclosed embodiments to other alternative embodiments or uses and obvious modifications and equivalents thereof, including embodiments which do not provide all of the features and advantages set forth herein. Accordingly, the scope of the present disclosure is not intended to be limited by the described embodiments, and may be defined by claims as presented herein or as presented in the future. 
     Conditional language, such as “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally 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 features, elements, or steps are in any way required for one or more embodiments or that one or more embodiments necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, or steps are included or are to be performed in any particular embodiment. The terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Likewise the term “and/or” in reference to a list of two or more items, covers all of the following interpretations of the word: any one of the items in the list, all of the items in the list, and any combination of the items in the list. Further, the term “each,” as used herein, in addition to having its ordinary meaning, can mean any subset of a set of elements to which the term “each” is applied. Additionally, the words “herein,” “above,” “below,” and words of similar import, when used in this application, refer to this application as a whole and not to any particular portions of this application. 
     Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain embodiments require the presence of at least one of X, at least one of Y, and at least one of Z. 
     Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially” as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms “approximately”, “about”, “generally,” and “substantially” may 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 stated amount. As another example, in certain embodiments, the terms “generally parallel” and “substantially parallel” refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 15 degrees, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degree. 
     Any of the embodiments described herein can be used with a canister or without a canister. Any of the dressing embodiments described herein can absorb and store wound exudate. 
     The scope of the present disclosure is not intended to be limited by the description of certain embodiments and may be defined by the claims. The language of the claims is to be interpreted broadly based on the language employed in the claims and not limited to the examples described in the present specification or during the prosecution of the application, which examples are to be construed as non-exclusive. 
     Various modifications to the implementations described in this disclosure may be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other implementations without departing from the spirit or scope of this disclosure. Thus, the disclosure is not intended to be limited to the implementations 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 claim set listed below or presented in the future. 
     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.