Wound dressing control and activation

Abstract

To provide materials, devices, methods, and systems configured for nitric oxide (NO) delivery to a wound.SOLUTION: A wound dressing 13000 for treating a wound includes: a moisture permeable cover layer 13002, an activator layer 13006 positioned under the cover layer, a nitric oxide source layer 13010, a separating layer 13008 positioned between the activator layer and the nitric oxide source layer, the separating layer configured to prevent contact between the activator layer and the nitric oxide source layer.SELECTED DRAWING: Figure 11A

Description

[Technical Field]

[0001] 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 include wound dressings configured for nitric oxide (NO) delivery and / or delivery of other actives. [Background technology]

[0002] 2. Description of Related Art Nitric oxide (NO) is a well-known molecule with multiple biological functions. For example, nitric oxide affects vascular vasodilation, stimulates angiogenesis, influences host immune responses, and exhibits potent broad-spectrum antibacterial and antibiofilm activity. Due to these multiple roles, NO exhibits potent effects on tissues, and increased levels of NO can support accelerated wound healing, particularly in chronic wounds.

[0003] In addition, diabetic patients often have lower levels of nitric oxide compared to healthy patients, and the reduced supply of nitric oxide in diabetic patients is an aggravating factor in healing chronic ulcers. The reduced supply of nitric oxide can lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can also lead to reduced blood flow to the extremities, thereby making diabetic patients more likely to develop neuropathy and non-healing ulcers, potentially putting them at higher risk of lower limb amputation.

[0004] Thus, there is a need for an improved mechanism for delivering effective doses of nitric oxide to wounds. Under normal conditions, nitric oxide (NO), a free radical, is short-lived and converted to a more stable chemical species within seconds of its generation. Thus, for example, when gaseous nitric oxide comes into contact with air, it is rapidly oxidized to generate nitrogen dioxide (NO). Therefore, it can be difficult to maintain high concentrations of nitric oxide within a wound dressing or other similar structure for an extended period of time. Therefore, a device or wound dressing having one or more layers containing a more stable composition can effectively generate nitric oxide over time upon activation for stable and sustained delivery of nitric oxide to biological tissue. Of particular note are mechanisms for delivering nitric oxide in combination with the use of wound dressings, particularly negative pressure wound dressings, and / or during negative pressure wound therapy and / or other appropriate therapies. Summary of the Invention [Means for solving the problem]

[0005] FIELD OF THE DISCLOSURE Embodiments of the present disclosure relate to materials, devices, methods, and systems for wound treatment. Some disclosed embodiments relate to materials, devices, methods, and systems for delivering nitric oxide to a wound. Those skilled in the art will understand that the application of the materials, devices, methods, and systems described herein is not limited to any particular tissue or to any particular injury.

[0006] In some embodiments, a wound dressing for treating a wound may comprise a cover layer configured to form a seal around the wound, an active agent layer, a dry nitric oxide source layer, a dry nitric oxide source layer that is free or relatively free of liquid, and a moisture distribution layer.

[0007] In certain embodiments, the wound dressing further comprises a masking layer, the masking layer configured to at least partially limit visualization of the wound. The dry nitric oxide source layer may comprise a nitrite. The nitrite may comprise sodium nitrite. The active agent layer may be positioned on the nitric oxide source layer. In some embodiments, the nitric oxide source layer may be positioned on the active agent layer. The water-absorbing and dispersing layer may be positioned between the active agent layer and the dry nitric oxide source layer. The active agent layer may comprise a hydrogel or a xerogel. The wound dressing may comprise a second dry nitric oxide source layer. The wound dressing may be configured to generate nitric oxide when placed on the wound. In embodiments, the wound dressing may be configured not to generate nitric oxide prior to placement on the wound.

[0008] In certain embodiments, a wound dressing for treating a wound may include a cover layer, an active agent layer positioned below the cover layer, a nitric oxide source layer, and a separation layer positioned between the active agent layer and the nitric oxide source layer, the separation layer being configured to prevent contact between the active agent layer and the nitric oxide source layer. In some embodiments, the separation layer may include a tab configured to be removed from the wound dressing, such that upon removal of the tab, contact occurs between the active agent layer and the nitric oxide source layer. The separation layer may include a degradable material configured such that upon decomposition of the degradable material, contact occurs between the active agent layer and the nitric oxide source layer.

[0009] In some embodiments, the wound treatment device may include an active agent hydrogel, the active agent hydrogel including a plurality of capsules, each capsule including a separation layer encapsulating a nitric oxide source material, the separation layer configured to prevent contact between the active agent hydrogel and the nitric oxide source material. The separation layer may be configured to break upon application of mechanical pressure, such that contact occurs between the active agent hydrogel and the nitric oxide source material upon breaking of the separation layer.

[0010] In some embodiments, a wound dressing for treating a wound may comprise an active agent hydrogel and a nitric oxide source hydrogel, the nitric oxide source hydrogel comprising a surface facing the active agent hydrogel, the surface facing the active agent hydrogel comprising a layer of sodium nitrite. The active agent hydrogel may comprise a plurality of perforations. The nitric oxide source hydrogel may comprise a plurality of perforations.

[0011] In certain embodiments, a method for delivering an active ingredient to a wound may include placing an active ingredient platform on the wound, the active ingredient platform comprising a dosing portion and an adhesive frame, the dosing portion comprising the active ingredient, and adhering a reactive platform onto the active ingredient platform to form a seal, the reactive platform comprising a reactive portion configured to activate the dosing portion so that the active ingredient is delivered to the wound. The active ingredient may comprise a therapeutic drug configured to promote wound healing. The dosing platform may be inactive until the reactive platform is adhered to the active ingredient platform.

[0012] In some configurations, a wound dressing for treating a wound includes a cover layer, a nitrite-donating layer, an acid-donating layer positioned below the cover layer, and a central absorbent material for absorbing wound exudate. The cover layer is configured to form a seal around the wound. The nitrite-donating layer includes nitrite. The acid-donating layer includes acidic groups and includes a window in the center of the acid-donating layer. The central absorbent material is positioned within the window in the acid-donating layer.

[0013] The wound dressing of the above paragraph may include one or more of the following features: The acid-donating layer may be configured to be positioned on the skin surrounding the wound or on the wound edges when the wound dressing is applied to the wound. The central absorbent material may be configured to be positioned on the wound when the wound dressing is applied to the wound. The central absorbent material may be completely encompassed by the acid-donating layer. The wound dressing may include a moisture-wicking distribution layer configured to wick fluid horizontally. The wound dressing may further include a frame layer positioned below the acid-donating layer, the frame layer defining a window in the center of the frame layer. The frame layer may be configured to be attached to the skin surrounding the wound. The frame layer may be attached to the cover layer. The nitrite-donating layer may be positioned within the window of the frame layer. The acid-donating layer may include a xerogel or a hydrogel.

[0014] In some configurations, a method for treating a wound includes applying a wound dressing to the wound. The wound dressing includes a cover layer configured to form a seal around the wound, a nitrite-donating layer including nitrite, an acid-donating layer positioned below the cover layer, and a central absorbent material for absorbing wound exudate. The acid-donating layer includes acidic groups and also includes a window in the center of the acid-donating layer. The central absorbent material is positioned within the window in the acid-donating layer.

[0015] The method of the above paragraph may include one or more of the following features. The method may further include generating nitric oxide such that the nitric oxide is delivered to the skin surrounding the wound or to the wound edges. The method may further include positioning the wound dressing such that the acid-providing layer is at least partially positioned over the skin surrounding the wound or to the wound edges. The method may further include positioning the wound dressing such that the central absorbent material is at least partially positioned over the wound. The central absorbent material may be completely encompassed by the acid-providing layer. The wound dressing may further include a moisture-wicking distribution layer configured to wick fluid horizontally. The wound dressing may further include a frame layer positioned below the acid-providing layer, the frame layer defining a window in the center of the frame layer. The method may further include attaching the frame layer to the skin surrounding the wound. The frame layer may be attached to the cover layer. The acid-providing layer may include a xerogel or a hydrogel.

[0016] In some configurations, a wound dressing for treating a wound 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 nitrite. The acid-providing layer includes acidic groups and also includes a window in the center of the acid-providing layer.

[0017] The wound dressing of the above paragraph may include one or more of the following features: The acid-donating layer may be configured to be positioned on the skin surrounding the wound or on the wound edge when the wound dressing is applied to the wound. The wound dressing may include a moisture-wicking layer configured to wick fluid horizontally. The wound dressing may further include a frame layer positioned below the acid-donating layer, the frame layer defining a window in the center of the frame layer. The frame layer is configured to be attached to the skin surrounding the wound. The frame layer may be attached to the cover layer. The nitrite-donating layer may be positioned within the window of the frame layer. The acid-donating layer may include a xerogel or a hydrogel.

[0018] In embodiments, a wound dressing for treating a wound may include a cover layer, an active agent layer positioned below the cover layer, a nitric oxide source layer, a folded separation layer positioned between the active agent layer and the nitric oxide source layer, the separation layer being configured to prevent contact between the active agent layer and the nitric oxide source layer, and an upper frame positioned above the separation layer and below the cover layer, the upper frame having an adhesive on an upper side of the frame.

[0019] Alternative or additional embodiments described herein provide compositions that include one or more features of any of the descriptions above or elsewhere herein.

[0020] Alternative or additional embodiments described herein provide a wound contact layer that includes one or more features of any of the descriptions above or elsewhere herein.

[0021] Alternative or additional embodiments described herein provide wound dressings that include one or more features of any of the descriptions above or elsewhere herein.

[0022] Alternative or additional embodiments described herein provide wound treatment systems that include one or more features of any of the descriptions above or elsewhere herein.

[0023] Alternative or additional embodiments described herein provide methods of treating wounds that include one or more features of any of the descriptions above or elsewhere herein. [Brief explanation of the drawings]

[0024] [Figure 1] 1 is a schematic diagram of an example of a negative pressure wound therapy system. [Figure 2A] 1 illustrates an embodiment of a negative pressure wound therapy system using a pump, a flexible fluid connector, and a wound dressing capable of absorbing and storing wound exudate. [Figure 2B]1 illustrates an embodiment of a negative pressure wound therapy system using a flexible fluid connector and a wound dressing capable of absorbing and storing wound exudate. [Figure 2C] 1 illustrates a cross section of one embodiment of a fluid connector connected to a wound dressing. [Figure 2D] 1 illustrates a cross section of one embodiment of a wound dressing. [Figure 3A] 1 illustrates an embodiment of a wound dressing capable of absorbing and storing wound exudate that is used without negative pressure. [Figure 3B] 1 illustrates an embodiment of a wound dressing capable of absorbing and storing wound exudate that is used without negative pressure. [Figure 3C] 1 illustrates an embodiment of a wound dressing capable of absorbing and storing wound exudate that is used without negative pressure. [Figure 3D] 1 illustrates an embodiment of a wound dressing capable of absorbing and storing wound exudate that is used without negative pressure. [Figure 3E] 1 illustrates a cross section of one embodiment of a wound dressing capable of absorbing and storing wound exudate, used without negative pressure. [Figure 4] FIG. 1 is an exploded view of an embodiment of a wound dressing capable of generating nitric oxide. [Figure 5] FIG. 5 is a cross-sectional view of the wound dressing (12) of FIG. 4. [Figure 6] 1 illustrates an example of a chemiluminescence experimental protocol instrumentation. [Figure 7A] Illustrates negative pressure and nitric oxide delivery experiments. [Figure 7B] Illustrates negative pressure and nitric oxide delivery experiments. [Figure 8A] An example of chemiluminescence experimental results for sodium nitrate mesh is shown. [Figure 8B] 1 illustrates an example of chemiluminescence experimental results for a full dressing design with a pull-out tab and a self-sealing boundary. [Figure 8C] 1 illustrates an example of chemiluminescence experimental results for a dressing containing a degradable film. [Figure 9]1 illustrates an example of a graph displaying peak NO and NO2 outputs for an acrylic adhesive containing hydrogel. [Figure 10A] Illustrated are examples of chemiluminescence experimental results for nitric oxide coatings. [Figure 10B] Illustrated are examples of chemiluminescence experimental results for nitric oxide coatings. [Figure 10C] Illustrated are examples of chemiluminescence experimental results for nitric oxide coatings. [Figure 10D] Illustrated are examples of chemiluminescence experimental results for nitric oxide coatings. [Figure 11A] 1 illustrates an embodiment of a wound dressing configured to generate nitric oxide. [Figure 11B] 1 illustrates an embodiment of a wound dressing configured to generate nitric oxide. [Figure 11C] 1 illustrates an embodiment of a wound dressing configured to generate nitric oxide. [Figure 11D] 1 illustrates an embodiment of a wound dressing configured to generate nitric oxide. [Figure 12] 1 illustrates an embodiment of a wound dressing having a folded layer. [Figure 13A] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 13B] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 13C] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 13D] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 13E] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 13F] 1 illustrates an embodiment of a wound dressing having one or more separate layers. [Figure 14] 1 illustrates one embodiment of a wound dressing having a hydrogel nitrite-donating layer. [Figure 15A]1 illustrates an embodiment of a multi-part wound dressing configured to generate nitric oxide. [Figure 15B] 1 illustrates an embodiment of a multi-part wound dressing configured to generate nitric oxide. [Figure 16] FIG. 1 is an exploded view of an embodiment of a nitric oxide generating wound dressing. [Figure 17] FIG. 17 is a cross-sectional view of the wound dressing of FIG. 16. [Figure 18] 1 illustrates a process for producing layers for a wound dressing. [Figure 19] 1 illustrates a process for producing layers for a wound dressing. [Figure 20] FIG. 1 is an exploded view of an embodiment of a nitric oxide generating wound dressing. [Figure 21] FIG. 21 is a cross-sectional view of the wound dressing of FIG. 20. DETAILED DESCRIPTION OF THE INVENTION

[0025] overview Embodiments described herein relate to materials, devices, methods, and systems that incorporate, include, or utilize one or more compositions and / or materials that, upon activation, effectively generate a gas (e.g., nitric oxide) over time. Embodiments herein are directed to devices and / or wound dressings having one or more layers containing compositions and / or materials that, upon activation, effectively generate nitric oxide over time. For example, one or more nitric oxide-generating layers may include a nitrite-delivery layer that contains nitrite and can release nitrite ions, which can then generate nitric oxide upon reaction with an acid. In some embodiments, one or more nitric oxide-generating layers may further include an acidic group-providing layer in addition to the nitrite-delivery layer. One or more nitric oxide-generating layers may be utilized as stand-alone components for separate positioning at the wound site or may be incorporated into any number of multi-layer wound dressings and wound treatment devices, such as those described below with respect to FIGS. 1-11. Embodiments of the present disclosure are generally applicable for use in negative or reduced pressure therapy systems, or compression therapy systems, under ambient conditions.

[0026] Some of the preferred embodiments described herein incorporate, include, or utilize one or more nitric oxide-generating layers. Such one or more nitric oxide-generating layers may possess one or more of the following functional characteristics: inflammation-related activity, blood flow-related activity, antibacterial, antiplankton, and antibiofilm activity, ease of application and / or removal as a single component, cuttability / tearability, conformance to the three-dimensional contours of the wound surface, abrasion resistance, compatibility with negative pressure wound therapy and / or pressure wound therapy, exudate management, ability to facilitate autolytic debridement of the wound, ability to promote wound healing, and self-representation of compositional or functional changes. Antibacterial activity, such as in vitro antibacterial activity, may include one or more of broad-spectrum antibacterial activity, antibiofilm activity, rapid killing of microorganisms, and persistent killing of microorganisms, which may include one or more of the following: gram-negative bacteria, gram-positive bacteria, fungi, yeast, viruses, algae, archaea, and protozoa.

[0027] Certain preferred embodiments described herein provide a wound treatment system. Such a wound treatment system may include a nitric oxide-generating layer sized and configured for positioning over a wound and / or peri-wound area. Those skilled in the art will understand that when a device / dressing / layer is described as being placed over or across a wound, such a device / dressing / layer may extend over and treat the peri-wound area. In some instances, stimulation of the peri-wound area and / or wound edges may play a role in initiating the wound healing process, which may be activated through delivery of nitric oxide to the peri-wound area and / or wound edges. Delivery of nitric oxide to the peri-wound area and / or wound edges may target, for example, epithelial cell activity to promote epithelial lining migration, vasodilation of the peri-wound skin microcirculation to promote replenishment by providing oxygen and nutrients, and angiogenesis to promote granulation tissue formation. The wound treatment systems described herein may further include a secondary wound dressing configured to be separately positioned on top of the nitric oxide-generating layer. The nitric oxide-generating layer may have an adhesive adhered to its underside, which may be configured to allow the nitric oxide-generating layer to be positioned adjacent to the wound. When used, the secondary wound dressing may adhere to the skin surrounding the wound and may be the same size as or larger than the nitric oxide-generating layer, such that the nitric oxide-generating layer contacts or is positioned adjacent to the wound and / or peri-wound area. Alternatively or additionally, the secondary wound dressing may be configured to form a seal against the skin surrounding the wound, such that the nitric oxide-generating layer contacts or is positioned adjacent to the wound. The wound treatment system may further include a negative pressure source configured to supply negative pressure through the secondary wound dressing and through the wound contact layer to the wound.

[0028] Certain other preferred embodiments described herein provide multi-layer wound dressings, as described herein with respect to Figures 1-11. Such multi-layer wound dressings may incorporate one or more nitric oxide-generating layers as its component layers, or may comprise a composite or laminate including one or more nitric oxide-generating layers as part of one of its component layers. The multi-layer wound dressing may comprise a nitric oxide-generating layer as described above or elsewhere herein, a transmission layer and / or absorbent layer above / below the one or more nitric oxide-generating layers, a wound contact layer below 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 located on or above the cover layer. The one or more nitric oxide-generating layers may have a perimeter substantially the same as that of the cover layer. Alternatively, the one or more nitric oxide-generating layers may have a perimeter smaller than that of the cover layer.

[0029] Those skilled in the art will understand that any nitric oxide-generating composition disclosed herein, such as in this "Summary" section or elsewhere herein, can be loaded into one or more nitric oxide-generating layers in any suitable form, such as via adsorption, absorption, chemical and / or physical attachment entanglements, and / or via powder form. Those skilled in the art will further understand that any reactive composition, such as disclosed in this section or elsewhere herein, can be incorporated by any suitable means into any suitable absorbent layer disclosed in this section or elsewhere herein, and / or any suitable permeation layer disclosed in this section or elsewhere herein, and / or any foam layer disclosed in this section or elsewhere herein.

[0030] In certain embodiments, the wound treatment systems and multi-layer wound dressings disclosed hereinabove or elsewhere herein may incorporate or comprise a nitric oxide-generating layer. As described in this section or elsewhere herein, particularly below, the nitric oxide-generating layer may be configured to be activated to release nitric oxide. At least a portion of the released nitric oxide may be released, for example, by diffusion. To facilitate the release and diffusion of nitric oxide, the nitric oxide-generating layer may be positioned in proximity to the wound.

[0031] Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other suitable locations. Such methods may include placing a nitric oxide-generating layer on the wound, either separately or by placing a multi-layer wound dressing having the nitric oxide-generating layer. The methods may include adhering the separate nitric oxide-generating layer and / or the multi-layer wound dressing having the nitric oxide-generating layer to healthy skin surrounding the wound. Such methods may further include one or more of the following steps: An additional wound dressing may be placed on the separate nitric oxide-generating layer or the multi-layer wound dressing having the nitric oxide-generating layer placed on the wound. Wound exudate, or any moist or aqueous medium other than wound exudate, may be provided to reach and / or contact the nitric oxide-generating layer. Wound exudate, or any moist or aqueous medium other than wound exudate, can be diffused or wicked into a wound dressing incorporating a nitric oxide-generating layer or into a wound dressing provided on top of a nitric oxide-generating layer. Negative pressure can be applied to a separate nitric oxide-generating layer or a multi-layer wound dressing having a nitric oxide-generating layer, whereby wound exudate is drawn directly into the nitric oxide-generating layer or into a wound dressing incorporating a nitric oxide-generating layer or into a wound dressing provided on top of a nitric oxide-generating layer.

[0032] Those skilled in the art will understand that the wound dressings, devices, and systems disclosed in this "Summary" section or elsewhere herein 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 layer, composition, or material. For example, a wound dressing or device may include one or more layers that, upon activation, effectively generate a vasodilator, such as carbon monoxide or hydrogen sulfide, over time.

[0033] Those skilled in the art will further appreciate that carbon monoxide and / or hydrogen sulfide can be used in place of or in combination with a nitric oxide delivery element (e.g., layer), if appropriate. Further details regarding the generation and delivery of carbon monoxide and / or hydrogen sulfide can be found in Chapter 6 of the text "Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells," ISBN 978-0-12-803814-7, which is incorporated herein by reference. For example, hydrogen sulfide can be generated from an element / layer containing 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 can be generated from elements / layers that provide complexes of carbon monoxide bound to suitable metals such as chromium, molybdenum, tungsten, manganese, rhenium, iron, ruthenium, cobalt, rhodium, and iridium. Such complexes release carbon monoxide and are photocleavable and / or can be enzymatically triggered to induce carbon monoxide release in response to interaction with a suitable ligand.

[0034] How to treat a wound Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other suitable locations. Such methods may include placing one or more nitric oxide-generating layers on the wound, either separately or by placing a multi-layer wound dressing having one or more nitric oxide-generating layers. The methods may include 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 surrounding the wound, such as the peri-wound area. The methods may further include one or more of the following steps: An additional wound dressing may be placed over the separate one or more nitric oxide-generating layers or the multi-layer wound dressing having one or more nitric oxide-generating layers placed over the wound. Wound exudate, or any moist or aqueous medium other than wound exudate, may be provided to reach and / or contact the one or more nitric oxide-generating layers. Wound exudate, or any moist or aqueous medium other than wound exudate, can be diffused or wicked into a wound dressing incorporating one or more nitric oxide-generating layers, or into a wound dressing provided over one or more nitric oxide-generating layers. Negative pressure can be applied to one or more separate nitric oxide-generating layers, or to a multi-layer wound dressing having one or more nitric oxide-generating layers, as described in the "Negative Pressure Wound Therapy (NPWT) Systems" section below, or elsewhere herein, such that wound exudate is drawn directly into the one or more nitric oxide-generating layers, or into a wound dressing incorporating one or more nitric oxide-generating layers, or into a wound dressing provided over one or more nitric oxide-generating layers.

[0035] As described above or elsewhere herein, the method of treating a wound, intact tissue, or other suitable location may further include delivering negative pressure to the wound through a wound contact layer, as described in the "Negative Pressure Wound Therapy (NPWT)" section below or elsewhere herein. The wound contact layer may substantially maintain the delivered negative pressure for at least about 24 hours, or at least about 48 hours, or at least about 72 hours. Alternatively, the method of treating a wound, intact tissue, or other suitable location may include applying compressive (positive) pressure to the wound through the wound contact layer. Alternatively, the method may include varying atmospheric pressure, negative pressure, and compressive pressure to the wound through the wound contact layer in a programmable manner.

[0036] In embodiments, a method of treating a wound, intact tissue, or other suitable location may include using a wound contact layer, or a wound treatment system or wound dressing comprising a wound contact layer, under ambient conditions not associated with a negative pressure wound therapy system, as described above or elsewhere herein.

[0037] In some embodiments, the method of treating a wound, intact tissue, or other suitable location may reduce wound bioburden, for example, by reducing the number of viable microorganisms (CFU / sample) at least in vitro within the first four hours after application of the wound contact layer. In some instances, the number of viable microorganisms may be reduced by 4 logs or more 48-72 hours after placing the wound dressing in contact with the microorganisms.

[0038] Negative Pressure Wound Therapy (NPWT) System It will be appreciated that embodiments of the present disclosure are generally applicable for use with, but not limited to, topical negative pressure ("TNP") therapy systems. Briefly, negative pressure wound therapy may assist in the closure and healing of many forms of "difficult-to-heal" wounds by reducing tissue edema, promoting blood flow and granulation tissue formation, and removing excessive exudate, reducing bacterial load (and therefore infection risk). In addition, therapy may reduce wound unrest, leading to faster healing. TNP therapy systems may also assist in the healing of surgically closed wounds by removing fluid and helping to stabilize tissue in an apposed position for closure. Further beneficial uses of TNP therapy may be found in grafts and flaps, where removal of excess fluid is important and graft proximity to tissue is required to ensure tissue viability.

[0039] As used herein, a reduced pressure or negative pressure level, such as −X mmHg, represents a pressure level relative to normal ambient air pressure, which may correspond to 760 mmHg (or 1 atm, 29.93 inHg, 101.325 kPa, 14.696 psi, etc.). Thus, a negative pressure value of −X mmHg reflects an absolute pressure that is X mmHg less than 760 mmHg, or in other words, an absolute pressure of (760−X) mmHg. Furthermore, a negative pressure “lower” or “less” than X mmHg corresponds to a pressure closer to atmospheric pressure (e.g., −40 mmHg is lower than −60 mmHg). A negative pressure “higher” or “greater” than −X mmHg corresponds to a pressure further from atmospheric pressure (e.g., −80 mmHg is higher than −60 mmHg). In some embodiments, the local ambient air pressure is used as a reference point, and such local air pressure need not necessarily be, for example, 760 mmHg.

[0040] The negative pressure range for some embodiments of the present disclosure may be approximately -80 mmHg, or approximately -20 mmHg to -200 mmHg. Note that these pressures are relative to normal ambient air pressure, which may be 760 mmHg. Therefore, -200 mmHg would effectively be approximately 560 mmHg. In some embodiments, the pressure range may be approximately -40 mmHg to -150 mmHg. Alternatively, pressure ranges of -75 mmHg or less, -80 mmHg or less, or greater than 80 mmHg may be used. In other embodiments, pressure ranges below -75 mmHg may be used. Alternatively, pressure ranges of approximately -100 mmHg or even above -150 mmHg may be provided by the negative pressure device.

[0041] In some embodiments of the wound closure devices described herein, increased wound contraction can lead to increased tissue expansion in the surrounding wound tissue. This effect can be enhanced, in some cases, by varying the force applied to the tissue, e.g., varying the negative pressure applied to the wound over time, in conjunction with increasing the tension force applied to the wound by an embodiment of the wound closure device. In some embodiments, the negative pressure can be varied over time, e.g., using a sine wave, a square wave, or synchronized with one or more patient physiological indicators (e.g., heart rate). Examples of such applications, for which further disclosure may be found, include U.S. Pat. No. 8,235,955, entitled "Wound treatment apparatus and method," issued August 7, 2012, and U.S. Pat. No. 7,753,894, entitled "Wound cleansing apparatus with stress," issued July 13, 2010. The disclosures of both of these patents are incorporated herein by reference in their entireties.

[0042] Embodiments of the wound dressings, wound dressing components, wound treatment devices and methods described herein may also be used in combination with, or in addition to, those described in International Application No. PCT / IB2013 / 001469, filed May 22, 2013, and published November 28, 2013 as WO 2013 / 175306(A2), entitled "APPARATUSES AND METHODS FOR NEGATIVE PRESSURE WOUND THERAPY," and International Application No. PCT / IB2013 / 002060, filed July 31, 2013, and published as WO 2014 / 020440, entitled "WOUND DRESSING," the disclosures of which are incorporated herein by reference in their entireties. Embodiments of the wound dressings, wound treatment devices and methods described herein may also be used in combination with, or in addition to, those described in U.S. Patent No. 9,061,095, issued June 23, 2015, entitled "WOUND DRESSING AND METHOD OF USE," and U.S. Patent Application Publication No. 2016 / 0339158, published November 24, 2016, entitled "FLUIDIC CONNECTOR FOR NEGATIVE PRESSURE WOUND THERAPY," the disclosures of each of which, including further details regarding wound dressing embodiments, wound dressing components and principles, and materials used in wound dressings, are incorporated herein by reference in their entirety.

[0043] Additionally, some embodiments relating to TNP wound treatment including wound dressings in combination with pumps or associated electronics described herein may also be used in combination with or in addition to those described in WO 2016 / 174048 A1, entitled "REDUCED PRESSURE APPARATUSES," published November 3, 2016, and incorporated herein by reference in its entirety. In some of these embodiments, the pump or associated electronics may be integrated within the wound dressing to provide a single article that is applied to the wound.

[0044] Multilayer wound dressings for NPWT FIG. 1 illustrates one example of a negative pressure wound therapy system 700. The system includes a wound cavity 710 covered by a wound dressing 720, which may be a dressing according to any of the examples described herein. The dressing 720 may be positioned over, within, across, or around the wound cavity 710 to further seal the wound cavity so that negative pressure may be maintained within the wound cavity. For example, a film layer of the wound dressing 720 may provide a substantially fluid-tight seal over the wound cavity 710. In some embodiments, a wound filler, such as a layer of foam or gauze, may be utilized to fill 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 in this section or elsewhere herein. For example, in conventional negative pressure wound therapy systems that utilize foam or gauze, such as the Smith & Nephew RENASYS negative pressure wound therapy system that utilizes foam (RENASYS-F) or gauze (RENASYS-G), the foam or gauze may be supplemented with a nitric oxide-generating layer as described above. When supplementing a foam or gauze layer or other wound packing material, one or more nitric oxide-generating layers may be inserted separately into the wound or may be pre-attached to the wound packing material for insertion into the wound.

[0045] A single or multiple 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 may be a canisterless device (meaning that exudate is collected in the wound dressing and / or transferred via the tube 740 for collection elsewhere). In some embodiments, the negative pressure device 750 may include or be configured to support a canister. Additionally, in any of the embodiments disclosed herein, the negative pressure device 750 may be fully or partially embedded in, attached to, or supported by the wound dressing 720.

[0046] The conduit 740 may be any suitable article configured to provide an at least substantially sealed fluid flow path or pathway between the negative pressure device 750 and the wound cavity 710 to supply reduced pressure to the wound cavity. The conduit 740 may be formed from polyurethane, PVC, nylon, polyethylene, silicone, or any other suitable rigid or flexible material. In some embodiments, the wound dressing 720 may have a port configured to receive an end of the conduit 740. For example, the port may include a hole in a film layer. In some embodiments, the conduit 740 may otherwise pass through and / or beneath a film layer of the wound dressing 720 to supply reduced pressure to the wound cavity 710 to maintain a desired level of reduced pressure within the wound cavity. In some embodiments, at least a portion of the conduit 740 is integral with or attached to the wound dressing 720.

[0047] FIG. 2A illustrates one embodiment of a negative pressure wound therapy system 10 using a wound dressing 100 with a fluid connector 110. Additional examples of negative pressure wound therapy including wound dressings combined with the pumps described herein may also be used in combination with or in addition to those described in U.S. Pat. No. 9,061,095, which is incorporated by reference in its entirety. In the figure, the fluid connector 110 may comprise an elongated conduit, more preferably a bridge 120 having a proximal end 130 and a distal end 140, and an applicator 180 at the distal end 140 of the bridge 120. The system 10 may include a negative pressure source, such as a pump or negative pressure unit 150 capable of providing negative pressure. The pump may include a canister or other container for storing wound exudate and other fluids that may be removed from the wound. The canister or container may also be provided separately from the pump. In some embodiments, pump 150 may be a canisterless pump, such as a PICO™ pump sold by Smith & Nephew. Pump 150 may be connected to bridge 120 via tubing, or pump 150 may be connected directly to bridge 120. During use, dressing 100 is placed over a suitably prepared wound, which in some cases may be filled with a wound packing material, such as foam or gauze, as described above. Applicator 180 of fluid connector 110 has a sealing surface that is placed over the gap in dressing 100 and sealed to the top surface of dressing 100. Either before, during, or after connecting fluid connector 110 to dressing 100, pump 150 is connected to coupler 160 via tubing or directly to bridge 120. The pump is then activated, thereby providing negative pressure to the wound. Application of negative pressure may be performed until a desired level of wound healing is achieved.

[0048] As shown in FIG. 2B , the fluid connector 110 preferably includes an enlarged distal end or head 140 in fluid communication with the dressing 100, as described in more detail below. In one embodiment, the enlarged distal end has a rounded or circular shape. While the head 140 is illustrated as being positioned near an edge of the dressing 100 in the figures, it may be positioned anywhere on the dressing. For example, some embodiments may be provided in a central or off-center location that is not on or near an edge or corner of the dressing 100. In some embodiments, the dressing 10 may include two or more fluid connectors 110, each with one or more heads 140 in fluid communication therewith. In a preferred embodiment, the heads 140 may measure 30 mm along their widest edge. The heads 140 at least partially form the applicator 180, described above, configured to seal against the top surface of the wound dressing.

[0049] FIG. 2C illustrates a cross section through a wound dressing 100 similar to the wound dressing 10 described in International Patent Application Publication No. WO 2013 / 175306 A2, which is incorporated by reference in its entirety, along with a fluid connector 110. Alternatively, the wound dressing 100, which may be any of the wound dressing embodiments disclosed herein or any combination of features of any number of the wound dressing embodiments disclosed herein, may be placed over the wound site to be treated. The dressing 100 may be arranged to form a sealed cavity over the wound site. In a preferred embodiment, the dressing 100 comprises a backing layer 220 attached to a top or cover layer, or optional wound contact layer 222, both of which are described in more detail below. These two layers 220, 222 are preferably joined or sealed together to define an 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 that will be described in more detail below. Examples of such structures described below include the transmission layer 226 and the absorbent layer 221.

[0050] As used herein, the top, uppermost, or upper layer refers to the layer that is furthest from the surface of the skin or wound while the dressing is in use and positioned over the wound, and the bottom, lower, lower, or lower layer thus 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.

[0051] As illustrated in FIG. 2C , the wound contact layer 222 may be a polyurethane layer, a polyethylene layer, or other flexible layer that has been perforated or otherwise made permeable to liquids and gases, for example, via a hot pin process, a laser ablation process, an ultrasonic process, or in some other manner. The wound contact layer 222 has a lower surface 224 and an upper surface 223. Perforations 225 preferably comprise through-holes in the wound contact layer 222, thereby allowing fluid to flow through the layer 222. The wound contact layer 222 serves to prevent tissue ingrowth into other materials of the wound dressing. Preferably, the perforations are small enough to meet this requirement while allowing fluid to flow therethrough. For example, perforations formed as slits or holes having dimensions in the range of 0.025 mm to 1.2 mm are believed to be 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 airtight seal around the absorbent pad to maintain negative pressure at the wound.

[0052] Some embodiments of the wound contact layer 222 may also act as a carrier for optional upper and lower adhesive layers (not shown). For example, a lower pressure-sensitive adhesive may be provided on the lower surface 224 of the wound dressing 100, while an upper pressure-sensitive adhesive layer may be provided on the upper surface 223 of the wound contact layer. The pressure-sensitive adhesive, which may be a silicone, hot melt, hydrocolloid, or acrylic-based adhesive, or other such adhesive, may be formed on both sides of the wound contact layer, or on an optionally selected side, or on neither side of the wound contact layer. When utilized, a lower pressure-sensitive adhesive layer may help adhere the wound dressing 100 to the skin surrounding the wound site. In some embodiments, the wound contact layer may comprise a 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, the polyurethane film layer may be provided with adhesive layers on both its top and bottom surfaces, and all three layers may be perforated together.

[0053] A transmission layer 226 may be located above the wound contact layer 222. In some embodiments, the transmission layer may be a porous material. As used herein, the transmission layer may be referred to as a spacer layer, and this term may be used interchangeably to refer to the same component as described herein. This transmission layer 226 allows the transmission of fluids, including liquids and gases, away from the wound site and into the upper layers of the wound dressing. In particular, the transmission layer 226 preferably ensures that open air channels can be maintained to transmit negative pressure over the wound area even when the absorbent layer absorbs a significant amount of exudate. The layer 226 should preferably remain open under the normal pressures that will be applied during negative pressure wound therapy, as described above, so that the entire wound site experiences equal negative pressure. The layer 226 may be formed from a material having a three-dimensional structure. For example, a knitted or woven spacer fabric (e.g., Baltex 7970 weft knit polyester) or a nonwoven fabric may be used. The three-dimensional material may include a 3D spacer fabric material similar to the materials described in International Publication Nos. WO2013 / 175306(A2) and WO2014 / 020440, the disclosures of which are incorporated by reference in their entireties.

[0054] In certain embodiments, the wound dressing 100 may incorporate or include one or more nitric oxide-generating layers (e.g., nitrite delivery layer, acidic group-providing layer) as described in this section or elsewhere herein. Those skilled in the art will understand that the wound dressing 100 may incorporate any of one or more nitric oxide-generating layers disclosed in this section or elsewhere herein. Those skilled in the art will also understand that one or more nitric oxide-generating layers may be incorporated as all or part of a component layer. In some embodiments, one or more nitric oxide-generating layers may be provided below the transmission layer 226. In some embodiments, one or more nitric oxide-generating layers may be provided above the wound contact layer 222. In certain embodiments, one or more nitric oxide-generating layers may replace the transmission layer 226, such that one or more nitric oxide-generating layers are provided between the absorbent layer 221 (described further below) and the wound contact layer 222. In some embodiments, one or more nitric oxide-generating layers may supplement or replace the absorbent layer 221. In some embodiments, the wound dressing 100 does not have a wound contact layer 222, and the one or more nitric oxide-generating layers may be the bottom layer of the wound dressing 100. The one or more nitric oxide-generating layers may have the same or substantially similar size and shape as the transmission layer 226 and / or the absorption layer 221.

[0055] The one or more nitric oxide-generating layers may be constructed to be flexible yet rigid enough to withstand negative pressure so that the one or more nitric oxide-generating layers do not collapse excessively, thereby sufficiently transmitting negative pressure 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 pores of a sufficient number or size to allow the transmission of negative pressure. The one or more nitric oxide-generating layers may include gaps or holes, for example, underlying ports, to transmit negative pressure and / or wound fluid. Furthermore, the one or more nitric oxide-generating layers may have a thickness suitable for transmitting a suitable negative pressure to the wound. For example, the one or more nitric oxide-generating layers may have a thickness of approximately 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.

[0056] In some embodiments, an absorbent layer 221 is provided above the transmission layer 226. The absorbent material, which may comprise a foam or nonwoven natural or synthetic material, and may optionally include a superabsorbent material, forms a reservoir for fluids, particularly liquids, that are removed from the wound site. In some embodiments, layer 221 may also assist in drawing fluids toward the backing layer 220.

[0057] The absorbent layer 221 material may also prevent fluid collected within the wound dressing 100 from flowing freely within the dressing and preferably acts to contain any collected fluid within the dressing. The absorbent layer 221 also helps distribute the fluid throughout the layer by wicking, drawing fluid away from the wound site and storing it throughout the absorbent layer. This helps prevent clumping in the absorbent layer area. The absorbent capacity must be sufficient to manage the rate at which wound exudate flows when negative pressure is applied. During use, the absorbent layer experiences negative pressure, so the absorbent layer material is selected to absorb fluid under such conditions. Several materials exist that can absorb fluid when under negative pressure, such as superabsorbent materials. The absorbent layer 221 may typically be made from ALLEVYN™ foam Freudenberg 114-224-4 or Chem-Posite™ 11C-450. In some embodiments, the absorbent layer 221 may comprise a composite including superabsorbent powder, a fibrous material such as cellulose, and bonding fibers. In a preferred embodiment, the composite is an air-laid, thermally bonded composite.

[0058] In some embodiments, the absorbent layer 221 is a layer of nonwoven cellulose fibers with superabsorbent material in the form of dry particles dispersed throughout the layer. The use of cellulose fibers introduces a fast wicking element that helps quickly and evenly distribute liquid absorbed by the dressing. The parallel arrangement of many strand-like fibers leads to strong capillary action in the fibrous pad, which helps distribute the liquid, thus efficiently delivering liquid to the superabsorbent material. The wicking action also helps bring liquid into contact with the upper cover layer to help increase the dressing's evaporation rate.

[0059] A gap, hole, or orifice 227 is preferably provided in the backing layer 220 to allow negative pressure to be applied to the dressing 100. A fluid connector 110 is preferably attached or sealed to the top of the backing layer 220 over the orifice 227 made in the dressing 100 and transmits the negative pressure through the orifice 227. A length of tubing may be coupled to the fluid connector 110 at a first end and to a pump unit (not shown) at a second end to allow fluid to be pumped from the dressing. If the fluid connector is adhered to the top layer of the wound dressing, the length of tubing can be coupled at a first end of the fluid connector such that the tubing or conduit extends parallel to, or substantially toward, the top surface of the dressing. The fluid connector 110 can be adhered and sealed to the backing layer 220 using an adhesive such as an acrylic, cyanoacrylate, epoxy, UV-curable, or hot-melt adhesive. The fluid connector 110 may be formed from a soft polymer, such as polyethylene, polyvinyl chloride, silicone, or polyurethane, having a hardness of 30 to 90 on the Shore A scale. In some embodiments, the fluid connector 110 may be made from a soft or compliant material.

[0060] Optionally, the absorbent layer 221 includes at least one through-hole 228 positioned to underlie the fluid 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 larger or smaller. As illustrated in FIG. 2C , a single through-hole may be used to provide an opening underlying the fluid connector 110. It will be understood that multiple openings may alternatively be utilized. Additionally, if one or more ports are to be utilized in accordance with certain embodiments of the present disclosure, one or more openings may be created in the absorbent layer in registration with each respective fluid connector. While not required for certain embodiments of the present disclosure, the use of through-holes in the superabsorbent layer may provide a fluid flow path that remains unobstructed, particularly when the absorbent layer is near saturation.

[0061] 2C , a gap or through-hole 228 is preferably provided in the absorbent layer 221 below the orifice 227 such that the orifice is directly connected to the permeable layer 226. This allows negative pressure applied to the fluid connector 110 to be transmitted to the permeable layer 226 without passing through the absorbent layer 221. This ensures that negative pressure applied to the wound site is not inhibited by the absorbent layer as it absorbs wound exudate. In other embodiments, no gap may be provided in the absorbent layer 221, or alternatively, multiple gaps may be provided below the orifice 227. In further alternative embodiments, additional layers, such as another permeable layer, or an obscuring layer as described in International Patent Application Publication No. WO 2014 / 020440, the entire contents of which are incorporated by reference, may be provided above the absorbent layer 221 and below the backing layer 220.

[0062] The backing layer 220 is preferably gas-impermeable but water vapor-permeable and may extend across the width of the wound dressing 100. The backing layer 220, which may be, for example, a polyurethane film (e.g., Elastollan SP9109) with a pressure-sensitive adhesive on one side, is gas-impermeable; therefore, it covers the wound and acts to seal the wound cavity over which the wound dressing is placed. In this manner, an effective chamber is created between the backing layer 220 and the wound site, within which negative pressure can be established. The backing layer 220 is preferably sealed to the wound contact layer 222 within the dressing's perimeter boundary region, for example, via adhesive or welding techniques, to prevent air from being drawn into the boundary region. The backing layer 220 protects the wound from external bacterial contamination (a bacterial barrier) and allows liquid from wound exudate to migrate through the layer and evaporate from the film's outer surface. The backing layer 220 preferably includes two layers: a polyurethane film and an adhesive pattern spread on the film. The polyurethane film is preferably moisture-permeable and may be made from a material that increases its moisture permeability when wet. In some embodiments, the moisture permeability of the backing layer increases when the backing layer is wet. The moisture permeability of the wet backing layer may be up to about 10 times that of the dry backing layer.

[0063] The absorbent layer 221 may be of a larger area than the transmission layer 226 so 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 in the absorbent layer 221 that is in direct contact with the wound contact layer 222, assisting in more rapid absorption of exudate into the absorbent layer. Furthermore, this outer channel ensures that fluid cannot pool at the periphery of the wound cavity, which could otherwise seep through the seal around the dressing and lead to the formation of a leak. As illustrated in FIG. 2C , the absorbent layer 221 may define a perimeter that is smaller than the perimeter of the backing layer 220, such that a border or boundary area is defined between the edge of the absorbent layer 221 and the edge of the backing layer 220.

[0064] 2C, one embodiment of the wound dressing 100 includes a gap 228 in the absorbent layer 221 that underlies the fluid connector 110. During use, for example, when negative pressure is applied to the dressing 100, the wound-facing portion of the fluid connector may contact the transmission layer 226 and thus may assist in transmitting negative pressure to the wound site even when the absorbent layer 221 is filled with wound fluid. Some embodiments may have a backing layer 220 that is at least partially adhered to the transmission layer 226. In some embodiments, the gap 228 is at least 1-2 mm larger than the diameter of the wound-facing portion or orifice 227 of the fluid connector 110.

[0065] In particular, in embodiments with a single fluid connector 110 and through-hole, it may be preferable for the fluid connector 110 and through-hole to be located in an off-center position, as illustrated in Figure 2B. Such a location may allow the dressing 100 to be positioned on the patient such that the fluid connector 110 is elevated relative to the remainder of the dressing 100. So positioned, the fluid connector 110 and filter 214 may be less likely to come into contact with wound fluid that could prematurely block the filter 214, thereby preventing the transmission of negative pressure to the wound site.

[0066] Similar to the wound dressing embodiments described above, some wound dressings include a perforated wound contact layer with a silicone adhesive on the skin-contacting surface and an acrylic adhesive on the backside. In some embodiments, the wound contact layer may be constructed from polyurethane, polyethylene, or polyester. Above this bounded layer is a transmission layer. Above the transmission layer is an absorbent layer. The absorbent layer may include a superabsorbent nonwoven (NW) pad. The absorbent layer may contact the transmission layer approximately 5 mm beyond its perimeter. The absorbent layer may have gaps or perforations toward one end. The gaps may be approximately 10 mm in diameter. Above the transmission and absorbent layers is a backing layer. The backing layer may be a high moisture vapor transmission rate (MVTR) film that is patterned and coated with an acrylic adhesive. The high MVTR film and wound contact layer encapsulate the transmission and absorbent layers, creating a peripheral boundary of approximately 20 mm. The backing layer may have a 10 mm gap that overlaps the gap in the absorbent layer. Above the hole can be mated a fluid connector comprising a liquid-impermeable, gas-permeable semi-permeable membrane (SPM) or filter that overlies the gap described above.

[0067] FIG. 2D illustrates one embodiment of a wound dressing similar to that of FIGS. 2A-2C. Referring to FIG. 2D, a masking or concealing layer 2107 can be positioned under at least a portion of the backing layer 2140. In some embodiments, the concealing layer 2107 can have any of the same features, materials, or other details of any of the other embodiments of the concealing layer disclosed herein, including, but not limited to, having any viewing windows or holes. Examples of wound dressings with concealing layers and viewing windows are described in International Patent Publication No. WO 2014 / 020440, the entire contents of which are incorporated by reference in their entirety. Additionally, the concealing layer 2107 can be positioned adjacent to the backing layer or adjacent to any other dressing layer desired. In some embodiments, the concealing layer 2107 can be adhered to or integrally formed with the backing layer. Preferably, the obscuring layer 2107 has approximately the same size and shape as and is configured to overlay the absorbent layer 2110. Thus, in these embodiments, the obscuring layer 2107 will be of a smaller area than the backing layer 2140.

[0068] Preferably, the absorbent layer 2110 and the obscuring layer 2107 include at least one through-hole 2145 positioned so as to underlie the port 2150. Of course, the respective holes through these various layers 2107, 2140, and 2110 may be different sizes relative to one another. As illustrated in FIG. 2D , a single through-hole may be used to provide an opening underlying the port 2150. In certain embodiments, the port may be replaced with or used in combination with a fluid connector, such as that illustrated in FIG. 2C . It will be understood that multiple openings may alternatively be utilized. Additionally, if one or more ports are to be utilized in accordance with certain embodiments of the present disclosure, one or more openings may be made in the absorbent and obscuring layers in registration with each respective port. While not required for certain embodiments of the present disclosure, the use of through-holes in the superabsorbent layer may provide a fluid flow path that remains unobstructed, particularly when the absorbent layer 2110 is near saturation.

[0069] A gap or through-hole 2144 may be provided in the absorbent layer 2110 and the obscuring layer 2107 below the orifice 2144 such that the orifice is directly connected to the transmission layer 2105. This allows negative pressure applied to the port 2150 to be transmitted to the transmission layer 2105 without passing through the absorbent layer 2110. This ensures that negative pressure applied to the wound site is not inhibited by the absorbent layer as it absorbs wound exudate. In other embodiments, no gap may be provided in the absorbent layer 2110 and / or the obscuring layer 2107, or alternatively, multiple gaps below the orifice 2144 may be provided.

[0070] In some embodiments, the concealing layer 1404 may help reduce the unsightly appearance of the dressing during use by using a material that provides partial concealment or masking of the dressing surface. The concealing layer 1404 of one embodiment only partially conceals the dressing, allowing clinicians to access necessary information by observing the spread of exudate across the dressing surface. The partial masking nature of this embodiment of the concealing layer allows clinicians to perceive different colors caused by exudate, blood, by-products, etc. on the dressing, allowing for visual assessment and monitoring of the extent of spread across the dressing. However, because the change in color of the dressing from its clean state to its exudate-containing state is only a subtle change, patients are unlikely to notice any aesthetic difference. Reducing or eliminating visual indicators of wound exudate from a patient's wound is likely to have a positive impact on the patient's health, e.g., reducing stress.

[0071] In some embodiments, the obscuring layer may be formed from a nonwoven fabric (e.g., polypropylene) and thermally bonded using a diamond pattern with a 19% bond area. In various embodiments, the obscuring layer may be hydrophobic or hydrophilic. Depending on the application, in some embodiments, a hydrophilic obscuring layer may provide additional moisture permeability. However, in some embodiments, a hydrophobic obscuring layer may still provide sufficient moisture permeability (i.e., through appropriate material selection and thickness of the obscuring layer) while also allowing for better retention of the dye or color in the obscuring layer. As such, the dye or color may be trapped beneath the obscuring layer. In some embodiments, this may allow the obscuring layer to be colored in a light color or white. In a preferred embodiment, the obscuring layer is hydrophobic. In some embodiments, the obscuring layer material may be sterilizable using ethylene oxide. Other embodiments may be sterilized using gamma radiation, electron beam, steam, or other alternative sterilization methods. Additionally, in various embodiments, the obscuring layer may be colored or tinted, for example, medical blue. The opacifying layer may also be constructed from multiple layers, including a colored layer laminated or fused to a stronger non-colored layer. Preferably, the opacifying layer is odorless and exhibits minimal fiber shedding.

[0072] Multilayer dressing for use without negative pressure 3A-3D illustrate various embodiments of a wound dressing 500 that can be used to heal a wound without negative pressure. FIG. 3E illustrates a cross-section of the wound dressing of FIGS. 3A-3D. As shown in the dressings of FIGS. 3A-3E, the wound dressing may have multiple layers similar to the dressing described with reference to FIGS. 2A-2D, except that the dressings of FIGS. 3A-3E do not include ports or fluid connectors. The wound dressings of FIGS. 3A-3E may include a cover layer 501 and a wound contact layer 505, as described herein. In some embodiments, the cover layer 501 may be permeable to moisture and / or air. The wound dressing may include various layers positioned between the wound contact layer 505 and the cover layer 501. For example, the dressing may include one or more absorbent layers or one or more transmission layers, as described herein with reference to FIGS. 2A-2C.

[0073] As shown in Figures 3A-3E, 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 size suitable for covering the recommended dimensions of the wound corresponding to the particular dressing size selected. An optional layer of activated charcoal cloth (not shown) of similar or slightly smaller dimensions to layer 504 may be provided to allow for odor control. An absorbent layer 502, such as a layer of superabsorbent aeolian material containing cellulose fibers and superabsorbent polyacrylate particles, is provided over layer 504 and is slightly larger in size than layer 504, allowing for overlap of the superabsorbent material and acting as a leak prevention layer. A masking or concealing layer 503, such as a layer of three-dimensional knitted spacer fabric, is provided over layer 502 to provide pressure protection while allowing for partial masking of the top surface of the superabsorbent where colored exudate remains. In this embodiment, it is of smaller dimensions (plan view) than layer 502, allowing visualization of the edges of the absorbent layer, which can be used by the clinician to assess whether the dressing needs to be changed.

[0074] The wound dressing 500 may incorporate or include one or more nitric oxide-generating layers (e.g., nitrite delivery layer, acidic group-providing layer) as described in this section or elsewhere. Those skilled in the art will understand that the wound dressing 500 may incorporate any one or more nitric oxide-generating layers disclosed in this section or elsewhere herein. Those skilled in the art will also understand that one or more nitric oxide-generating layers may be incorporated as all or part of the component layers. In some embodiments, a nitric oxide-generating layer may be provided under the cover layer 501. In some embodiments, a nitric oxide-generating layer may be provided over the wound contact layer 505. In certain embodiments, the dressing 500 may not include a wound contact layer 505, such that one of the nitric oxide-generating layers may be the bottom layer and configured to contact the wound surface. In some embodiments, a nitric oxide-generating layer may be provided under the foam layer 504. In embodiments, a nitric oxide-generating layer may replace the foam layer 504. In some embodiments, the dressing 500 may include only the cover layer 501 and one or more nitric oxide-generating layers.

[0075] As explained above, one or more nitric oxide-generating layers may be incorporated into or used in conjunction 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, etc. In some embodiments, the wound dressing 500 may include a cover layer 501, a wound contact layer 505, and a nitric oxide-generating layer sandwiched therebetween. In some embodiments, the wound dressing 500 may include a cover layer 501, an absorbent layer 502, a nitric oxide-generating layer below the absorbent layer 502, and the wound contact layer 505.

[0076] Further details regarding wound dressings that may be used in combination with or in addition to the embodiments described herein can be found in U.S. Patent No. 9,877,872, issued January 30, 2018, entitled "WOUND DRESSING AND METHOD OF TREATMENT," the disclosure of which is hereby incorporated by reference in its entirety, including further details relating to wound dressing embodiments, components and principles of wound dressings, and materials used in wound dressings.

[0077] Multi-layer wound dressing with integrated negative pressure source In some embodiments, the negative pressure source (e.g., a pump) and some or all other components of a TNP system, such as a power source, sensors, connectors, user interface components (e.g., buttons, switches, speakers, screens), etc., may be integrated with a wound dressing, such as the dressing described above in connection with Figures 1-3D. Additionally, some embodiments relating to wound treatment with wound dressings described herein may also be used in combination with, and in addition to, embodiments described in International Application No. WO 2016 / 174048, entitled "WOUND TREATMENT APPARATUSES AND METHODS WITH NEGATIVE PRESSURE SOURCE INTEGRATED INTO WOUND DRESSING," filed March 6, 2017, and International Patent Application No. PCT / EP2017 / 055225, the disclosures of which are incorporated herein by reference in their entireties, including further details regarding wound dressing embodiments, wound dressing components and principles, and materials used in wound dressings and wound dressing components.

[0078] In some embodiments, the pump and / or other electronic components may be configured to be positioned adjacent to or next to the absorbent and / or permeable layer of the wound dressing such that, while the pump and / or other electronic components are positioned away from the wound site, the pump and / or other electronic components are still part of a single device that will be applied to the patient.

[0079] Nitric oxide generating layer 4 and 5 illustrate a wound dressing 12000 including a nitric oxide-generating layer, according to some embodiments. In the illustrated embodiment, the wound dressing 12000 may include a cover layer 12200, an active agent layer 12400, and a nitric oxide source layer 12600. In some embodiments, the wound dressing 12000 may include additional layers, as further described herein. Those skilled in the art will understand that, although the various sections of the dressing may be referred to as "layers," such sections may be of other suitable shapes or configurations.

[0080] The cover layer 12200 may be gas-impermeable but moisture-permeable and may extend across the width of the wound dressing 12000. For example, the cover layer 12200 may be a polyurethane film (e.g., Elastollan SP9109 or Elastollan SP806) with a pressure-sensitive adhesive on one side. The cover layer 12200 may be gas-impermeable and therefore act to cover the wound and seal the wound cavity over which the wound dressing is placed. A chamber or sealed wound space is therefore created between the cover layer 12200 and the wound site. In some embodiments, negative pressure may be established within the chamber or sealed wound space created between the cover layer 12200 and the wound site. The cover layer 12200 protects the wound from external bacterial contamination (a bacterial barrier) and allows liquid from wound exudate to migrate through the layer and evaporate from the outer surface of the film. The cover layer 12200 may include two or more layers, such as a polyurethane film and an adhesive pattern extending over the film. In certain examples, the polyurethane film may be breathable and may be made of a material that increases its water permeability when wet. In some embodiments, the breathability of the cover layer increases when the cover layer is wet. The breathability of the wet cover layer may be up to about 10 times that of the dry cover layer. In some embodiments, the cover layer 12200 may be replaced or supplemented with an additional wound dressing described elsewhere herein, whereby the additional wound dressing is positioned above the nitric oxide-generating layer. The cover layer may also be waterproof so that a dressing incorporating such a cover layer can be used in the shower. The cover layer may be configured to prevent nitric oxide from immediately leaking through the cover layer, meaning that the cover layer is nitric oxide impermeable or semi-impermeable, thereby trapping nitric oxide against the tissue so that it can interact with the user's body. Those skilled in the art will appreciate that the cover layer can be made to be vapor permeable but nitric oxide impermeable.

[0081] The nitric oxide source layer 12600 can provide one or more nitric oxide-releasing agents to the wound site. The nitric oxide-releasing agent can include any chemical entity that generates 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 ions, nitrite salts, organic and inorganic nitrite salts, or any pharmacologically acceptable nitrite source, thereby reducing nitrite ions for generating nitric oxide at the wound site. For example, the nitric oxide source layer 12600 and / or element can include one or more of ammonium nitrite, lithium nitrite, calcium nitrite, sodium nitrite, and potassium nitrite. In some embodiments, the nitric oxide source layer can be a suitable material layer or element including alkali metal nitrites and / or alkaline earth metal nitrites. In certain embodiments, the nitrite may include LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2, Ra(NO2)2, or any other suitable nitrite. In some embodiments, a precursor of the nitrite ion, such as nitrous acid, nitrate ion, nitroprusside ion, or any pharmacologically acceptable salt thereof, may be used as a source of nitrite. In some embodiments, the nitric oxide-releasing agent may include a nitrite, such as a nitro-functionalized compound.For example, nitric oxide releasing agents include nitroglycerin, isoamyl nitrite, mononitrite isobide, N-(ethoxycarbonyl)-3-(4-morpholinyl)sydnimine, 3-morpholinosydnimine, 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-chloride, 1,2,3,4-oxatriazolium, 5-amino-3-(chloro-2-methyl-phenyl)chloride, 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)chloride. [4',5'-bis(carboxymethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3,diethyl-1-triazene dipotassium salt, and [1-(4',5'-bis(carbomethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3-diethyl-1-triazine diacetoxymethyl ester.

[0082] In some embodiments, the nitric oxide releasing agent of the nitric oxide source layer 12600 can include a diazeniumdiolate, including O-alkylated diazeniumdiolates, O-derivatized diazeniumdiolates, and non-O-derivatized diazeniumdiolates. 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 an S-nitrosothiol, such as S-nitro-glutathione, S-nitroso-N-acetylcysteine, or S-nitroso-acetylpinicillamine. In some embodiments, the nitric oxide releasing agent of the nitric oxide source layer 12600 can include nitric oxide-modified silica or silica nanoparticles. In some embodiments, the nitric oxide releasing agent can be a polymer modified with nitric oxide to contain nitric oxide. For example, polyethyleneimine, polypropyleneimine, polybutyleneimine, polyurethane, or polyamide can be modified with nitric oxide to form a diazeniumdiolate. In some embodiments, the nitric oxide source layer 12600 may be constructed from such polymers modified with nitric oxide. Further examples of nitric oxide releasing agents are provided in International Publication No. WO 2006 / 058318 and Liang et al., "Nitric oxide generating / releasing materials," Future Science OA, 1(1) (2015), which are incorporated herein by reference in their entireties.

[0083] In some embodiments, nitric oxide source layer 12600 can include a nitric oxide-releasing agent (e.g., sodium nitrite) in an aqueous solution. For example, nitric oxide source layer 12600 can include a material soaked in a nitric oxide-releasing agent (e.g., sodium nitrite) solution. In some embodiments, nitric oxide source layer 12600 can include a dry nitric oxide-releasing agent (e.g., sodium nitrite) in solid form.

[0084] The nitric oxide source layer 12600 may include a mesh, foam, gel, or any other material suitable for containing a nitric oxide-releasing agent. For example, the nitric oxide source layer 12600 may include a mesh soaked with a solution of a nitric oxide-releasing agent (e.g., sodium nitrite). The mesh may be knitted, woven, or nonwoven. The mesh may be made from a polymeric material, such as 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 may also be made from a hydrogel without acidic groups to prevent reaction with nitrite ions, which release nitric oxide. In some embodiments, the nitric oxide source layer 12600 may be constructed from a colored material so that the nitric oxide source layer 12600 may be visible to aid in positioning 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.

[0085] In some embodiments, the nitric oxide source layer 12600 is the bottom layer of the dressing 12000 such that the nitric oxide source layer 12600 can contact the wound. In some embodiments, the nitric oxide source layer 12600 can be positioned within and / or on the wound. The nitric oxide source layer can be constructed so that the nitric oxide source layer 12600 does not substantially adhere to the skin or wound or cause damage to the wound when in contact with the wound. In some embodiments, the dressing 12000 can include one or more layers, such as a wound contact layer, below the nitric oxide source layer 12600. In some embodiments, the dressing 12000 can include two or more nitric oxide source layers. For example, the wound dressing 12000 can include two, three, four, five, six, seven, or more nitric oxide source layers.

[0086] The active agent layer 12400 may contain chemical agents, functional groups, or functional moieties that can activate and / or facilitate the release of nitric oxide from the nitric oxide-releasing agent. For example, protons or an acidic environment promote the reduction of nitrite to nitric oxide, and the active agent layer 12400 may contain acidic groups or moieties that can donate protons in an aqueous environment, thereby lowering the pH at the site of application. In certain embodiments, the acidic groups or moieties are immobilized in the active agent layer 12400, for example, on the surface of the active agent layer 12400. The acidic groups or moieties may be covalently bonded in the active agent layer 12400. In some embodiments, the active agent layer 12400 may contain an acidic solution. The active agent layer 12400 may include a mesh, foam, gel, or any other material suitable for containing acidic groups or moieties. In embodiments, the active agent layer 12400 may be positioned above the nitric oxide source layer 12600, or the active agent layer 12400 may be positioned below the nitric oxide source layer 12600. In some embodiments, the active agent layer 12400 may include a proton source such as water, methanol, ethanol, propanol, butanol, pentanol, hexanol, phenol, naphthol, or a polyol, a phosphate, a succinate, a carbonate, an acetate, a format, a propionate, a butyrate, a fatty acid, an amino acid, or ascorbic acid, or any suitable enzymatic or catalytic compound. In some embodiments, bodily fluids such as blood, lymph, bile, or wound exudate may function as an active agent and may supplement the active agent layer 12400. In some embodiments, the wound dressing 12000 may not include an active agent layer 12400, and wound fluid or wound exudate may function as the active agent. Further examples of active agents for nitric oxide-releasing agents are provided in International Publication No. WO 2006 / 058318 and Liang et al., “Nitric oxide generating / releasing materials,” Future Science OA, 1(1) (2015), which are incorporated herein by reference in their entireties.

[0087] In some embodiments, the wound dressing 12000 may include two or more nitric oxide source layers and / or two or more active agent layers. For example, the wound dressing 12000 may include 2, 3, 4, 5, 6, 7 or more nitric oxide source layers and / or active agent layers.

[0088] In some embodiments, the active agent layer 12400 includes a hydrogel so that the active agent layer 12400 can absorb wound exudate. In certain examples, the active agent layer 12400 can be constructed from a xerogel. The active agent layer 12400 can be constructed from any suitable material disclosed herein. The gel of the active agent layer 12400 can be presented in different physical formats. For example, the active agent layer 12400 can be foamed during curing. The hydrogel can be poured into a foam and then cured within the foam. In some embodiments, the active agent layer 12400 can be perforated through its thickness. The perforations can be sized to allow fluid absorption and to allow the desired therapeutic dose of nitric oxide to be released from the wound dressing. For example, the perforations can have a diameter of approximately 0.1 mm to 10 mm, 0.15 mm to 7 mm, 0.2 mm to 5 mm, 0.5 mm to 4 mm, or 0.7 mm to 3 mm. The perforations may have a circular, square, triangular, or any other suitable shape. The foamed structure and / or perforations may contribute to the fluid handling capabilities of the active agent layer.

[0089] In some embodiments, the active agent material for the active agent layer may be provided as a dispensable composition, such as a prepolymer solution or otherwise moldable form, instead of being provided as an active agent layer, such as active agent layer 12400, so that it can be more freely applied to the wound and / or surrounding area. For example, the active agent material may be provided as a gel prepolymer solution so that it can be applied by a clinician to or in close proximity to wounds having irregular shapes and sizes. In some embodiments, the active agent material, such as a gel prepolymer solution, may be provided in a syringe and / or applied using a syringe, and the gel prepolymer solution may have a viscosity suitable for dispensing from a syringe. The active agent material may also be formulated to be rapidly cured and no longer flowable once applied to or surrounding the wound. The active agent material may include an evaporating solvent, such as isopropanol. The active agent material may have a suitable secondary cure mechanism, such as photoinitiated acrylate functionality. In some embodiments, the active agent material may be provided as a reactive two-part system. For example, the first and second parts may be provided to be mixed immediately prior to dispensing to result in polymer formation. In some embodiments, the first and second parts may be oppositely charged flowable gels that interact upon mixing to provide a substantially non-flowable gel. In some embodiments, the active agent material may include a material, such as a gel, that changes in response to a change in environment. For example, the active agent material may include a material, such as certain Pluronics®, that may harden upon a change in temperature when applied to the skin from a dispenser or syringe. The active agent material may be applied such that it may interact with nitrite from the nitric oxide source layer 12600 (which may provide the nitrite) to generate nitric oxide. Once the active agent material has been applied and hardened or otherwise becomes non-flowable, the cover layer 18200 may be applied.

[0090] When coating 12000 is activated, for example, by placing activator layer 12400 in contact with nitric oxide source layer 12600, the nitric oxide releasing agent from nitric oxide source layer 12600 releases nitric oxide. For example, in some embodiments, nitrite can be reduced to nitric oxide in the presence of an acidic environment provided by activator layer 12400, as shown below.

number

[0091] The active agent layer 12400 and the nitric oxide source layer 12600 may be positioned such that the nitric oxide-releasing agent reacts to provide nitric oxide. For example, the active agent layer 12400 and the nitric oxide source layer 12600 may contact each other within the dressing 12000 during use. In some embodiments, one or more additional layers may be positioned between the active agent layer 12400 and the nitric oxide source layer 12600. In some embodiments, the active agent layer 12400 and the nitric oxide source layer 12600 may be fluidly separated from each other before applying the dressing 12000 to a patient to prevent premature release of nitric oxide. For example, the nitric oxide source layer 12600 may be provided in a separate package from the rest of the dressing 12000. When the dressing 12000 is activated, the nitric oxide-releasing agent from the nitric oxide source layer 12600 may disperse within the dressing 12000. In some embodiments, the nitric oxide-releasing agent may be dissolved in wound exudate, which may facilitate dispersion of the nitric oxide-releasing agent. At least a portion of the nitric oxide-releasing agent will react to release nitric oxide in the presence of the active agent in active agent layer 12400. The generated nitric oxide may diffuse into the wound or be delivered to the wound by any suitable mechanism. In some embodiments, the generated nitric oxide is not delivered immediately or at all, but instead is retained within the dressing, for example, by a selectively permeable membrane, whereby the nitric oxide may prevent the growth of or kill microorganisms within the dressing.

[0092] In some embodiments, the wound dressing 12000 may include a reducing agent that facilitates the reduction of a nitric oxide-releasing agent (e.g., nitrite ion) to nitric oxide. Physiologically acceptable examples of such reducing agents include, but are not limited to, iodide anion, ascorbic acid, ascorbic acid (e.g., sodium ascorbate), isoascorbic acid (e.g., sodium isoascorbate), hydroquinone, butylquinone, and 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 active agent layer 12400, the nitric oxide source layer 12600, the wound contact layer 12800, and / or any suitable layer of the nitric oxide-generating wound dressing described herein. The reducing agent may be incorporated into one or more layers by, for example, physical entrapment, physical mixing, coating, covalent bonding, or any other suitable method. The reducing agent may be incorporated into the dressing in an appropriate layer, such as a hydrogel activation layer, at about 0.01-5.0%, 0.1-4.5%, 1.0-3.0%, 1.0-1.5%, and / or 1.5-2.5% w / w. 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, but very high levels of reducing agent may be toxic.

[0093] As described herein, the nitric oxide source layer may include a nitrite and may be referred to herein as a nitrite delivery layer or nitrite-providing layer. As described herein, the activator layer may include an acid and may be referred to herein as an acid-providing layer or acid-delivery layer. The nitric oxide source layer / nitrite delivery layer / nitrite-providing layer and the activator layer / acid-providing layer may be collectively or individually referred to herein as nitric oxide generating layers.

[0094] Nitric oxide coating materials and constructs As will be appreciated by those skilled in the art, the materials and dressing constructions described above in connection with the nitric oxide delivery dressing 1200 in FIGS. 4 and 5 and elsewhere herein can include multiple suitable constructions and different types of materials. For example, the top layer furthest from the wound can be a top or cover film layer, such as a polyurethane material, as disclosed herein. Such a top or cover film can be constructed from materials used for the cover layer of RENASYS drapes sold by Smith+Nephew. Beneath the top or cover film layer can be a masking or fabric layer, which can be constructed from any suitable material disclosed herein as a masking or fabric layer. The masking layer can be constructed from stretchable and non-stretchable polyester, polyethylene, polypropylene, polypropylethylene, and nonwoven fabrics, as well as suitable blends thereof. Further suitable nonwoven fabrics and blends can also be utilized. In certain embodiments, the masking layer can be a foam. Beneath the masking or fabric layer is an active agent layer, similar to the active agent layers described herein and throughout. Such an active agent layer may be constructed from a hydrogel adhesive, optionally containing a central polyester support mesh and / or support-release liner. The active agent layer may be constructed from any suitable hydrogel material disclosed herein, such as acrylic acid hydrogel and / or sulfonic acid hydrogel. Beneath the active agent layer may be a moisture-wicking distribution layer, which may be constructed from any suitable moisture-wicking distribution layer material disclosed herein, such as those associated with FIG. 2. For example, the moisture-wicking distribution layer may be constructed from a 3D knit, gauze, and / or stretch polyester fiber woven into a net-like configuration, similar to the material used in Smith+Nephew's Acticoat Flex, although silver is optional. In some embodiments, the moisture-wicking distribution layer may be constructed from a prepolymer solution containing a mixture of water, surfactant, and polyethylene glycol, such as the foam used in Smith+Nephew's Allevyn foam. The masking layer and moisture-wicking distribution layer may use the same material and be interchangeable.In certain embodiments, the water-absorption / distribution layer may be pressed into the active agent layer and / or cured into the active agent layer. Curing the water-absorption / distribution layer into the active agent layer may improve the rate of nitric oxide formation due to more rapid transport. Beneath the water-absorption / distribution layer may be a contact layer, which may be constructed from any suitable material disclosed herein, such as those described in connection with FIG. 2. For example, the wound contact layer may include a silicone adhesive and a perforated polyurethane film. The wound contact layer may include an acrylic adhesive. A nitric oxide source layer, such as a nitrite layer constructed from any suitable material disclosed herein, may be positioned below the wound contact layer such that the nitric oxide source layer is directly against the wound or other tissue. In some embodiments, the nitric oxide source layer may be in other locations, such as above the active agent layer and / or elsewhere within the dressing. In certain embodiments, the ALLEVYN or PICO dressings disclosed in FIGS. 2 and 3 may be placed directly on the active agent layer and the underlying nitric oxide source layer. Placing a nitric oxide source layer directly against a wound, peri-wound area, and / or other tissue may allow for increased release of nitric oxide directly into the tissue.

[0095] chemiluminescence FIG. 6 shows an exemplary configuration 600 for a chemiluminescence protocol for testing nitric oxide delivery coatings, such as those disclosed above in connection with FIGS. 4 and 5. The protocol may include a sample 602, a 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 a T-piece connector 616. In certain embodiments, a ThermoFisher 42i-HL detector may be used as the chemiluminescence detector 608. After warming the instrument with airflow at atmospheric pressure, the sample box 602 and nitrogen supply may be connected to the instrument. The nitrogen flow through the mass flow controller may be set to a suitable value, such as about 1-100, 10-90, 25-75, 40-60, or about 50 mL / min. After flushing the system (e.g., for about 1-60, 10-50, 20-40, or about 30 minutes), a nitric oxide source layer (e.g., a nitrite mesh) and an activator layer (e.g., an acid-providing hydrogel) may be placed in sample chamber 602. In embodiments, the nitrite mesh has a smaller total area than the activator layer. In certain embodiments, the nitric oxide source layer and / or the activator layer may have a length and / or width of about 0.5-20, 1-10, 2-8, or about 4-6 centimeters. In certain embodiments, the nitric oxide source layer may be 2.5 cm x 2.5 cm, while the activator layer may be 3 cm x 3 cm.

[0096] The NO / NO2 emission concentration may be measured at an appropriate rate by a chemiluminescence detector, checking the concentration in ppb or ppm, and monitored periodically, such as about every 1, 2, 5, 10, 30, 60, or 90 seconds. In certain embodiments, the NO / NO2 concentration may be checked in ppm.

[0097] As will be appreciated by those skilled in the art, maximizing NO over NO is desirable for the coatings disclosed herein, such as those described in connection with FIGS. 4 and 5. While nitrogen dioxide (NO) can exert antibacterial properties, NO lacks the vasodilatory properties and cell proliferation-activating ability of NO. Therefore, it is generally desirable to reduce the generation of NO as much as possible during nitrite acidification, such as by reducing the oxidation of dissolved nitric oxide (NO) by removing oxygen from the bulk of the hydrogel where nitrite acidification occurs. The nitric oxide-delivery coatings disclosed herein can generate both NO and NO. In some embodiments, the nitric oxide coatings disclosed herein can generate NO and NO at an NO / NO ratio of 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, etc. For example, the ratio can be about or at least about 0.5:1, 1.01:1, 1.1:1, 1:1, 2:1, 5:1, 10:1, 20:1, 30:1, 50:1, 100:1, 200:1, or 500:1.

[0098] FIGS. 7A-7B show an example of an experimental setup 700 and subsequent results 750 demonstrating nitric oxide delivery from a combination of an active agent layer and a nitric oxide source layer while under negative pressure, similar to the dressings described in connection with FIGS. 4 and 5. As shown in FIG. 7A, a negative pressure wound therapy pump 702 is connected to a negative pressure wound therapy dressing 704, such as described herein in FIGS. 2A-2D. The dressing is sealed over a chamber 706 containing a nitrite test solution 708 that changes color in the presence of NO. FIG. 7B shows an example of the results of the negative pressure nitric oxide experiment shown in FIG. 7A. Before applying negative pressure, the test solution did not change color (750). After applying negative pressure for a period of time to ensure no background color change occurred, as shown in 760, an active agent layer 710 (e.g., an acid-providing hydrogel) such as described herein was placed in the chamber and negative pressure was applied. Again, no color change occurred (770). Finally, a nitric oxide source layer 712 (such as a sodium nitrite mesh) as described herein was placed on the activator layer 780 without contacting the nitric oxide source layer with the nitrite test solution, and negative pressure was applied. After 15 minutes of negative pressure, the indicator solution changed color (790), thereby demonstrating that the interaction between the activator layer and the nitric oxide layer can produce nitric oxide even under negative pressure.

[0099] As will be appreciated by those skilled in the art, negative pressure can be applied to any of the nitric oxide delivery dressings disclosed herein, such as the dressings described in Figures 4 and 5 and elsewhere herein. A dressing, such as the dressing described in Figures 2A-2D, can be placed over an active agent layer and a nitric oxide source layer that are placed within the wound, thereby delivering nitric oxide to the wound while simultaneously applying negative pressure wound therapy.

[0100] 8A-8C show example chemiluminescence experimental runs using protocols similar to those described above. As will be appreciated by those skilled in the art, the measurements obtained in these experimental runs are merely exemplary, and the disclosure herein is not limited to such values. FIG. 8A shows experimental results when testing a dry sodium nitrite mesh with the configuration shown in FIG. 8A, including a polyurethane cover layer overlying a stretchable polyester ADL layer, positioned on a hydrogel active agent layer sandwiched between separate stretchable polyester ADL layers on the dry sodium nitrite mesh as shown. In this experimental run, after DI water was added, the dry sodium nitrite mesh released a peak of approximately 550 ppm NO and 75 ppm NO at the 25-minute mark, gradually decreasing to approximately 80 ppm NO and 10 ppm NO at the 50-minute mark.

[0101] 8B shows experimental results when testing the full dressing design with pull-out tabs and self-sealing boundaries. The pull-out tabs were initially used to separate the nitric oxide source layer from the activator layer, so that when the tabs were removed and the dressing was wetted, interaction between the nitric oxide source layer and the activator layer produced nitric oxide. In this experimental run, after DI water was added, the full dressing design with pull-out tabs and self-sealing boundaries emitted approximately 84 ppm NO and 15 ppm NO2 at its peak at the 17-minute mark, gradually decreasing to approximately 25 ppm NO and 5 ppm NO2 at the 50-minute mark.

[0102] FIG. 8C shows an example of experimental results for a coating containing a degradable film. Here, the degradable film was placed between the activator layer and the nitric oxide source layer, thereby generating nitric oxide once the degradable layer decomposed. In this experimental run, after DI water was added, the coating containing the degradable film released a peak of approximately 1000 ppm NO and 45 ppm NO at the 25-minute mark, gradually decreasing to approximately 225 ppm NO and 20 ppm NO at the 50-minute mark. The experimental protocol was also utilized to test an activator layer containing sodium isoascorbate. In this experimental run, after DI water was added, the activator layer containing sodium isoascorbate released its first peak of about 52 ppm NO and 4 ppm NO at the 80 minute mark, its second and maximum peak of 66 ppm NO and 5 ppm NO at the 110 minute mark, and gradually decreased in concentration to about 45 ppm NO and 2 ppm NO at the 160 minute mark.

[0103] Figure 9 shows the various gsm (g / m 2 1 shows an example of relative peak power in ppm for an active agent hydrogel (acid-bearing) with or without a water-absorption / distribution layer, including polypropylene, polypropylethylene, or stretch polyester water-absorption / distribution layers having a 17 gsm polypropylene compressive water-absorption / distribution layer. Without the water-absorption / distribution layer, the peak NO and NO concentrations were approximately 55 ppm and 10 ppm, respectively; however, one skilled in the art will appreciate that a water-absorption / distribution layer can allow for improved fluid distribution and handling throughout a larger area, such as a dressing. With a 17 gsm polypropylene compressed water-absorption / distribution layer, the peak NO and NO concentrations were approximately 20 ppm and 2 ppm, respectively. With a 17 gsm polypropylene cured water-absorption / distribution layer, the peak NO and NO concentrations were approximately 40 ppm and 5 ppm, respectively. As explained above, curing the water-absorption / distribution layer can allow for increased fluid transport and improved rates of nitric oxide formation. Polypropylene 30 g / m 2 The peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively, for the compressed water absorption and dispersion layer of polypropylene 30 g / m 2The peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively, for the water absorption / dispersion layer of polypropylene 40 g / m 2 The peak NO and NO2 concentrations were approximately 30 ppm and 2 ppm, respectively, for the compressed water absorption and dispersion layer of polypropylene 40 g / m 2 In the cured water-absorbing dispersion layer of 30 g / m2, the peak NO and NO2 concentrations were approximately 38 ppm and 5 ppm, respectively. 2 The peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively, when the pressure-absorbent dispersion layer was used. 2 For the cured water-absorbing / dispersion layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. For the stretch polyester pressed water-absorbing / dispersion layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. For the FLEX pressed water-absorbing / dispersion layer, the peak NO and NO2 concentrations were approximately 55 ppm and 8 ppm, respectively.

[0104] 10A-10D show examples of NO and NO2 concentrations over time for several embodiments incorporating an activator layer and a nitric oxide-providing layer. As shown in FIGS. 10A-10B, activator layers containing approximately 2-3% sodium isoascorbate were tested with and without different moisture-distribution layers pressed or cured. The gel without a moisture-distribution layer produced pNO = 785 ppm and pNO2 = 78 ppm (p indicates peak). The activator layer with stretchable polyester pressed into the gel produced pNO = 506 ppm and pNO2 = 24 ppm. For stretchable polyester cured on the activator layer, pNO = 625 ppm and pNO2 = 50 ppm. For polypropylene pressed into the gel, pNO = 508 ppm and pNO2 = 26 ppm. For polypropylene cured into a gel, pNO = 624 ppm and pNO2 = 26 ppm.

[0105] Figures 10C and 10D show examples of NO and NO2 concentrations over time for activator layers containing approximately 1-2% sodium isoascorbate with or without different water-absorption-distribution layers pressed or cured. The activator layer without ADL produced pNO = 334 ppm and pNO2 = 40 ppm. For a stretchable polyester water-absorption-distribution layer pressed into the activator layer, pNO = 211 ppm and pNO2 = 10 ppm. For a stretchable polyester water-absorption-distribution layer cured into the activator layer, pNO = 247 ppm and pNO2 = 14 ppm. For a polypropylene water-absorption-distribution layer pressed into the activator layer, pNO = 112 ppm and pNO2 = 5 ppm. For a polypropylene water-absorption-distribution layer cured into the activator layer, pNO = 184 ppm and pNO2 = 8 ppm. As explained elsewhere herein, curing a water absorption and distribution layer within the active agent layer may improve fluid handling and nitric oxide production relative to nitrogen dioxide production.

[0106] Xerogel and Hydrogel Constructs Reference may be made herein to a xerogel. A xerogel may be formed from a gel by drying in an unhindered contraction state. As will be understood by those skilled in the art, a xerogel is a gel with a very low water content, so low that minimal reaction to form nitric oxide occurs without the addition of additional water and / or liquid. For example, a xerogel may be substantially free of water in a dry state. Drying may be completed by any suitable means known in the art.

[0107] In certain examples, hydrogels (which can then become xerogels after drying) can be generated with or without glycerol and can contain the standard amount of crosslinker PEG diacrylate, or two, three, or four times the required amount, as needed. A solution of 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt can be present in the xerogel. Hydrogels and xerogels can be made by converting as-supplied MEHQ-stabilized acrylamido-2-methyl-1-propanesulfonic acid (SA) to its sodium salt by dissolving it in water, followed by neutralization with 50% NaOH to pH 7.0 while cooling from a 10°C water bath to form a solution of the neutralized acid (NaAMPS). Hydrogel prepolymers can be prepared by pre-dispersing 2-hydroxy-2-methylpropiophenone photoinitiator in PEG diacrylate under minimal light, then mixing for 10-20 minutes with a mixture of 58% aqueous sodium 2-acrylamido-2-methyl-1-propanesulfonate (NaAMPS), (sodium isoascorbate), pre-ground 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS acid), and glycerol. The AMPS acid can be completely dissolved in the stirred NaAMPS solution before gradually adding the glycerol, and then the photoinitiator / diacrylate mixture can be completely dissolved in a water bath. In certain embodiments, hydrogels can also be prepared using twice the usual amount of photoinitiator / crosslinker and / or omitting the glycerol, and / or using three times the amount of prepolymer mixture in a mold to form a gel three times thicker.

[0108] Nitric oxide generating coatings using dry sodium nitrite 11A-11D illustrate embodiments of nitric oxide-generating wound dressings having various arrangements of layers. Those skilled in the art will understand that the various layers illustrated in FIGS. 11A-11D may be ordered in any suitable order, and the order illustrated in the figures is merely exemplary. In some embodiments, the top layer may be a cover layer 13002, which may have any of the same characteristics, materials, or other details as the cover layers disclosed herein, such as being constructed from a film. The cover layer 13002 may be suitable for sealing the dressing on the wound and for connecting to a negative pressure source and / or maintaining negative pressure at the wound site. In certain embodiments, a border region of the cover layer 13002 may attach to the skin surrounding the wound to form a seal so that wound exudate can be contained within the wound dressing 13000. Beneath the cover layer may be a masking or concealing layer 13004 (referred to herein as a "masking layer") to prevent or limit visibility of the wound or wound exudate through the cover layer 13002. The masking layer 13004 may be positioned under at least a portion of the cover layer 13002. In some embodiments, the masking layer 13004 may have any of the same features, materials, or other details of any of the other embodiments of masking layers disclosed herein, including, but not limited to, having any viewing windows or holes. Examples of wound dressings having a concealing layer and a viewing window are described in International Patent Publications WO 2013 / 007973 and WO 2014 / 020440, which are incorporated by reference in their entireties. Additionally, the masking layer 13004 may be positioned adjacent to the cover layer or adjacent to any other dressing layer as desired. In the illustrated embodiment, the masking layer 13004 is positioned between the cover layer 13002 and the acid-providing layer 13006. As described elsewhere herein and as would be understood by one of ordinary skill in the art, the activator layer may be an acid-providing layer or other suitable layer. In certain embodiments, the masking layer 13004 may be adhered to or integrally formed with the cover layer 13002. The masking layer 13004 may have approximately the same size and shape as and be configured to overlay the activator layer 13006.The masking layer 13004 may be smaller in area than the cover layer 13002. In certain embodiments, the masking layer 13004 may wick fluid horizontally and may also function as a moisture distribution layer.

[0109] In certain embodiments, the active agent layer 13006 can have any of the same features, materials, or other details of any of the other embodiments of the active agent layer disclosed herein. For example, the active agent layer 13006 can be an adhesive or can be constructed from a hydrogel or xerogel configured with multiple acidic groups or moieties capable of donating protons in an aqueous environment. As described elsewhere herein, under such acidic conditions, nitrite ions from the nitric oxide source layer 13010 can be reduced to nitric oxide for delivery to the wound or intact skin. As described elsewhere herein and as would be understood by one of ordinary skill in the art, the active agent layer can be a nitrite-providing layer or other suitable layer. The active agent layer 13006 (e.g., a hydrogel layer) can include multiple perforations extending through the thickness of the active agent layer, as described elsewhere herein. The multiple perforations may enable or facilitate the passage of wound exudate through the active agent layer such that wound exudate beneath or around the active agent layer may be transported to one or more additional absorbent and / or evaporative layer(s) (e.g., cover layer) above the active agent layer, thus preventing excessive buildup of wound exudate beneath the active agent layer 13004. Additionally, the multiple perforations may provide an increased surface area of the active agent layer, thereby increasing the absorption rate of the active agent layer.

[0110] 11A , in embodiments, the water absorption / distribution layer 13008 may be disposed between the active agent layer 13006 and the nitrite-providing layer 13010. In certain embodiments, the water absorption / distribution layer 13008 may be constructed to advantageously wick fluid, such as wound exudate, horizontally as it is absorbed through the layers of the dressing 13000. Such lateral wicking of fluid may allow for maximum dispersion of fluid through the active agent layer 13006, allowing the active agent layer 13006 to reach its full holding capacity. Furthermore, the water absorption / distribution layer 13008 may facilitate the production of nitric oxide because nitrite ions dissolved in the liquid may spread more quickly across the surface of the active agent layer 13006. Some embodiments of the water absorption / distribution layer 13008 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these, and the material may be needle-punched. Some embodiments of the water absorption distribution layer 13008 may comprise cellulose in the range of 40 to 160 gsm (or about 40 to about 160 gsm), for example, 80 (or about 80) gsm. Some embodiments of the water absorption distribution layer 14800 may comprise polyethylene in the range of 40 to 150 grams per square meter (gsm). In some embodiments, the water absorption distribution layer 13008 may have a thickness of 1.2 mm or about 1.2 mm, or may have a thickness in the range of about 0.5 mm to 3.0 mm, about 0.5 mm to about 3.0 mm, 0.7 mm to 2.5 mm, 0.9 mm to 2.1 mm, or 1.1 mm to 1.5 mm. In certain embodiments, the water absorption distribution layer 13008 may be constructed from a material that will withstand compression under levels of negative pressure typically applied during negative pressure therapy.

[0111] The water absorption / distribution layer 13004 may comprise a plurality of loosely wrapped fibers that may be arranged in a substantially horizontal fibrous network. In some embodiments, the water absorption / distribution layer 13004 may be comprised of a blend of two fiber types. One may be a flat fiber that may be 20 μm to 50 μm wide, or about 20 μm to about 50 μm wide, and may comprise a cellulosic material. The other fiber may be a bicomponent fiber having an inner core that is 8 μm to 10 μm in diameter, about 8 μm to about 10 μm in diameter, 7 μm to 11 μm in diameter, 6 μm to 12 μm in diameter, or 5 μm to 13 μm in diameter, and an outer layer that is 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm thick. The bicomponent fiber may be a blend of polyethylene (PE)-type material and polyethylene terephthalate (PET). In some embodiments, the inner core of the bicomponent fiber may be PET and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may comprise about 60% to about 90% cellulose fibers, e.g., approximately 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, e.g., about 25% PE / PET fibers. In some embodiments, the moisture absorption / distribution layer 13004 may comprise split microfibers.

[0112] The majority of the fiber volume may extend horizontally (i.e., parallel to the planes of the top and bottom surfaces of the material), or substantially or nearly horizontally. In other embodiments, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In other embodiments, all or substantially all of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some embodiments, the majority of the fibers, 80% to 90% (or about 80% to about 90%) or more, or even all or substantially all of the fibers span a distance perpendicular to the thickness of the water absorption-distribution layer 13004 (horizontal or lateral distance) that is greater than the thickness of the water absorption-distribution layer 13004. In some embodiments, the horizontal or lateral distance spanned by such fibers is at least 2 times (or about 2 times) greater, 3 times (or about 3 times) greater, 4 times (or about 4 times) greater, 5 times (or about 5 times) greater, or 10 times (or about 10 times) greater than the thickness of the water absorption / distribution layer 13004. Such fiber orientation may promote lateral wicking of fluid through the water absorption / distribution layer 113004. This may cause fluids, such as wound exudate, to be more evenly distributed throughout the water absorption / distribution layer 13004. In some embodiments, the ratio of the amount of fluid wicked laterally across the water absorption / distribution layer 13004 to the amount of fluid wicked vertically through the water absorption / distribution layer 13004 under negative pressure may be at least 2:1, or about 2:1, or in some embodiments, up to at least 10:1, or about 10:1.

[0113] Continuing with FIG. 11A , in embodiments, a nitric oxide source layer 13010 may be provided below the water-absorbing distribution layer 13004. Such a nitric oxide source layer 13010 may have any of the same features, materials, or other details of any of the other embodiments of nitric oxide source layers disclosed herein; for example, the nitric oxide source layer 13010 may be a nitrite-providing layer. For example, the nitric oxide source layer may be a wet mesh soaked with a sodium nitrite solution. In some embodiments, the nitric oxide source layer 13010 may be dry and may include a dry nitrite source, such as dry sodium nitrite. Such dry sodium nitrite may be loaded into a material layer, which is constructed from a suitable material, such as any of the materials disclosed herein. As will be appreciated by those skilled in the art, a dry material and / or substance is one that is free or relatively free of liquid. For example, polypropylene, polyethylene, or melt-extrudable fibers may be suitable materials for such a layer. In embodiments, such a nitric oxide source layer 13010 layer may need to be first separated from the active agent layer 13006 when the active agent layer is a hydrogel to avoid reaction and nitric oxide generation prior to application to the wound and / or skin. As illustrated in FIG. 14A , a dry fluid-absorbing layer 13008 may serve to separate the nitric oxide source layer 13010 and the hydrogel active agent layer 13004 prior to application. However, such a dry sodium nitrite-providing layer may be adjacent to the xerogel active agent layer 13006, as the xerogel would not be wetted. In the case of a xerogel, activation may occur upon contact with fluid, such as wound exudate, as the exudate wicks through the dressing. In the case of a hydrogel, when fluid such as wound exudate comes into contact with the water absorption / distribution layer 13008, nitrite ions may then come into contact with the acidic environment created by the active agent layer, thereby generating nitric oxide, which may then migrate into the wound and / or skin. In some embodiments, each of the layers, such as the nitric oxide source layer, the active agent layer, and any other suitable layers, may be stored dry before use. Prior to application to the skin or wound, the layers may be moistened with a suitable liquid, such as saline.

[0114] As shown in FIG. 11B, to maintain nitric oxide release, there may be several layers containing dry sodium nitrite, such as a first nitric oxide source layer 13010 and a second nitric oxide source layer 13012, which become "activated" when wound fluid reaches and wets the layers, allowing the sodium nitrite to contact the acidic groups of the hydrogel or xerogel of the active agent layer 13006, thereby producing nitric oxide. In certain embodiments, there may be two, three, four, five, six, or more layers containing dry sodium nitrite. As shown in FIG. 14B, a masking layer 13004 may serve to prevent contact between the second nitric oxide source layer 13012 and the active agent layer 13004. In certain embodiments, additional moisture-wicking and / or masking layers may be sandwiched between the active agent layers to provide additional nitric oxide sources.

[0115] As shown in Figures 11C and 11D, in embodiments, the active agent layer 13006 may be positioned below the nitric oxide source layer, thereby relying on the dressing to wet (from wound exudate) and activate the nitrite providing layer 13010.

[0116] FIG. 12 illustrates one embodiment of a wound dressing 14000 similar to the dressings of FIGS. 4, 5, and 11A-11D. However, here, a nitric oxide source layer 14002, such as those disclosed herein, may be attached to the dressing 14000 by a tether 14004 such that the nitric oxide source component or layer 14002 (hereinafter, "layer") may be kept separate from an active agent layer 14006, such as those disclosed herein. In certain embodiments, the tether may be constructed from any suitable material, such as a screw. The nitric oxide source layer (dry or wet) may be kept separate from the rest of the dressing on a foldable tether 14004, such that the nitric oxide source layer may be folded into an underlying configuration under the dressing when the dressing is applied to the wound and / or skin and needs to be activated to deliver nitric oxide (as shown in FIG. 12). In some embodiments, a water absorption / distribution layer 14008, such as those disclosed herein, may be disposed beneath the active agent layer 14006. However, those skilled in the art will appreciate that such a water absorption / distribution layer 14008 may be optional, and that the nitric oxide source layer 14002 may be disposed in direct contact with the active agent layer. In certain embodiments, the nitric oxide source layer 14002 may need to be packaged in a separate pouch so that it cannot come into contact with the rest of the dressing before activation is required. Also, as will be appreciated by those skilled in the art, such a dressing 14000 may include a cover layer 14010, such as those disclosed herein, to seal the dressing. In certain embodiments, the nitric oxide source may be tethered directly to a standard wound dressing, such as those disclosed herein. Such a nitric oxide source may be folded beneath a standard wound dressing such that nitric oxide is delivered to the wound and / or intact tissue.

[0117] 13A-13F illustrate an embodiment of a wound dressing 15000 similar to the dressings of FIGS. 4, 5, and 11A-11D, including a cover layer 15002 as disclosed herein, an active agent layer 15004 as disclosed herein, and a nitric oxide source layer 15008 as disclosed herein. In certain embodiments, a separation layer 15006 may be positioned between the nitric oxide source layer 15008 and the active agent layer 15004, thereby preventing contact between the nitric oxide source layer 15008 and the active agent layer 15004 while the separation layer 15004 is in place. The separation layer 15004 may be constructed from any suitable material disclosed herein, such as a film, that may prevent interaction between the active agent layer 15004 and the nitric oxide source layer 15008. Once separation layer 15006 is removed, the activator layer and the nitric oxide source layer can then come into contact, thereby generating nitric oxide as described elsewhere herein. Those skilled in the art will appreciate that such an arrangement can be similar to a removable tab on an electronic or battery-operated device.

[0118] Those skilled in the art will understand that separation layers, such as those described above in connection with FIGS. 13A-13F , and any separation layers described herein, can be altered in various suitable ways to allow interaction between the nitric oxide source layer and the active agent layer in addition to simply being removed. For example, the separation layer can generally be biodegradable and / or degradable, such that the active agent layer and the nitric oxide layer can interact when the separation layer is degraded. The separation layer can be destroyed via interaction with acid or enzymes. The separation layer can be a temperature-reversible gel to become more molten, thereby allowing interaction between the active agent layer and the nitric oxide source layer. The separation layer can be dissolvable, such that the layer dissolves upon interaction with wound exudate. In certain embodiments, the separation layer can be bioabsorbable. The separation layer can be passivated in a suitable manner to allow interaction between the active agent layer and the nitric oxide layer. The separation layer can be thermally decomposed / melted. Finally, those skilled in the art will understand that the separation layer can be removed in any suitable manner, such as partially or completely at a time. Moreover, one skilled in the art will understand that such a separation layer may incorporate some of all of these options into a single separation layer, for example, the separation layer may be partially removable by mechanical means but degradable.

[0119] In certain embodiments, the dressing may be in the form of a skin having an adhesive wound contact layer, such as those disclosed herein, and a cover layer having one edge with a pull tab extending to the outside of the dressing. Within the skin, a nitric oxide source layer (such as sodium nitrite) may be adhered to the wound contact layer, covered by the pull tab with an active agent layer on the top side of the film layer. During use, the pull tab may be removed, and the skin may be secured to the wound and / or skin surface using a sealing strip to cover the area where the pull tab was removed. Once the pull tab is removed, the active agent layer and the nitric oxide source layer may then interact, thereby generating nitric oxide for delivery to the wound and / or skin.

[0120] In some embodiments, the nitric oxide-generating reaction can be pressure-activated through the use of a capsule configuration. For example, a nitric oxide source (such as those disclosed herein) can be encapsulated by a separating layer that prevents interaction between the nitric oxide source and the active agent source (such as those disclosed herein) and placed within an active agent source, such as a hydrogel. Applying pressure to the combination can rupture the capsule, thus initiating nitric oxide production. In certain embodiments, the active agent source can be encapsulated and surrounded by the nitric oxide source. Alternatively, the capsule material can be degraded by fluids such as wound exudate; such degradable materials can degrade quickly or slowly over an appropriate time scale. Once the capsule is sufficiently degraded, the nitric oxide source and the active agent source can then interact to generate nitric oxide. Those skilled in the art will understand that such an approach can be applied to multiple configurations within a wound dressing, such as walled area(s) of nitric oxide-providing or active agent material, multiple capsules / beads, or other suitable configurations.

[0121] FIG. 13B illustrates one embodiment of a wound dressing 15100 similar to the dressing 15000 of FIG. 13A and the same dressing 15101 after removal of the separation layer 15106. The wound dressings 15100, 15101 include a top film or cover layer 1502 on top of the dressing, similar to the cover layers disclosed herein. The wound contact layer 15110, similar to the other wound contact layers disclosed herein, may be positioned underneath the dressing and may include a handle (not shown) that can be removed prior to placing the dressing. Similar to the cover layers disclosed herein, the underside of the cover layer may be covered with a pattern-spread pressure-sensitive adhesive or any suitable adhesive disclosed herein. The pattern-spread adhesive allows for breathability even after the separation layer 15106 is removed as in 15101. In certain embodiments, the separation layer 15106 can be positioned between the nitric oxide source layer 15108 and the active agent layer 15104, thereby preventing contact between the nitric oxide source layer 15108 and the active agent layer 15104 while the separation layer 15104 is in place. The active agent layer 15104 can be further surrounded by a stretchable polyester wrap 15103, such as described elsewhere herein. The separation layer 15106 can be constructed from any suitable material disclosed herein, such as a film, that can prevent interaction between the active agent layer 15104 and the nitric oxide source layer 15108. In certain embodiments, the separation layer can be folded once, twice, three times, four times, or more. The separation layer also includes a tab 15107 that can be pulled to remove the separation layer. Above the separation layer may be an upper frame layer 15112, which may be a film material such as those used for the cover layers disclosed herein, and may include adhesive only on the upper side so that the adhesive is not adhered to the top of the separation layer 15106, allowing the separation layer to be more easily removed. The upper frame 15114 further provides a window 15116 to allow interaction between the active agent layer 15104 and the nitric oxide source layer 15108. The lower frame 15114 may have only adhesive on the bottom surface, thereby presenting a non-adhesive top surface to the separation layer 15106 and allowing for ease of removal of the separation layer.The lower frame 15114 may also include a window 15116 to allow interaction between the activator layer 15104 and the nitric oxide source layer 15108 after removal of the separation layer. Once the separation layer 15106 is removed, the activator layer and the nitric oxide source layer may then contact as shown in 15101, thereby generating nitric oxide as described elsewhere herein. Also, once the separation film is removed, the top film or cover layer 15102 then seals the covering material (15118) as shown in 15101. Those skilled in the art will appreciate that such an arrangement may be similar to a removable tab on an electronic or battery-powered device. The embodiment of FIG. 13B was used to generate the example data in FIG. 8B above.

[0122] Figure 13C is an enlarged version of the dressing 5100 of Figure 13B showing the positioning of the adhesives 15118, 15120 to allow for ease of removal of the folded separation layer 5106. Figure 13D shows a top view of the dressing of Figures 13B and 13C showing the separation layer 15106, cover film 15102, and top frame 15112.

[0123] FIG. 13E illustrates an embodiment of a wound dressing 15200, 15201 similar to the dressing 15100 of FIGS. 15B-15D. Here, a nitric oxide source layer 5208 (which may be dry sodium nitrate mesh or sodium nitrate powder) may be surrounded by a water-soluble film skin 5214 (such as polyvinyl alcohol film or any suitable material disclosed herein), which may include one, two, three, four, or more layers of water-soluble film, with a gap 15212 underlying the wound contact layer 15210. In certain embodiments, the water-soluble film skin may be sealed with a cover layer film. In some embodiments, the gap is about 0.1-5, 0.5-3, 1-2, or 1 cm. 2When fluid enters the dressing, the water-soluble material may dissolve and, optionally, pass through the gaps, thereby allowing the nitric oxide layer to interact with the active agent layer 15204. As shown in 15201, a water-soluble film 15216 may be a layer separating the active agent layer from the nitric oxide source layer; when fluid enters the dressing, the film layer may dissolve, thereby allowing the active agent layer to interact with the nitric oxide source layer to generate nitric oxide. The embodiment of FIG. 13E was used to generate the example data of FIG. 8C, shown above.

[0124] Figure 13F illustrates an embodiment of a wound dressing 15300 similar to the dressings of Figures 13B-13D. Here, a nitric oxide source (such as a sodium nitrate solution) 15308 can be encapsulated in a bubble wrap structure. Manual pressure on the bubble wrap (such as via pressing with a finger or suitable tool) bursts the bubbles and releases the nitric oxide source, thereby allowing the nitric oxide source to interact with the active agent layer 15304 and release the nitric oxide.

[0125] Hydrogel nitric oxide source layer As described in WO / 2014 / 188174, which is incorporated herein by reference in its entirety, dressings utilized meshes saturated with an aqueous solution of sodium nitrite. Such wet meshes can be placed in contact with acid-containing hydrogels, as described above, to trigger the release of nitric oxide through the interaction of sodium nitrite with protons from the acid. However, controlling the precise dose of sodium nitrite delivered to the hydrogel can be difficult due to potential loss of sodium nitrite solution into the packaging containing the mesh and during transport to the hydrogel.

[0126] Figure 14 illustrates a wound dressing 16000 similar to the wound dressings of Figures 4, 5, 11A-11D, and 12-13, except that the cover layer and certain other layers are not shown. However, one skilled in the art will understand that any suitable layer disclosed herein, such as a cover layer, wound contact layer, masking layer, or moisture absorption / distribution layer, may be incorporated into wound dressing 16000. As will be appreciated by one skilled in the art, within a wound dressing such as wound dressing 16000, nitrite administration may be controlled to generate a specific dose of nitric oxide.

[0127] In embodiments, the wound dressing 16000 can include a hydrogel active agent layer 16002, such as those disclosed herein, adjacent to a hydrogel nitric oxide source layer 16004, where the hydrogel nitric oxide source layer comprises a non-acidic or weakly acidic hydrogel containing sodium nitrite or another suitable molecule. In certain embodiments, the two hydrogels can be initially kept separate and then placed together at the time of application. In some embodiments, the two hydrogels can be separated by a separating layer, such as those disclosed herein, to prevent interaction between the two hydrogels. One skilled in the art will appreciate that by contacting the nitric oxide source hydrogel 16004 with the active agent hydrogel, the concentrations of sodium nitrite from the nitric oxide source hydrogel and protons from the active agent hydrogel will equalize in the two hydrogels, tending to cause the sodium nitrite to interact with the protons of the active agent hydrogel and generate nitric oxide for delivery to the wound and / or skin. Those skilled in the art will appreciate that such hydrogels may be oriented in any suitable arrangement, such as a nitric oxide source hydrogel below an active agent hydrogel, or an active agent hydrogel below a nitric oxide source hydrogel, etc. In some instances, two hydrogels may be positioned side by side, or one hydrogel may be surrounded by the other.

[0128] In some embodiments, to facilitate delivery of nitric oxide to the wound, the wound-side hydrogel or both hydrogels can be perforated with holes or other suitable structures to increase surface area and facilitate interaction between the two hydrogels. For example, grooves on the surface of the hydrogel that contacts the other hydrogel can be used to release nitric oxide.

[0129] In certain embodiments, rather than forming a nitric oxide source hydrogel as a non-acidic hydrogel with sodium nitrite incorporated therein, powdered sodium nitrite can be evenly scattered across the surface of the non-acidic hydrogel where it will interact with the active agent hydrogel (e.g., the acid that provides the hydrogel). The high adhesiveness of the non-acidic hydrogel surface can preserve the entire dose if a relatively even distribution is achieved. Although an even distribution can avoid excessive overloading of the adhesive gel surface, in embodiments, sodium nitrite can be unevenly scattered across the surface of the non-acidic hydrogel. By controlling the amount of sodium nitrite available per unit area of the dressing, the precise dose of released nitric oxide can be controlled. In some embodiments, controlling the amount of sodium nitrite available per unit area can ensure the desired delivery of therapeutic levels of nitric oxide to all parts of the wound. For example, sodium nitrite can be applied in a range of about 0-100 mg / cm. 2 , about 20~80mg / cm 2 , 40-60mg / cm 2 , or about 50 mg / cm 2 may be incorporated in an amount of

[0130] Multi-part cladding 15A and 15B illustrate one embodiment of an active ingredient delivery dressing 17000 configured to deliver an active ingredient to a wound and / or skin surface, similar to the wound dressings of FIGS. 4, 5, 11A-11D, and 12-14. Those skilled in the art will appreciate that while the ingredient delivery device 17000 of FIGS. 15A and 15B may be configured to deliver nitric oxide to a wound and / or skin surface, the embodiment of FIGS. 15A and 15B may deliver any suitable type of active ingredient and is not limited to the delivery of nitric oxide. In particular, the ingredient delivery dressing 17000 of FIGS. 15A and 15B is suitable for the delivery of active ingredients that require a reaction to facilitate the production and / or delivery of the active ingredient. For example, the active ingredient may be a molecule that has a healing effect or some other positive physiological effect on the wound and / or skin.

[0131] In embodiments, the active ingredient platform 17002 may be configured to contact the wound and / or skin surface. The active ingredient platform 17002 may include an adhesive frame 17004 configured to adhere the active ingredient platform 17002 to the wound and / or skin surface and / or to another platform, such as the reactive platform 17008. The adhesive frame may be constructed from any suitable material disclosed herein, such as the material from which the wound contact layer disclosed herein is constructed. The dosing portion 17006 of the active ingredient platform 17002 may be rectangular, oval, square, polygonal, or any suitable shape. In embodiments, the dosing portion may include a hydrophilic material doped with the active ingredient. The dosing portion may be solid or liquid.

[0132] In some embodiments, the active ingredient delivery dressing 17000 can include a reactive platform 17008, which can include an adhesive frame 17010, which can be constructed from any suitable material disclosed herein, such as the material from which the cover layer disclosed herein is constructed. The reactive portion 17012 of the reactive platform 17008 can include a substance, such as an active absorbent, such as a gel, that activates the active ingredient so that it can be delivered to the wound and / or skin surface when combined with the administration portion 17006 of the active ingredient platform. The reactive portion can be a solid or a liquid.

[0133] 15B, in embodiments, when delivery to a wound and / or skin is desired, the active ingredient platform may be adhered to the wound and / or skin surface, and the reactive platform may be placed on the active ingredient platform and sealed together to facilitate a reaction between the reactive moiety and the active ingredient moiety to generate the active ingredient for delivery to the wound. As will be appreciated by one of ordinary skill in the art, in embodiments, the active ingredient of the dosing portion 17006 may not be activated for delivery to the wound until after interaction with the active portion 17012. However, in some embodiments, the dosing portion 17006 may deliver some amount of the active ingredient prior to activation by the reactive moiety.

[0134] In some embodiments, the reactive platform can be removed from the active ingredient platform, for example, by peeling, and reapplied for re-administration to the wound and / or skin without disrupting the wound and / or skin. The active ingredient delivery dressing may also allow a physician the ability to access the wound area without complete removal of the dressing, such as via swabbing and / or via the administration portion.

[0135] Nitric oxide generating coating layer Figures 16 and 17 illustrate a wound dressing 14100 having a nitric oxide-generating layer. Wound dressing 14100 may be similar to the wound dressings of Figures 4, 5, and 11A-13A, such as dressing 12000. Wound dressing 14000 may include a cover layer 14200, an acid-providing layer 14400, and a nitrite-providing layer 14600, each of which may be similar to cover layer 12200, active agent layer or acid-providing layer 12400, and nitric oxide source layer or nitrite-providing layer 12600, respectively.

[0136] The cover layer 14200 may be similar to the cover layer 12200. The cover layer 14200 may have a length and width that is greater than the other layers 14400, 14600, 14800 such that the cover layer 14200 defines a boundary region that extends between the periphery of the other layers and the periphery of the cover layer 14200. The boundary region of the cover layer 14200 may attach to the skin around the wound to form a seal such that wound exudate may be contained within the wound dressing 14100.

[0137] In the illustrated embodiment, the wound dressing 14100 further includes a water absorption / distribution layer 14800. The water absorption / distribution layer 14800 may be constructed to advantageously wick fluid, such as wound exudate, horizontally as it is absorbed through the layers of the dressing 14100. Such lateral wicking of fluid may allow for maximum distribution of fluid through the acid donating layer 14400, allowing the acid donating layer 14400 to reach its full holding capacity. Furthermore, the water absorption / distribution layer 14800 may facilitate the production of nitric oxide because nitrite ions dissolved in liquid may spread more quickly across the surface of the acid donating layer 14400. Some embodiments of the water absorption / distribution layer 14800 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these, and the material may be needle punched. Some embodiments of the moisture absorption / distribution layer 14800 may comprise cellulose in the range of 3 to 200 grams per square meter (gsm) (or about 3 to about 200 gsm), 5 to 190 gsm (or about 5 to about 190 gsm), 10 to 180 gsm (or about 10 to about 180 gsm), 20 to 170 gsm (or about 20 to about 170 gsm), or 40 to 160 gsm (or about 40 to about 160 gsm), for example, 80 (or about 80) gsm. Some embodiments of the moisture absorption distribution layer 14800 may comprise polyethylene in the range of 3 to 200 gsm (or about 3 to about 200 gsm), 5 to 190 gsm (or about 5 to about 190 gsm), 10 to 180 gsm (or about 10 to about 180 gsm), 20 to 170 gsm (or about 20 to about 170 gsm), or 40 to 150 gsm. In some embodiments, the moisture absorption 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 0.1 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 moisture absorption distribution layer 14800 may be constructed from a material that will withstand compression under the levels of negative pressure typically applied during negative pressure therapy.

[0138] The water absorption / distribution layer 14800 may comprise a plurality of loosely wrapped fibers that may be arranged in a substantially horizontal fibrous network. In some embodiments, the water absorption / distribution layer 14800 may be comprised of a blend of two fiber types. One may be a flat fiber that may be 20 μm to 50 μm wide, or about 20 μm to about 50 μm wide, and may comprise a cellulosic material. The other fiber may be a bicomponent fiber having an inner core that is 8 μm to 10 μm in diameter, about 8 μm to about 10 μm in diameter, 7 μm to 11 μm in diameter, 6 μm to 12 μm in diameter, or 5 μm to 13 μm in diameter, and an outer layer that is 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm thick. The bicomponent fiber may be a blend of polyethylene (PE) type material and polyethylene terephthalate (PET). In some embodiments, the inner core of the bicomponent fiber may be PET and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may comprise about 60% to about 90% cellulose fibers, e.g., approximately 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, e.g., about 25% PE / PET fibers. In some embodiments, the moisture absorption / distribution layer 14800 may comprise split microfibers.

[0139] A majority of the fiber volume may extend horizontally (i.e., parallel to the planes of the top and bottom surfaces of the material), or substantially or nearly horizontally. In other embodiments, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In other embodiments, all or substantially all of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some embodiments, a majority of the fibers, 80% to 90% (or about 80% to about 90%) or more, or even all or substantially all of the fibers span a distance perpendicular to the thickness of the water absorption-distribution layer 14800 (a horizontal or lateral distance) that is greater than the thickness of the water absorption-distribution layer 14800. In some embodiments, the horizontal or lateral distance spanned by such fibers is at or about 2 times or more, 3 times or more, 4 times or more, 5 times or more, or 10 times or more the thickness of the water absorption / distribution layer 14800. Such fiber orientation may promote lateral wicking of fluid through the water absorption / distribution layer 14800. This may cause fluids, such as wound exudate, to be more evenly distributed throughout the water absorption / distribution layer 14800. In some embodiments, the ratio of the amount of fluid wicked laterally across the water absorption / distribution layer 14800 to the amount of fluid wicked vertically through the water absorption / distribution layer 14800 under negative pressure may be at or about 2:1 or more, or in some embodiments, up to at or about 10:1 or more.

[0140] In some embodiments, at least a portion of the fiber volume of the water absorption / distribution layer 14800 may extend vertically (i.e., perpendicular to the plane of the top and bottom surfaces of the material), or substantially or nearly 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%, more than 80%, or more than 90% of the fiber volume may extend vertically, or substantially or nearly vertically. Such fiber orientation may facilitate vertical wicking of fluid through the water absorption / distribution layer 14800. In some embodiments, the ratio of the amount of fluid wicked vertically across the water absorption / distribution layer 14800 to the amount of fluid wicked laterally through the water absorption / distribution layer 14800 under negative pressure may be 2:1 or greater, or about 2:1 or greater, or in some embodiments, up to 10:1 or greater, or about 10:1 or greater.

[0141] In some embodiments, the water absorption / distribution layer 14800 may be positioned below the acid-providing layer 14400, as shown in Figures 16 and 17. In some embodiments, the water absorption / distribution layer 14800 may be positioned above the acid-providing layer 14400.

[0142] The wound dressing 14100 may further include a masking or concealing layer 14900 to prevent visualization of the wound or wound exudate through the cover layer 14200 or the acid-providing layer 14400. The masking or concealing layer 14900 may be positioned under at least a portion of the cover layer 14200. In some embodiments, the masking or concealing layer 14900 may be positioned on top of the cover layer 14200. In some embodiments, the concealing layer 14900 may have any of the same features, materials, or other details of any of the other embodiments of the concealing layer disclosed herein, including, but not limited to, having an optional viewing window or hole. Examples of wound dressings with concealing layers and viewing windows are described in International Patent Publication Nos. WO 2013 / 007973 and WO 2014 / 020440, which are incorporated by reference in their entireties. Additionally, the obscuring layer 14900 may be positioned directly below or above the cover layer, or adjacent to any other dressing layer desired. In the illustrated embodiment, the obscuring layer 14900 is positioned between the cover layer 14200 and the acid-providing layer 14400. In some embodiments, the obscuring layer 14900 may be adhered to the cover layer or integrally formed with the cover layer 14200. The obscuring layer 14900 may have approximately the same size and shape as the acid-providing layer 14400 and be configured to overlay it. Thus, in these embodiments, the obscuring layer 14900 will be the same or smaller in area than the cover layer 14200. In some embodiments, the masking or obscuring layer 14900 may wick fluid horizontally and / or vertically and may also function as a moisture distribution layer. In some embodiments, the cover layer 14200 may be partially or completely opaque or colored so that the cover layer 14200 may act as a masking or concealing layer to prevent visualization of the wound or wound exudate through the cover layer 14200 and / or to prevent visualization of layers below the cover layer 14200.

[0143] Material layer having a hydrogel layer As described elsewhere herein, acid-donating layers 12400 and 14400 may be constructed from a gel, such as a hydrogel. In embodiments, the hydrogel may have a tacky surface with adhesive properties, and in some configurations, it may be desirable to reduce the stickiness of the hydrogel of the acid-donating layer, such as the acid-donating layers described above and further herein, to improve acid-donating hydrogel layer and ease of handling.

[0144] In some embodiments, the acid-donating hydrogel layer 14400 may include one or more material layers 14420 as shielding layers to mask at least a portion of the adhesive properties of the hydrogel. The material layer(s) 14420 may be applied to the wound-facing underside of the acid-donating hydrogel layer 14400 and / or to at least a portion of the upper, non-wound-facing side of the hydrogel layer 14400. In some embodiments, the hydrogel layer may be completely encapsulated by the material layer. In some embodiments, the material layer may cover the entire upper and / or lower sides of the hydrogel layer. In some embodiments, the material layer may at least partially cover the upper and / or lower sides 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 and / or lower sides of the hydrogel layer. Partial coverage of the hydrogel layer by the material layer may allow for a limited level of adhesion through partial masking.

[0145] In some embodiments, the material layer can be constructed from a suitable net, mesh, knit, woven, or nonwoven material. In some embodiments, the material layer can be constructed from polypropylene, polyester, or combinations / copolymers thereof. The material layer can be permeable to fluids, such as water or wound exudate, so that the acid-providing hydrogel layer can absorb wound exudate and / or the acid groups of the acid-providing hydrogel layer can react with nitrite ions to produce nitric oxide.

[0146] Although hydrogels have adhesive properties, in embodiments, the material layer may not be attached to the hydrogel layer solely by its adhesive properties. In certain hydrogel examples, the adhesive properties of the hydrogel may be reduced or lost when the hydrogel absorbs fluids, such as wound exudate. Therefore, the material layer may need to be secured to the hydrogel layer via additional suitable means. For example, the material layer may be secured to the hydrogel layer through the use of flexible strings, staples, or by suturing the material layer to the hydrogel. In some embodiments, the hydrogel layer may be encapsulated within a bag formed by the material layer.

[0147] In some embodiments, a material layer can be physically implanted or secured to a hydrogel layer during the formation and / or curing of the hydrogel layer. FIG. 18 illustrates a process for physically implanting or adhering a material layer within or onto a hydrogel layer during the formation of the hydrogel layer, according to some embodiments. As illustrated in FIG. 18 , material layer 16200 can be positioned in mold 16400 to cure the hydrogel layer, for example, at the bottom of mold 16400. Prior to being positioned in mold 16400, material layer 16200 can be pre-treated to be hydrophilic, for example, with a wetting agent to improve affinity with the hydrogel prepolymer.

[0148] After the material layer 16200 is positioned at the bottom of the mold 16400, a first portion of hydrogel prepolymer can be added. When the first portion of hydrogel prepolymer is added, the pre-treated material layer 16200 can be substantially wetted with the first portion of hydrogel prepolymer. The pre-treated material layer 16200 positioned at the bottom of the mold 16400 further facilitates lateral spreading of the hydrogel prepolymer, and the bottom of the mold 16400 can also be substantially wetted with a continuous layer of the first portion of hydrogel prepolymer. After the first portion of hydrogel prepolymer is added, the material layer 16200 can rise from the bottom of the mold 16400 to the top of the hydrogel prepolymer. In some embodiments, the material layer 16200 can 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 material layer 16200 is raised, a first portion of hydrogel prepolymer may be cured to form first hydrogel layer 16500, and material layer 16200 may be secured on top of first hydrogel layer 16500, thereby masking the top side of the cured hydrogel. The first portion of hydrogel prepolymer may be UV coated from above, below, or both sides, or any other suitable method known in the art.

[0149] In some embodiments, after the first hydrogel layer 16500 is formed, a second portion of hydrogel prepolymer can be added to the mold over the first hydrogel layer 16500 and the material layer 16200. After the second portion of hydrogel prepolymer is added, the material layer 16200 can be encapsulated by the second portion of hydrogel prepolymer and the first hydrogel layer 16500. The material layer 16200 may not rise or float because it is fixed to the first hydrogel layer 16500. The second portion of hydrogel prepolymer can then be cured to form the second hydrogel layer 16700, and the material layer 16200 can be encapsulated by the hydrogel layers 16500 and 16700, which may be integrated into a single layer. The implanted material layer 16200, embedded within the integrated hydrogel layer formed by the hydrogel layers 16500 and 16700, can improve the structural integrity of the hydrogel layer. For example, when the hydrogel layer absorbs water, the hydrogel expands, and the material layer can act as a reinforcing layer to prevent the hydrogel from stretching and falling off. In some embodiments, the refractive index of the material layer and the hydrogel layer can be similar so 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 those skilled in the art and repeated later in this specification, the above description of methods for adding material layers to a hydrogel is not intended to be limiting and may be performed in any suitable order and may involve the addition or removal of certain steps. Figure 19 illustrates the process of physically grafting material layers onto both the top and bottom sides of a hydrogel layer during the formation of the hydrogel layer, according to some embodiments. However, those skilled in the art will understand that material layers may be added to only one side. As illustrated in FIG. 19, after the first hydrogel layer 16500 having the material layer 16200 is formed as described in connection with FIG. 18, it is removed from the mold 16400, inverted, and placed back into the mold 16400 so that the side of the hydrogel layer 16500 having the material layer 16200 faces the bottom of the mold 16400.Another material layer 16800 is then positioned on top of hydrogel layer 16500, after which a second portion of hydrogel prepolymer is added over hydrogel layer 16500 and material layer 16800. Material layer 16800 may float and rise to the top of the second portion of hydrogel prepolymer in a manner similar to material layer 16200 being suspended during the formation of hydrogel layer 16500, as described in connection with FIG. 18 . After material layer 16800 rises to the top of the second portion of hydrogel prepolymer, the second portion of hydrogel prepolymer may be cured to form hydrogel layer 16900 together with hydrogel layer 16500, and material layer 16800 may be fixed to the top of hydrogel layer 16900, thereby masking the upper side of hydrogel layer 16900. The second portion of hydrogel prepolymer can be cured by UV from the top, bottom, or both sides, or any other suitable method known in the art. As a result, hydrogel layer 16900 can be sandwiched between material layers 16200 and 16800, which are secured to hydrogel layer 16900.

[0150] Perforated hydrogel layer The acid-providing layer (e.g., a hydrogel layer) may include a plurality of perforations extending through the thickness of the acid-providing layer, as described elsewhere herein. The plurality of perforations may enable or facilitate the passage of wound exudate through the acid-providing layer such that wound exudate beneath or around the acid-providing layer may be transported to one or more additional absorbent and / or evaporative layer(s) (e.g., cover layers) above the acid-providing layer, thus preventing excessive accumulation of wound exudate beneath the acid-providing layer. Additionally, the plurality of perforations may provide an increased surface area of the acid-providing layer, thereby increasing the absorption rate of the acid-providing layer.

[0151] In some embodiments, the plurality of perforations may be formed after the acid-providing layer has hardened, for example, by punching holes from the acid-providing layer via ultrasonic perforation, via flame perforation, or via any other suitable method.

[0152] In some embodiments, multiple perforations can be formed during the formation of the acid-donating layer. For example, multiple perforations can be formed during the curing of the acid-donating layer. The perforations can be formed by guiding the location of the hydrogel prepolymer solution applied to the mold bottom or release sheet so that there are small areas where the hydrogel prepolymer solution is not applied. In some embodiments, a template with high surface energy (i.e., wettability) can be used in conjunction with a lower-surface-energy surface, such as a mold bottom or release sheet. The template can be perforated, and the hydrogel prepolymer solution can preferentially wet the template, excluding the perforations; the hydrogel prepolymer solution may not be positioned over the perforations in the template. Such a dispersed hydrogel prepolymer solution can form a perforated hydrogel layer when cured. The hydrogel prepolymer can be cured by UV or any other suitable method known in the art.

[0153] In some embodiments, the template may be hydrophilic or may be pretreated with a wetting agent to make it 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 a woven or nonwoven material, or any other suitable material. In some embodiments, the template may be constructed from a spunbond material. The perforations in the template may have a diameter of approximately 0.1 mm to 10 mm, 0.15 mm to 7 mm, 0.2 mm to 5 mm, 0.5 mm to 4 mm, or 0.7 mm to 3 mm.

[0154] 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 a perforated hydrogel layer, and the template may be secured to the top of the perforated hydrogel layer. A second portion of the hydrogel prepolymer may then 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 secured to the perforated hydrogel layer. The second portion of the hydrogel prepolymer may then 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.

[0155] In some embodiments, shielding layers, such as shielding layers 16200 and 16800, may be perforated and may serve as templates for perforated hydrogel layers. Such perforated hydrogel layers may be prepared according to methods similar to those described with respect to Figures 18 and 19.

[0156] In some embodiments, a template for a hydrogel layer can include multiple pillars, and a hydrogel prepolymer can be poured around the pillars and cured to form a hydrogel layer with perforations. In some embodiments, perforations or other patterns can be formed in the hydrogel layer by screen printing, or by laying down "fibers" of hydrogel using a die, spinneret, or electrospun process, followed by curing. The hydrogel prepolymer for these processes can include viscosity modifiers (e.g., thixotropic agents) and / or be placed on a hydrophobic release paper to limit the diffusion of the laid down prepolymer before curing.

[0157] Nitric oxide-generating wound dressing for treating peri-wound areas In some cases, stimulation of the periwound (skin surrounding the wound) and wound edge may play a role in initiating the wound healing process. In certain embodiments, the wound healing process may be activated through delivery of nitric oxide to the periwound and / or wound edge. Delivery of nitric oxide to the periwound and / or wound edge may target, for example, epithelial cell activity to promote epithelial tongue migration, vasodilation of the periwound skin microcirculation to promote perfusion by providing oxygen and nutrients, and angiogenesis to promote granulation tissue formation.

[0158] 20 and 21 illustrate a wound dressing 18000 for delivery of nitric oxide to the wound periphery and / or wound edges, according to some embodiments. Wound dressing 18000 may be similar to wound dressing 14100 of FIG. 16 and may include a cover layer 18200, an acid-providing layer 18400, a water-absorbing and distribution layer 18800, and a nitrite-providing layer 18600. The layers of wound dressing 18000 may be similar to the corresponding layers of wound dressings 14000 and / or 14100.

[0159] In the illustrated embodiment, the acid-providing layer 18400 is provided in a border region that encompasses the central absorbent material 18450. The acid-providing layer 18400 and the central absorbent material 18450 may or may not be attached to one another. In some embodiments, the acid-providing layer 18400 and the central absorbent material 18450 may be provided as a unitary component. The acid-providing layer 18400 may define a window in the center, and the central absorbent material 18450 may be shaped and / or sized to fit within the window of the acid-providing layer 18400.

[0160] The acid-providing layer 18400 may be constructed from materials similar to the acid-providing layers 12400 and 14400. For example, the acid-providing layer 18400 may be constructed from a hydrogel or xerogel and contain acidic groups or moieties. In some embodiments, the acid-providing layer 18400 may be constructed from a mesh, foam, gel, or any other material suitable for containing acidic groups or moieties. The acid-providing layer 18400 may provide an acidic environment to the boundary region of the wound dressing 18000, thereby generating nitric oxide from the boundary region of the wound dressing 18000 for delivery to the wound periphery or wound border. As illustrated in FIG. 21 , the acid-providing layer 18400 may be sized and / or positioned such that the acid-providing layer 18400 is positioned at least partially over the wound periphery 18920. Acid-donating layer 18400 may include a plurality of perforations or one or more layers of material, such as layers of material 16200 and 16800 described elsewhere herein.

[0161] In the illustrated embodiment, the acid-donating layer 18400 is frame-shaped. However, the acid-donating layer 18400 may have any other suitable shape or configuration. In some embodiments, the acid-donating layer 18400 may be provided as multiple acid-donating strips rather than as a frame-shaped layer, so that the acid-donating strips may be applied separately to the border region near the immediate wound perimeter. Each of the acid-donating strips may be positioned on a side of the wound to create an acid-donating layer 18400 that fits near the wound perimeter. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more acid-donating strips may be provided and / or applied around the wound perimeter. The acid-donating strips may be constructed from the same materials as the acid-donating layers described herein.

[0162] The central absorbent material 18450 may be positioned over the wound to absorb wound exudate. For example, as illustrated in FIG. 21 , the central absorbent material 18450 may be sized and / or positioned such that the central absorbent material 18450 is positioned at least partially over the wound 18910. In some embodiments, the central absorbent material 18450 may be the same size as the wound or larger such that the central absorbent material 18450 completely covers the wound. In some embodiments, the central absorbent material 18450 may be smaller than the wound such that the acid-donating layer 18400 may be positioned near the wound edge.

[0163] The central absorbent material 18450 may comprise a foam or nonwoven natural or synthetic material, and may optionally comprise a superabsorbent material, to form a reservoir for fluids, particularly liquids removed from the wound site. In some embodiments, the central absorbent material 18450 may also assist in drawing fluids toward the cover layer 18200. The material of the central absorbent material 18450 may also prevent liquids collected within the wound dressing 18000 from flowing freely within the dressing, and preferably acts to contain any liquids collected within the dressing. The capacity of the absorbent material may be sufficient to manage the rate at which wound exudate flows when negative pressure is applied. In some embodiments, the central absorbent material 18450 may be selected to absorb liquids under negative pressure. Some materials exist that can absorb liquids when under negative pressure, such as superabsorbent materials. The central absorbent material 18450 may be made from ALLEVYN™ foam Freudenberg 114-224-4 or Chem-Posite™ 11C-450. In some embodiments, the central absorbent material 18450 may include superabsorbent powder, fibrous material such as cellulose, and bonding fibers. In some embodiments, the composite is an aeolian, thermally bonded composite. In some embodiments, the central absorbent material 18450 is a layer of nonwoven cellulose fibers with superabsorbent material in the form of dry particles dispersed throughout. The use of cellulose fibers may introduce a fast wicking element that helps quickly and evenly distribute liquid absorbed by the dressing. The parallel arrangement of multiple strand-like fibers may lead to strong capillary action in the fibrous pad, which helps distribute liquid. In this way, the superabsorbent material may more efficiently deliver liquid. In certain embodiments, wicking action may also help bring liquid into contact with the upper cover layer, helping to increase the dressing's evaporation rate.

[0164] The wound dressing 18000 further includes a frame layer 18100, which may further support the acid-donating layer 18400. The frame layer 18100 may be positioned on the wound-facing or bottom side of the dressing 18000 and may cover at least the border region of the wound dressing 18000. The frame layer 18100 may be a polyurethane layer or a polyethylene layer, or another suitable flexible layer. The frame layer 18100 has a lower surface and an upper surface. In some embodiments, at least a portion of the upper surface of the frame layer 18100 is attached to the cover layer 18200. In some embodiments, at least a portion of the lower surface of the frame layer 18100 may be attached to the skin surrounding the wound. In some embodiments, the frame layer 18100 includes a window 18110 to enable fluid communication between the nitrite-donating layer 18600 and the other layers of the wound dressing 18000. In some embodiments, the window 18110 has a size the same as or larger than the nitrite-providing layer 18600 such that the nitrite-providing layer 18600 is positioned within the window 18110. In some embodiments, the frame layer 18100 is positioned below the water absorption and distribution layer 18800 and / or the acid-providing layer 18400. In some embodiments, the water absorption and distribution layer 18800 and / or the acid-providing layer 18400 are completely surrounded by the cover layer 18200 and frame layer 18100, except for the window 18110. In some configurations, the frame layer 18100 may help maintain the integrity of the entire dressing 18000 while also forming a fluid-tight seal around the wound.

[0165] In some embodiments, the acid-providing material may be provided as a dispensable composition, such as a prepolymer solution or another moldable form, instead of being provided as the acid-providing layer 18400, so that it can be applied more freely around the wound. For example, the acid-providing material may be provided as a gel prepolymer solution so that it can be closely applied around wounds having irregular shapes and sizes by a clinician. In some embodiments, the acid-providing material, such as a gel prepolymer solution, may be provided in a syringe and / or applied using a syringe, and the gel prepolymer solution may have a viscosity suitable for dispensing from a syringe. The acid-providing material may also be formulated so that it can be rapidly cured and no longer flowable once applied around the wound. The acid-providing material may include an evaporating solvent, such as isopropanol. The acid-providing material may have a suitable secondary cure mechanism, such as photoinitiated acrylate functionality. In some embodiments, the acid-providing material may include a material that can expand and bond together when contacted with wound fluid or moisture, such as a methacrylate. In some embodiments, the acid-providing material may be provided as a reactive two-part system. For example, a first part including an isocyanate and a second part including water or a polyol may be provided to be mixed immediately prior to dispensing to result in urethane formation. In some embodiments, the first and second parts may be oppositely charged flowable gels that interact upon mixing to provide a substantially non-flowing gel. In some embodiments, the acid-providing material may include a material, such as a gel, that changes in response to a change in environment. For example, the acid-providing material may include a material, such as certain Pluronics®, that may harden upon a change in temperature when applied to the skin from a dispenser or syringe. The acid-providing material may be applied such that it can interact with nitrite from the nitrite-providing layer 18600 to generate nitric oxide. Once the acid-providing material has been applied and hardened or otherwise becomes non-flowing, the cover layer 18200 may be applied.

[0166] In some embodiments, nitrite ions or nitrite salts may be provided as a dispensable composition instead of or in addition to the nitrite-providing layer 18600, in a manner similar to the acid-providing material described herein. In some embodiments, both the acid-providing material and the nitrite ions or nitrite salt may be provided as one or more dispensable compositions so that they can be applied more freely around the wound. For example, in a two-part system, a first part may contain an acid-providing material such as a gel prepolymer solution, and a second part may contain nitrite ions or nitrite salts. The first and second parts may be mixed and dispensed cooperatively around the wound, thereby generating nitric oxide. In some embodiments, a static mixer, such as a dual-barrel syringe with a mixing head, may be used. The first and second parts may have a viscosity suitable for dispensing from a syringe. The first and second parts may also be formulated so that they can harden rapidly and no longer flow once applied around the wound. Either or both of the first and second parts may contain an evaporative solvent, such as isopropanol. Either or both of the first and second parts may have a suitable secondary cure mechanism, such as photoinitiated acrylate functionality. In some embodiments, the acid-providing material may include a material, such as a methacrylate, that can expand and bond together upon contact with wound fluid or moisture. In some embodiments, the first and second parts may be provided as a reactive two-part system. For example, a first part including an isocyanate and a second part including water or a polyol may be provided to be mixed immediately prior to dispensing to result in urethane formation. In some embodiments, the first and second parts may be oppositely charged flowable gels that interact upon mixing to provide a substantially non-flowing gel. In some embodiments, the first and / or second parts may include a material, such as a gel, that changes in response to changes in the environment. For example, the first and / or second parts may include a material, such as certain Pluronics®, that can cure upon temperature changes when applied to the skin from a dispenser or syringe.Once the first and second parts have been mixed, applied, cured, or otherwise made non-flowable, the cover layer 18200 may be applied.

[0167] term The above patents and specifications and other references, including any that may be listed in accompanying application documents, are incorporated herein by reference. Aspects of the present disclosure can be modified, if necessary, to provide still further embodiments using the systems, functions, and concepts of the various references described herein.

[0168] It should be understood that a feature, material, characteristic, or group described in connection with a particular aspect, embodiment, or example may be applied to any other aspect, embodiment, or example described herein, unless it is inconsistent with that aspect, embodiment, or example. All features disclosed in this specification (including any accompanying claims, abstract, and drawings), or all steps of any method or process similarly disclosed, may be combined in any combination, except combinations in which at least some of such features or steps are mutually exclusive. Protection is not limited to the details of any of the foregoing embodiments. Protection extends to any novel, or any novel combination, of features disclosed in this specification (including any accompanying claims, abstract, and drawings), or any novel, or any novel combination of steps of any method or process similarly disclosed.

[0169] While certain specific embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the protected subject matter. Indeed, the novel methods and systems described herein may be embodied in a variety of other forms. Additionally, various omissions, substitutions, and changes may be made in the form of the methods and systems described herein. Those skilled in the art will appreciate that, in some embodiments, the actual steps performed in the illustrated or disclosed processes may differ from those shown in the drawings. In some embodiments, certain of the steps described above may be omitted, or others may be added. For example, the actual steps or order of steps performed in the disclosed processes may differ from those shown in the drawings. In some embodiments, certain of the steps described above may be omitted, or others may be added. Furthermore, the features and characteristics of the specific embodiments disclosed above may be combined in different ways to form additional embodiments, all of which are within the scope of the present disclosure.

[0170] While the present disclosure includes certain specific embodiments, examples, and applications, those skilled in the art will recognize that the present disclosure extends beyond the specifically disclosed embodiments to other alternative embodiments or uses, and obvious variations and equivalents thereof, including embodiments that may not provide all of the features and advantages described herein. Accordingly, the scope of the present disclosure is not intended to be limited by the described embodiments, but may be defined by the claims presented herein or hereafter.

[0171] Conditional language such as "can," "could," "might," or "may," unless specifically stated otherwise or interpreted otherwise within the context of use, is typically intended to convey that certain embodiments include certain features, elements, or steps, while other embodiments do not. Thus, such conditional language is not generally intended to imply that features, elements, or steps are required in any way for one or more embodiments, or that one or more embodiments necessarily include logic for determining, with or without user input or instruction, whether those features, elements, or steps are included in or should be performed in any particular embodiment. Terms such as "comprise," "include," and "have" are synonymous and used in an inclusive, open-ended manner and do not exclude additional elements, features, acts, operations, etc. The term "or" is also used in an inclusive sense (rather than an exclusive sense), such that, for example, when used to connect a list of elements, the term "or" means one, some, or all of the elements in the list. Similarly, the term "and / or," in reference to a list of two or more items, encompasses 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. Additionally, the term "each," as used herein, in addition to having its ordinary meaning, can also refer to any subset of the list of elements to which the term "each" is applied. Furthermore, as used herein, the words "herein," "above," "below," and similar words, when used in this application, are meant to refer to the specification as a whole, and not to specific portions of the specification.

[0172] Conjunctive phrases such as "at least one of X, Y, and Z," unless specifically stated otherwise, are to be construed otherwise in accordance with the context in which they are generally used to suggest that an item, term, etc. can be either X, Y, or Z. Thus, such conjunctive phrases are generally not intended to suggest that a particular embodiment requires the presence of at least one X, at least one Y, and at least one Z.

[0173] As used herein, language expressing degrees, such as the terms "approximately," "about," "generally," and "substantially," refers to a value, amount, or characteristic that is close to a given value, amount, or characteristic that still performs a desired function or produces a desired result. For example, the terms "approximately," "about," "generally," and "substantially" can refer to an amount that is within less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of a given amount. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" refer to a value, amount, or characteristic that deviates from exactly parallel by no more than 15 degrees, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degrees.

[0174] Any of the embodiments described herein can be used with or without a canister. Any of the dressing embodiments described herein can absorb and store wound exudate.

[0175] The scope of the present disclosure is not intended to be limited by the description of particular embodiments, but may be defined by the claims, which claim language should be interpreted broadly based on the language used in the claims and not limited to the examples described herein or during the prosecution of this application, which examples should be interpreted as non-exclusive.

[0176] Various modifications to the embodiments described in this disclosure may be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the spirit or scope of the disclosure. Thus, the disclosure is not intended to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and features disclosed herein. Certain embodiments of the disclosure are covered by the set of claims listed below or presented below.

[0177] Particular embodiments of the present disclosure are encompassed by the claims presented at the end of this specification or by other claims presented later.

Claims

1. 1. A wound dressing for treating a wound, comprising: a breathable cover layer; an activator layer positioned below the cover layer; a nitric oxide source layer; a separation layer positioned between the active agent layer and the nitric oxide source layer, the separation layer configured to prevent contact between the active agent layer and the nitric oxide source layer; and A wound dressing comprising:

2. 2. The wound dressing of claim 1, wherein the separation layer comprises a tab, the tab being configured to be removed from the wound dressing, such that upon removal of the tab, contact occurs between the active agent layer and the nitric oxide source layer.

3. 2. The wound dressing of claim 1, wherein the separation layer comprises a degradable material configured such that contact occurs between the active agent layer and the nitric oxide source layer when the degradable material is degraded.

4. 1. A wound dressing for treating a wound, comprising: a cover layer configured to form a seal around the wound; a nitrite providing layer containing nitrite; an acid providing layer located below the cover layer, the acid providing layer including acidic groups, the acid providing layer including a window in the center of the acid providing layer; a central absorbent material for absorbing wound exudate, said central absorbent material being positioned within said window of said acid-donating layer; A wound dressing comprising:

5. 5. The wound dressing of claim 4, wherein the acid-providing layer is configured to be positioned on the skin surrounding the wound or on the edges of the wound when the wound dressing is applied to the wound.

6. 6. A wound dressing according to claim 4 or 5, wherein the central absorbent material is configured to be positioned over the wound when the wound dressing is applied to the wound.

7. A wound dressing according to any one of claims 4 to 6, wherein the central absorbent material is completely enclosed by the acid-providing layer.

8. 8. A wound dressing according to any one of claims 4 to 7, further comprising a moisture distribution layer configured to wick fluid horizontally.

9. 9. The wound dressing of claim 4, further comprising a frame layer positioned below the acid-providing layer, the frame layer defining a window in the center of the frame layer.

10. 10. The wound dressing of claim 9, wherein the frame layer is configured to be attached to the skin surrounding the wound.

11. 11. The wound dressing of claim 9 or 10, wherein the frame layer is attached to the cover layer.

12. A wound dressing according to any one of claims 9 to 11, wherein the nitrite-providing layer is positioned within the window of the frame layer.

13. A wound dressing according to any one of claims 4 to 12, wherein the acid-providing layer comprises a xerogel or a hydrogel.

14. 1. A wound dressing for treating a wound, comprising: a cover layer configured to form a seal around the wound; a nitrite providing layer containing nitrite; an acid providing layer located below the cover layer, the acid providing layer including acidic groups, the acid providing layer including a window in the center of the acid providing layer; A wound dressing comprising:

15. 15. The wound dressing of claim 14, wherein the acid-providing layer is configured to be positioned on the skin surrounding the wound or on the edges of the wound when the wound dressing is applied to the wound.

16. 16. A wound dressing according to claim 14 or 15, further comprising a moisture distribution layer configured to wick fluid horizontally.

17. 17. The wound dressing of any one of claims 14 to 16, further comprising a frame layer positioned below the acid-providing layer, the frame layer defining a window in the center of the frame layer.

18. 18. The wound dressing of claim 17, wherein the frame layer is configured to be attached to the skin surrounding the wound.

19. 19. The wound dressing of claim 17 or 18, wherein the nitrite-providing layer is positioned within the window of the frame layer.

20. 20. The wound dressing of any one of claims 14 to 19, wherein the acid-providing layer comprises a xerogel or a hydrogel.

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