Trauma Covering Material

Abstract

The disclosed embodiments relate to wound dressings capable of generating nitric oxide. The wound dressings may include combinable components, including a mesh component comprising a nitrite-providing layer and a composite component comprising an activator layer, such as an acid-providing layer. The activator layer may contain acidic groups and may be a hydrogel, xerogel, or other suitable material. The nitric oxide source layer may contain nitrite. The wound dressings may include a one-piece application embodiment, in which the mesh and composite components can be combined by removing a separating component. Alternatively, the wound dressings may include a two-piece application embodiment in which the mesh component is inserted into a composite pocket.

Description

Technical Field

[0001] Materials, devices, methods, and systems such as therapeutic compositions, wound care materials, their uses, and methods of treatment using them are disclosed herein. In some embodiments, the materials, devices, and systems described herein include wound dressings configured for the delivery of nitric oxide (NO) and / or the delivery of other active agents.

Background Art

[0002] Description of Related Art Nitric oxide (NO) is a well-known molecule with multiple biological functions. For example, nitric oxide affects vasodilation of blood vessels, stimulates angiogenesis, affects the host immune response, and exhibits a potent broad-spectrum of antibacterial and anti-biofilm activities. Due to these multiple roles, NO exhibits a strong effect on tissues, and an increase in the amount of NO can support the acceleration of healing in wounds, particularly chronic wounds.

[0003] Furthermore, diabetic patients often have lower levels of nitric oxide compared to healthy patients, and a decrease in the supply of nitric oxide in diabetic patients is a worsening factor in healing chronic ulcers. A decrease in the supply of nitric oxide can lead to vascular damage such as endothelial dysfunction and vascular inflammation. Vascular damage can also potentially lead to a decrease in blood flow to the extremities, thereby increasing the likelihood that diabetic patients will develop neuropathy and non-healing ulcers, and increasing the risk of lower limb amputation.

[0004] Therefore, there is a need for an improved mechanism for delivering an effective dose of nitric oxide to the wound. Under normal conditions, nitric oxide (NO), as a free radical, is short-lived and is converted to a more stable chemical species within seconds of its generation. For example, when gaseous nitric oxide comes into contact with air, it is rapidly oxidized to produce nitrogen dioxide (NO2). Therefore, it can be difficult to maintain high concentrations of nitric oxide over long periods within wound dressings or other similar structures. Thus, 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 is the mechanism for delivering nitric oxide in combination with the use of wound dressings, especially negative pressure wound dressings, and / or during negative pressure wound therapy and / or other appropriate therapies. [Overview of the Initiative]

[0005] Embodiments of this disclosure relate to materials, devices, methods, and systems for wound treatment. Some of the disclosed embodiments relate to materials, devices, methods, and systems for delivering nitric oxide to a wound. Those skilled in the art will understand that the applications of the materials, devices, methods, and systems described herein are not limited to specific tissues or specific injuries.

[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 activator layer, a dry nitric oxide source layer, a dry nitric oxide source layer that is free of or relatively free of liquid, and a water absorption / distributing layer.

[0007] In some embodiments, a wound dressing for treating a wound is provided, which may be a two-piece application comprising combinatorial components, the combinatorial components comprising a pocket composed of one or more composite layers and an insertable mesh component comprising a nitrite-providing layer. In some embodiments, the insertion of the mesh component into the pocket may be configured to generate nitric oxide. In some embodiments, the composite layer comprises a gelled fiber substrate loaded with an activator gel. In some embodiments, the activator gel may comprise a hydrogel. In some embodiments, the activator gel may comprise an acidic group or portion. In some embodiments, the wound dressing may be configured to generate nitric oxide when the wound dressing interacts with a fluid. In some embodiments, the fluid may be provided from a group consisting of an aqueous environment of a hydrogel, wound exudate, and ampoules of separately provided aqueous reagents. In some embodiments, the mesh component may be embedded with a nitric oxide precursor. In some embodiments, the mesh component may be embedded with sodium nitrite. In some embodiments, the pocket may be formed by attaching the sides of two composite layers together, or by attaching a composite layer to another layer of the covering material. In some embodiments, at least two sides of two composite layers may be attached together. In some embodiments, insertion of the mesh component into the pocket may be achieved using an insertion device. In some embodiments, the insertion device may be configured to control the depth to which the mesh component is positioned within the pocket, preventing over-insertion or protrusion beyond the composite pocket. In some embodiments, the mesh component and the insertion device may be configured such that the mesh component fits around an expansion tab of the insertion device, and once the mesh component is loaded into the composite pocket, the insertion device is removed from the mesh component and discarded. In some embodiments, the covering material may further include an upper layer. In some embodiments, the covering material may further include a masking layer. In some embodiments, the upper layer, or masking layer, may act as a guide for inserting the mesh component into the pocket.In some embodiments, the pockets may be fixed to an upper layer or a masking layer. In some embodiments, the pockets may be configured to have openings configured for the insertion of mesh components. In some embodiments, one or more composite layers of the pocket may further contain antioxidants and / or reducing agents. In some embodiments, the mesh components may further contain antioxidants and / or reducing agents co-localized with a nitrite-providing layer. In some embodiments, one or more composite layers of the pocket may not further contain antioxidants and / or reducing agents. In some embodiments, the mesh components may be embedded in a suspension containing antioxidants and / or reducing agents, as well as a nitrite-providing layer, suspended in a water-miscible anhydrous carrier. In some embodiments, the antioxidants and / or reducing agents may be sodium isoascorbate.

[0008] In some embodiments, a wound dressing for treating a wound is provided, which may be an integral application comprising combinable components, the combinable components comprising a composite component further comprising an activator gel and a mesh component further comprising a nitrite-providing layer. In some embodiments, the integral application may be operated to combine the composite component and the mesh component before application of the wound dressing. In some embodiments, the combination of the composite component and the mesh component may be configured to produce nitric oxide. In some embodiments, the composite component may comprise a gelled fiber substrate loaded with an activator gel. In some embodiments, the activator gel may comprise a hydrogel. In some embodiments, the activator gel may comprise an acidic group or portion. In some embodiments, the wound dressing may be configured to produce nitric oxide when the wound dressing interacts with a fluid. In some embodiments, the fluid may be provided from a group consisting of an aqueous environment for the hydrogel, wound exudate, and ampoules of separately provided aqueous reagents. In some embodiments, the mesh component may be embedded with a nitric oxide precursor. In some embodiments, the mesh components may be embedded with sodium nitrite. In some embodiments, the mesh components and the composite layer may be separated from each other by a removable handle. In some embodiments, removal of the handle may allow the mesh components and the composite layer to be combined. In some embodiments, the wound dressing may also further comprise a top layer or cover layer. In some embodiments, the wound dressing may further comprise a masking layer. In some embodiments, the wound dressing may further comprise one or more adhesive layers. In some embodiments, the wound dressing may further comprise one or more film layers. In some embodiments, the wound dressing may be configured such that the mesh components are positioned close to the wound. In some embodiments, the wound dressing may be configured such that the composite components are positioned close to the wound. In some embodiments, the activator gel may further comprise antioxidants and / or reducing agents.In some embodiments, the mesh components may further comprise an antioxidant and / or reducing agent co-localized with the nitrite-providing layer. In some embodiments, the activator gel may not further comprise an antioxidant and / or reducing agent. In some embodiments, the mesh components may be embedded in a suspension comprising an antioxidant and / or reducing agent, as well as a nitrite-providing layer, suspended in a water-miscible anhydrous carrier. In some embodiments, the antioxidant and / or reducing agent may be sodium isoascorbate.

[0009] Alternative or additional embodiments described herein provide compositions comprising one or more features described above or elsewhere herein.

[0010] Alternative or additional embodiments described herein provide wound contact layers comprising one or more features of the above description or any other description herein.

[0011] Alternative or additional embodiments described herein provide wound dressings that include one or more features of the above description or any other description herein.

[0012] Alternative or additional embodiments described herein provide wound treatment systems that include one or more features of the above description or any other description herein.

[0013] Alternative or additional embodiments described herein provide methods for treating wounds that include one or more features of the above description or any other description herein. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 is a schematic diagram of an example of a negative pressure wound therapy system. [Figure 2A]Figure 2A shows one embodiment of a negative pressure wound treatment system, which includes a pump, a flexible fluid connector, and a wound dressing capable of absorbing and storing wound exudate. [Figure 2B] Figure 2B shows one embodiment of a negative pressure wound treatment system using a flexible fluid connector and a wound dressing capable of absorbing and storing wound exudate. [Figure 2C] Figure 2C shows a cross-section of one embodiment of a fluid connector connected to a wound dressing. [Figure 2D] Figure 2D shows a cross-section of one embodiment of a wound dressing. [Figure 3A] Figures 3A to 3D show embodiments of wound dressings that can absorb and store wound exudate when used without negative pressure. [Figure 3B] Figures 3A to 3D show embodiments of wound dressings that can absorb and store wound exudate when used without negative pressure. [Figure 3C] Figures 3A to 3D show embodiments of wound dressings that can absorb and store wound exudate when used without negative pressure. [Figure 3D] Figures 3A to 3D show embodiments of wound dressings that can absorb and store wound exudate when used without negative pressure. [Figure 3E] Figure 3E shows a cross-section of one embodiment of a wound dressing that can absorb and store wound exudate when used without negative pressure. [Figure 4] Figure 4 is an exploded view of one embodiment of a wound dressing that can generate nitric oxide. [Figure 5] Figure 5 is a cross-sectional view of the wound dressing shown in Figure 4. [Figure 6] Figure 6 shows an example of the equipment configuration for a chemiluminescence experiment protocol. [Figure 7] Figure 7 shows negative pressure and nitric oxide delivery experiments. [Figure 8A] Figure 8A shows an example of chemiluminescence experimental results for sodium nitrate mesh. [Figure 8B]Figure 8B shows an example of the chemiluminescence experiment results for a fully coated material design with a pull-out tab and a self-sealing boundary. [Figure 8C] Figure 8C shows an example of the chemiluminescence experiment results for a coating material containing a degradable film. [Figure 9] Figure 9 shows an example of a graph displaying the peak NO and NO2 outputs for an acrylic adhesive containing a hydrogel. [Figure 10A] Figures 10A - D show examples of the chemiluminescence experiment results for a nitric oxide generating coating material. [Figure 10B] Figures 10A - D show examples of the chemiluminescence experiment results for a nitric oxide generating coating material. [Figure 10C] Figures 10A - D show examples of the chemiluminescence experiment results for a nitric oxide generating coating material. [Figure 10D] Figures 10A - D show examples of the chemiluminescence experiment results for a nitric oxide generating coating material. [Figure 11A] Figures 11A - D show embodiments of a wound dressing configured to generate nitric oxide. [Figure 11B] Figures 11A - D show embodiments of a wound dressing configured to generate nitric oxide. [Figure 11C] Figures 11A - D show embodiments of a wound dressing configured to generate nitric oxide. [Figure 11D] Figures 11A - D show embodiments of a wound dressing configured to generate nitric oxide. [Figure 12] Figure 12 shows an exploded view of an embodiment of a wound dressing configured to generate nitric oxide. [Figure 13] Figure 13 shows a side view of an embodiment of a wound dressing configured to generate nitric oxide. [Figure 14] Figure 14 shows an exploded view of an embodiment of a wound dressing having a plurality of water absorption and distribution layers, and the wound dressing is configured to generate nitric oxide. [Figure 15]Figure 15 shows a side view of one embodiment of a wound dressing having multiple water absorption and distribution layers, the wound dressing being configured to generate nitric oxide. [Figure 16A] Figures 16A and 16B show one embodiment of a wound dressing having a composite water absorption and distribution layer. [Figure 16B] Figures 16A and 16B show one embodiment of a wound dressing having a composite water absorption and distribution layer. [Figure 17] Figure 17 shows a side view of one embodiment of a wound dressing, which includes a composite absorbent layer. [Figure 18A] Figures 18A-C show embodiments of wound dressings that include a composite absorbent layer. [Figure 18B] Figures 18A-C show embodiments of wound dressings that include a composite absorbent layer. [Figure 18C] Figures 18A-C show embodiments of wound dressings that include a composite absorbent layer. [Figure 19] Figure 19 shows one embodiment of a wound dressing that includes a composite absorbent layer. [Figure 20A] Figures 20A to 20D show embodiments of wound dressings having a perforated composite water absorption and distribution layer. [Figure 20B] Figures 20A to 20D show embodiments of wound dressings having a perforated composite water absorption and distribution layer. [Figure 20C] Figures 20A to 20D show embodiments of wound dressings having a perforated composite water absorption and distribution layer. [Figure 20D] Figures 20A to 20D show embodiments of wound dressings having a perforated composite water absorption and distribution layer. [Figure 21] Figure 21 shows one embodiment of a wound dressing having a composite layer. [Figure 22A] Figures 22A to 22D show one embodiment of a two-piece wound dressing, which includes a composite pocket filled with acidic hydrogel and an insertable mesh embedded with sodium nitrite. [Figure 22B]Figures 22A to 22D show one embodiment of a two-piece wound dressing, which includes a composite pocket filled with acidic hydrogel and an insertable mesh embedded with sodium nitrite. [Figure 22C] Figures 22A to 22D show one embodiment of a two-piece wound dressing, which includes a composite pocket filled with acidic hydrogel and an insertable mesh embedded with sodium nitrite. [Figure 22D] Figures 22A to 22D show one embodiment of a two-piece wound dressing, which includes a composite pocket filled with acidic hydrogel and an insertable mesh embedded with sodium nitrite. [Figure 23A] Figures 23A-23B show one embodiment of a wound dressing in which an insertion tool is used to guide a sodium nitrite mesh pocket into a dressing composite pocket filled with acidic hydrogel. [Figure 23B] Figures 23A-23B show one embodiment of a wound dressing in which an insertion tool is used to guide a sodium nitrite mesh pocket into a dressing composite pocket filled with acidic hydrogel. [Figure 24A] Figures 24A-24E show experiments evaluating the antimicrobial efficacy of wound dressings containing a sodium nitrite mesh placed on top of a composite material loaded with acidic hydrogel. In 24D, the left column represents 24 hours and the right column represents 72 hours, while in 24E, the left three columns represent 24 hours and the right three columns represent 72 hours. [Figure 24B] Figures 24A-24E show experiments evaluating the antimicrobial efficacy of wound dressings containing a sodium nitrite mesh placed on top of a composite material loaded with acidic hydrogel. In 24D, the left column represents 24 hours and the right column represents 72 hours, while in 24E, the left three columns represent 24 hours and the right three columns represent 72 hours. [Figure 24C]Figures 24A-24E show experiments evaluating the antimicrobial efficacy of wound dressings containing a sodium nitrite mesh placed on top of a composite material loaded with acidic hydrogel. In 24D, the left column represents 24 hours and the right column represents 72 hours, while in 24E, the left three columns represent 24 hours and the right three columns represent 72 hours. [Figure 24D] Figures 24A-24E show experiments evaluating the antimicrobial efficacy of wound dressings containing a sodium nitrite mesh placed on top of a composite material loaded with acidic hydrogel. In 24D, the left column represents 24 hours and the right column represents 72 hours, while in 24E, the left three columns represent 24 hours and the right three columns represent 72 hours. [Figure 24E] Figures 24A-24E show experiments evaluating the antimicrobial efficacy of wound dressings containing a sodium nitrite mesh placed on top of a composite material loaded with acidic hydrogel. In 24D, the left column represents 24 hours and the right column represents 72 hours, while in 24E, the left three columns represent 24 hours and the right three columns represent 72 hours. [Figure 25] Figure 25 shows one embodiment of an integrated wound dressing comprising a combinable composite component and a sodium nitrite mesh. [Figure 26A] Figures 26A to 26B show embodiments of a wound dressing comprising a combinable composite component and a sodium nitrite mesh. [Figure 26B] Figures 26A to 26B show embodiments of a wound dressing comprising a combinable composite component and a sodium nitrite mesh. Detailed description of the invention

[0015] overview Embodiments described herein relate to materials, apparatus, methods, and systems that incorporate, include, or utilize one or more compositions and / or materials that effectively generate a gas (e.g., nitric oxide) over time upon activation. Embodiments herein may relate to devices and / or wound dressings having one or more layers containing compositions and / or materials that effectively generate nitric oxide over time upon activation. For example, one or more nitric oxide generating layers may include a nitrite delivery layer containing nitrites and capable of releasing nitrite ions, thereby enabling the nitrite ions to 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 used as standalone components for separate positioning at a wound site, or may be incorporated into any number of multilayer wound dressings and wound treatment devices, as described herein below with respect to Figures 1 to 28B. Embodiments of the present disclosure are generally applicable for use in negative pressure or decompression therapy systems or compression therapy systems under ambient conditions.

[0016] Some of the preferred embodiments described herein incorporate, include, or utilize one or more nitric oxide-producing layers. Such one or more nitric oxide-producing layers may possess one or more of the following functional characteristics: inflammation-related activity, blood flow-related activity, antimicrobial, antiplankton and antibiofilm activity, ease of application and / or removal as an integrated unit, cleavability / tearability, conformity to the three-dimensional contour of the wound surface, abrasion resistance, suitability for negative pressure wound therapy and / or pressure wound therapy, exudate management, ability to facilitate autolytic debridement of the wound, ability to promote wound healing, and self-expression of compositional or functional changes. Antimicrobial activity, such as antimicrobial activity in vitro, may include one or more of broad-spectrum antimicrobial activity, antibiofilm activity, rapid rate of killing of microorganisms, and sustained killing of microorganisms, and microorganisms may include one or more of the following: Gram-negative bacteria, Gram-positive bacteria, fungi, yeasts, viruses, algae, archaea, and protozoa.

[0017] Certain preferred embodiments described herein provide wound healing systems. Such wound healing systems may comprise a nitric oxide generating layer configured to be sized to position over a wound and / or peri-wound area. Those skilled in the art will understand that when the device / covering / layer is described to be positioned over or over a wound, such device / covering / layer may extend over and treat the peri-wound area. In some cases, stimulation of the peri-wound area and / or wound margin may play a role in initiating the wound healing process, which may be activated through the delivery of nitric oxide to the peri-wound area and / or wound margin. The delivery of nitric oxide to the peri-wound area and / or wound margin may target, for example, epithelial cell activity to promote epithelial tongue migration, vasodilation of the microcirculation of the peri-wound skin to promote abundance by providing oxygen and nutrients, and angiogenesis to promote granulation tissue formation. The wound treatment systems described herein may further comprise a secondary wound dressing configured to be positioned separately on top of the nitric oxide generating layer. The nitric oxide generating layer may have an adhesive bonded to its underside, the adhesive may be configured such that the nitric oxide generating layer is positioned in close proximity to the wound. The secondary wound dressing, if used, may be bonded to the skin surrounding the wound, and may be the same size as the nitric oxide generating layer or larger than the nitric oxide generating layer, so that the nitric oxide generating layer is in contact with or positioned in close proximity to the wound and / or the area surrounding the wound. The secondary wound dressing may be configured to form an alternative or additional seal to the skin surrounding the wound so that the nitric oxide generating layer is in contact with or positioned in close proximity to the wound. The wound treatment systems may further comprise a negative pressure source configured to supply negative pressure through the secondary wound dressing and to the wound through the wound contact layer.

[0018] Certain other preferred embodiments described herein provide multilayer wound dressings, such as those described herein with respect to Figures 1 to 28. Such multilayer wound dressings may include composites or laminates that incorporate one or more nitric oxide generating layers as constituent layers, or that include one or more nitric oxide generating layers as part of one of their constituent layers. A multilayer wound dressing may comprise a nitric oxide generating layer as described above or elsewhere herein, a permeable layer and / or absorbent layer above / below one or more nitric oxide generating layers, a wound contact layer below one or more nitric oxide generating layers, and a cover layer on the permeable layer and / or absorbent layer. The wound dressing may further comprise a negative pressure port located above or above the cover layer. One or more nitric oxide generating layers may have an outer periphery substantially the same as the outer periphery of the cover layer, or one or more nitric oxide generating layers may have an outer periphery smaller than the outer periphery of the cover layer.

[0019] Those skilled in the art will understand that nitric oxide generating compositions disclosed in any "Summary" section of this Spec. or elsewhere disclosed herein, etc., can be loaded into one or more nitric oxide generating layers in any preferred form, such as by adsorption, absorption, chemical and / or physical adhesion entanglement, and / or in powder form. Those skilled in the art will further understand that reaction compositions, such as those disclosed in any section of this Spec. or elsewhere disclosed herein, can be incorporated by any preferred means into any preferred absorbent layer disclosed in this section or elsewhere disclosed herein, and / or any preferred permeable layer disclosed in this section or elsewhere disclosed herein, and / or any foam layer disclosed in this section or elsewhere disclosed herein.

[0020] In certain embodiments, wound treatment systems and multilayer wound dressings disclosed above or elsewhere in this specification may incorporate or comprise a nitric oxide generating layer. As described in this section of this specification or elsewhere, particularly as described below, the nitric oxide generating layer may be configured to be activated to release nitric oxide. At least a portion of the released nitric oxide may be released, for example, by diffusion. To facilitate the release and diffusion of nitric oxide, the nitric oxide generating layer may be positioned in close proximity to the wound.

[0021] Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other preferred sites. Such methods may include placing a nitric oxide generating layer on a wound, either separately or by arranging a multilayer wound dressing having a nitric oxide generating layer. The methods may include adhering a separate nitric oxide generating layer and / or a multilayer wound dressing having a nitric oxide generating layer to healthy skin surrounding the wound. Such methods may further include one or more of the following steps: Further wound dressings may be placed on a separate nitric oxide generating layer or on a multilayer wound dressing having a nitric oxide generating layer placed on a wound. Wound exudate, or any other wet or aqueous medium, may be provided to reach and / or come into contact with the nitric oxide generating layer. Wound exudate, or any other moist or aqueous medium, may be diffused or drawn up 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 may be applied to a separate nitric oxide generating layer, or to a multilayer wound dressing having a nitric oxide generating layer, thereby drawing wound exudate 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.

[0022] Those skilled in the art will understand that wound dressings, devices, and systems disclosed in this "Summary" section of this Spec., or elsewhere in this Spec., may include, in addition to, or instead of, nitric oxide generating layers, compositions, or materials, one or more layers, compositions, materials, or components that generate gases other than nitric oxide. For example, a wound dressing or device may include one or more layers that, upon activation, over time effectively generate vasodilators such as carbon monoxide or hydrogen sulfide.

[0023] Those skilled in the art will further understand that carbon monoxide and / or hydrogen sulfide may be used, where appropriate, instead of or in combination with nitric oxide delivery elements (e.g., layers). Further details regarding the generation and delivery of carbon monoxide and / or hydrogen sulfide can be found in Chapter 6 of the text of Inorganic and Organometallic Transition Metal Complexes with Biological Molecules and Living Cells, ISBN 978-0-12-803814-7, which is incorporated herein by reference. For example, hydrogen sulfide may be generated from elements / layers containing cleavable / releaseable hydrogen sulfide, diallylthiosulfinate, GYY4137, S-mesalamine ATB-429, S-naproxen ATB-346, S-diclofenac ATB-337 / ACS-15. For example, carbon monoxide can be generated from elements / layers that provide a complex of carbon monoxide bound to a suitable metal such as chromium, molybdenum, tungsten, manganese, rhenium, iron, ruthenium, cobalt, rhodium, and iridium. Such a complex can be enzymatically triggered to release carbon monoxide, be photocleavable, and / or induce carbon monoxide release in response to interaction with a suitable ligand.

[0024] Methods for treating wounds Some preferred embodiments described herein provide methods for treating wounds, intact tissue, or other preferred sites. Such methods may include placing one or more nitric oxide-producing layers on a wound, either separately or by arranging a multilayer wound dressing having one or more nitric oxide-producing layers. Methods may include adhering separate, one or more nitric oxide-producing layers, and / or a multilayer wound dressing having one or more nitric oxide-producing layers, to healthy skin surrounding a wound, such as a peri-wound area. Methods may further include one or more of the following steps: Further wound dressings may be placed on top of a multilayer wound dressing having one or more separate nitric oxide-producing layers, or one or more nitric oxide-producing layers placed on a wound. Wound exudate, or any other moist or aqueous medium, may be provided to reach and / or come into contact with one or more nitric oxide-producing layers. Wound exudate, or any other moist or aqueous medium, may be diffused or drawn up into a wound dressing incorporating one or more nitric oxide-producing layers, or into a wound dressing provided on top of one or more nitric oxide-producing layers. Negative pressure may be applied to one or more separate nitric oxide-producing layers, or to a multilayer wound dressing having one or more nitric oxide-producing layers, as described in the following “Negative Pressure Wound Therapy (NPWT) Systems” section or elsewhere in this specification, thereby drawing wound exudate directly into one or more nitric oxide-producing layers, or into a wound dressing incorporating one or more nitric oxide-producing layers, or into a wound dressing provided on top of one or more nitric oxide-producing layers.

[0025] As described above or elsewhere in this specification, a method for treating a wound, intact tissue, or other preferred site may further include delivering negative pressure to the wound through a wound contact layer, as described in the following “Negative Pressure Wound Therapy (NPWT)” section or elsewhere in this specification. The wound contact layer may substantially maintain the delivered negative pressure for at least about 24 hours, or at least about 48 hours, or at least about 72 hours. Alternatively, a method for treating a wound, intact tissue, or other preferred site may include applying positive pressure to the wound through a wound contact layer. Alternatively, the method may include modifying atmospheric pressure, negative pressure, and positive pressure to the wound through a wound contact layer in a programmable manner.

[0026] In embodiments, a method for treating a wound, intact tissue, or other preferred site may include using a wound contact layer, or a wound treatment system comprising a wound contact layer, or a wound dressing, under ambient conditions unrelated to a negative pressure wound therapy system, as described above or elsewhere in this specification.

[0027] In some embodiments, methods for treating wounds, intact tissue, or other preferred sites can reduce wound bioburden by, for example, reducing the number of viable microorganisms (CFU / sample) at least in vitro within the first four hours after application of the wound contact layer. In some embodiments, the number of viable microorganisms can be reduced by 4 log or more 48 to 72 hours after the wound dressing material has been placed in contact with the microorganisms.

[0028] Negative Pressure Wound Therapy (NPWT) System Embodiments of this disclosure will be understood to be generally applicable, but not limited to, to use in topical negative pressure ("TNP") therapy systems. In short, negative pressure wound therapy can help close and heal many forms of “difficult-to-heal” wounds by reducing tissue edema, promoting blood flow and granular tissue formation, and removing excess exudate, thereby reducing bacterial load (and therefore risk of infection). In addition, the therapy can reduce wound anxiety and lead to more rapid healing. TNP therapy systems can also assist in the healing of surgically closed wounds by helping to remove fluid and stabilize tissue in parallel positions of closure. Further beneficial uses of TNP therapy may be found in grafts and flaps where removing excess fluid is important and it is required that the graft be in close proximity to the tissue to ensure tissue viability.

[0029] As used herein, a negative pressure level such as -X mmHg represents a pressure level relative to normal ambient pressure, which may correspond to 760 mmHg (or 1 atm, 29.93 inHg, 101.325 kPa, 14.696 psi, etc.). Therefore, a negative pressure value of -X mmHg reflects an absolute pressure that is X mmHg lower than 760 mmHg, or in other words, an absolute pressure of (760-X) mmHg. Furthermore, negative pressures "lower" or "smaller" than X mmHg correspond to pressures closer to atmospheric pressure (e.g., -40 mmHg is lower than -60 mmHg). Negative pressures "higher" or "greater" than -X mmHg correspond to pressures further away from atmospheric pressure (e.g., -80 mmHg is higher than -60 mmHg). In some embodiments, a local ambient pressure is used as a reference point, and such a local pressure does not necessarily have to be, for example, 760 mmHg.

[0030] The negative pressure range in some embodiments of this disclosure may be about -80 mmHg, or between about -20 mmHg and -200 mmHg. It should be noted that these pressures are relative to normal ambient pressure, which may be 760 mmHg. Therefore, -200 mmHg would be substantially about 560 mmHg. In some embodiments, the pressure range may be about -40 mmHg to -150 mmHg. Alternatively, pressure ranges of up to 75 mmHg, up to -80 mmHg, or above -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 supplied by the negative pressure device.

[0031] In some embodiments of the wound closure devices described herein, increased wound contraction may lead to increased tissue expansion in the surrounding wound tissue. This effect may be amplified, in some cases, by changing the force applied to the tissue, for example, by changing the negative pressure applied to the wound over time, in conjunction with an increase in the tensile force applied to the wound by an embodiment of the wound closure device. In some embodiments, the negative pressure may be changed over time, for example, using a sine wave, a square wave, or in synchronization with one or more physiological indicators of the patient (e.g., heart rate). Examples of such applications, for which further disclosures relating to the foregoing may be found, include U.S. Patent No. 8,235,955, entitled "Wound treatment apparatus and method," issued on 7 August 2012, and U.S. Patent No. 7,753,894, entitled "Wound cleansing apparatus with stress," issued on 13 July 2010. The disclosures of both of these patents are incorporated herein by reference in their entirety.

[0032] Embodiments of 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 herein, in "APPARATUSES AND METHODS FOR NEGATIVE PRESSURE WOUND THERAPY," filed on 22 May 2013 under International Application No. PCT / IB2013 / 001469 and published on 28 November 2013 under International Publication No. 2013 / 175306(A2), and in "WOUND DRESSING," filed on 31 July 2013 under International Application No. PCT / IB2013 / 002060 and published on 31 July 2013 under International Publication No. WO2014 / 020440, the disclosures thereof being incorporated herein in their entirety by reference. Embodiments of wound dressings, wound treatment devices, and methods described herein may also be used in combination with, or in addition to, those described herein, including embodiments of wound dressings, wound treatment devices, and methods described herein, including embodiments of wound dressings, components of wound dressings, and principles, and materials used in wound dressings.

[0033] Furthermore, several embodiments relating to TNP wound treatment, including wound dressings, in combination with the pumps or associated electronic devices described herein may also be used in combination with, or in addition to, those described in “REDUCED PRESSURE APPARATUSES,” published as International Publication No. 2016 / 174048(A1) on November 3, 2016, which are incorporated herein by reference in their entirety. In some of these embodiments, the pumps or associated electronic components may be integrated within the wound dressing to provide a single article to be applied to the wound.

[0034] Multilayer wound dressings for NPWT Figure 1 shows an example of a negative pressure wound therapy system 700. The system includes a wound cavity 710 covered with a wound dressing 720, which may be a dressing according to any of the examples described herein. The dressing 720 may be positioned on, inside, all over, or around the wound cavity 710 to further seal the wound cavity, thereby maintaining negative pressure within the wound cavity. For example, the film layer of the wound dressing 720 may provide a substantially fluid-impermeable seal over the wound cavity 710. In some embodiments, a wound filler, such as a foam or a layer of gauze, may be used to fill the wound. The wound filler may include one or more nitric oxide generating layers (e.g., a nitrite delivery layer, an acid group providing layer), as described in this section of this specification or elsewhere in this specification. For example, in conventional negative pressure wound therapy systems that utilize foam (RENASYS-F) or gauze (RENASYS-G), such as the Smith+Nephew RENASYS negative pressure wound therapy system, the foam or gauze may be supplemented with a nitric oxide generating layer, as described above. When supplementing with foam, gauze layers, or other wound packing materials, one or more nitric oxide generating layers may be inserted separately into the wound or pre-attached to the wound filling material for insertion into the wound.

[0035] One or more luminal tubes or conduits 740 connect the wound dressing 720 to a negative pressure device 750 configured to supply a pressure reduction. 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 moved through the tube 740 for collection to another location). In some embodiments, the negative pressure device 750 may include or be configured to support a canister. Furthermore, 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.

[0036] The conduit 740 may be any suitable article configured to provide at least substantially sealed fluid channels or pathways between the negative pressure device 750 and the wound cavity 710 to supply reduced pressure to the wound cavity. The conduit 740 may be formed from polyurethane, PVC, nylon, polyethylene, silicone, or any other suitable rigid or flexible material. In some embodiments, the wound dressing 720 may have ports configured to receive the ends of the conduit 740. For example, the ports may include holes in the film layer. In some embodiments, the conduit 740 may pass through and / or separately beneath the film layer of the wound dressing 720 to supply reduced pressure to the wound cavity 710 to maintain a desired level of reduced pressure within the wound cavity. In some embodiments, at least a portion of the conduit 740 is integrated with or attached to the wound dressing 720.

[0037] Figure 2A shows one embodiment of a negative pressure wound treatment system 10 using a wound dressing 100 together with a fluid connector 110. Additional examples of negative pressure wound treatment, including wound dressings combined with a pump, as described herein, may also be used in combination with or in addition to those described in U.S. Patent No. 9,061,095, which is incorporated by reference in whole. In the figure, the fluid connector 110 may comprise an elongated conduit, more preferably a bridge 120 having a proximal end 130 and a distal end 140, and an applicator 180 at the distal end 140 of the bridge 120. The system 10 may include a negative pressure source, such as a pump or a negative pressure unit 150 capable of supplying negative pressure. The pump may include a canister or other container for storing wound exudate and other fluids that can be removed from the wound. The canister or container may also be provided separately from the pump. In some embodiments, the pump 150 may be a canisterless pump, such as a PICO® pump sold by Smith+Nephew. The pump 150 may be connected to the bridge 120 via a tube, or the pump 150 may be connected directly to the bridge 120. During use, the dressing 100 is placed over a suitably prepared wound, which in some cases may be filled with wound filling material, such as foam or gauze, as described above. The applicator 180 of the fluid connector 110 has a sealing surface that is positioned over the opening of the dressing 100 and seals to the upper surface of the dressing 100. Either before, during, or after the connection of the fluid connector 110 to the dressing 100, the pump 150 is connected to a tube connector via a tube, or directly to the bridge 120. The pump is then started, thereby supplying negative pressure to the wound. The application of negative pressure may continue until the desired level of wound healing is achieved.

[0038] As shown in Figure 2B, the fluid connector 110 preferably comprises an enlarged distal end or head 140 that fluidly communicates with the covering material 100, as will be described in more detail below. In one embodiment, the enlarged distal end has a rounded or circular shape. The head 140 is shown in the figure positioned near the edge of the covering material 100, but can be positioned anywhere on the covering material. For example, in some embodiments, it may be provided in the center or off-center, not on or near the edge or corner of the covering material 100. In some embodiments, the covering material 10 may comprise two or more fluid connectors 110, each comprising one or more heads 140 that fluidly communicate with it. In a preferred embodiment, the head 140 may be 30 mm in dimension along the widest edge. The head 140 at least partially forms an applicator 180 configured to seal against the upper surface of the wound dressing as described above.

[0039] Figure 2C shows a cross-section through a wound dressing 100, similar to the wound dressing 10 described in International Patent Application Publication No. 2013 / 175306(A2), which is incorporated by reference in its entirety along with a fluid connector 110. Alternatively, the wound dressing 100 may be any embodiment of the wound dressings disclosed herein, or any combination of any number of features of the embodiments of the wound dressings disclosed herein, and may be positioned over the wound site to be treated. The dressing 100 may be positioned to form a sealed cavity over the wound site. In a preferred embodiment, the dressing 100 comprises a top layer, or cover layer, or a backing layer 220 attached to the wound contact layer 222, both of which are described in more detail below. These two layers 220, 222 are preferably joined or sealed together to define an internal space, or chamber. This internal space, or chamber, may include additional structures that can be adapted to distribute or transmit negative pressure and to store wound exudate and other fluids removed from the wound, and other functions which will be described in more detail below. Examples of such structures described below include a permeable layer 226 and an absorbent layer 221.

[0040] As used herein, the upper layer, upper layer, or superior layer refers to the layer furthest from the skin or wound surface while the dressing is in use and positioned over the wound. Conversely, the lower layer, lower layer, bottom layer, or inferior layer refers to the layer closest to the skin or wound surface while the dressing is in use and positioned over the wound.

[0041] As shown in Figure 2C, the wound contact layer 222 may be a polyurethane layer, a polyethylene layer, or another flexible layer perforated or otherwise permeable to liquids and gases, for example, via a hot-pinning process, a laser ablation process, or an ultrasonic process, or in several other ways. The wound contact layer 222 has a bottom surface 224 and an top surface 223. The perforations 225 preferably include through-holes in the wound contact layer 222, thereby allowing fluid to flow through the layer 222. The wound contact layer 222 helps prevent tissue infiltration into other materials of the wound dressing. Preferably, the perforations are small enough to satisfy this requirement while allowing fluid to flow through them. For example, perforations formed as slits or holes having a size in the range of 0.025 mm to 1.2 mm are considered small enough to help prevent tissue infiltration into the wound dressing while allowing wound exudate to flow into the dressing. In some configurations, the wound contact layer 222 may help maintain the overall integrity of the dressing 100 while also creating an airtight seal around the absorbent pad to maintain negative pressure at the wound.

[0042] 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, hydrophilic colloid, or acrylic-based adhesive, or other such adhesives, may be formed on both sides of the wound contact layer, on one optionally selected side, or not on either side of the wound contact layer. When a lower pressure-sensitive adhesive layer is used, it may help to adhere the wound dressing 100 to the skin 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, thereby helping the dressing maintain its integrity. In some embodiments, the polyurethane film layer may have adhesive layers provided on both its upper and lower surfaces, and all three layers may be perforated together.

[0043] The permeable layer 226 may be located above the wound contact layer 222. In some embodiments, the permeable layer may be a porous material. As used herein, the permeable layer may also be referred to as a spacer layer, and this term may be used interchangeably to refer to the same component as described herein. The permeable layer 226 is spaced away from the wound site and allows the permeation of fluids, including liquids and gases, into the upper layers of the wound dressing. In particular, the permeable layer 226 preferably ensures that open air channels are maintained so that negative pressure is transmitted over the wound area even if the absorbent layer absorbs a considerable amount of exudate. The layer 226 should preferably remain open under the normal pressure that will be applied during negative pressure wound therapy as described above, so that the entire wound site is subjected to equal negative pressure. The layer 226 may be formed from a material having a three-dimensional structure. For example, knitted or woven spacer cloth (e.g., Baltex 7970 weft-knitted polyester) or nonwoven fabric may be used. The three-dimensional materials may include 3D spacer fabric materials similar to those described in International Publication No. WO2013 / 175306(A2) and International Publication No. WO2014 / 020440, the disclosures of which are incorporated in their entirety by reference.

[0044] In certain embodiments, the wound dressing 100 may incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layers, acid group providing layers) as described in this section of this specification or elsewhere in this specification. Those skilled in the art will understand that the wound dressing 100 may incorporate any of the one or more nitric oxide generating layers as described in this section of this specification or elsewhere in this specification. Those skilled in the art will also understand that one or more nitric oxide generating layers may be incorporated as part of all constituent layers or as part of constituent layers. In some embodiments, one or more nitric oxide generating layers may be provided below the permeable layer 226. In some embodiments, one or more nitric oxide generating layers may be provided above the wound contact layer 222. In certain embodiments, one or more nitric oxide generating layers may replace the permeable layer 226 such that one or more nitric oxide generating layers are provided between the absorbent layer 221 (further described below) and the wound contact layer 222. In some embodiments, one or more nitric oxide generating layers may supplement or replace the absorbent layer 221. In some embodiments, the wound dressing 100 does not have a wound contact layer 222, and one or more nitric oxide generating layers may be the bottom layer of the wound dressing 100. One or more nitric oxide generating layers may have the same or substantially the same size and shape as the permeable layer 226 and / or absorbent layer 221. In some embodiments, one or more nitric oxide generating layers, or their components (e.g., nitrite-providing layers as described herein), may be separated from the wound dressing 100. For example, one or more nitric oxide generating layers or their components may be provided as separate layers that can be placed on a wound, and the wound dressing 100 may be placed on top of them.

[0045] One or more nitric oxide generating layers may be constructed to be flexible but rigid enough to withstand negative pressure, so as not to collapse excessively and thereby to adequately transmit negative pressure to the wound when negative pressure is supplied to the wound dressing 100. One or more nitric oxide generating layers may be constructed to include a sufficient number or size of pores to allow for the transmission of negative pressure. One or more nitric oxide generating layers may include, for example, openings or holes below ports that can transmit negative pressure and / or wound fluid. Furthermore, one or more nitric oxide generating layers may have a thickness(s) suitable for transmitting a suitable negative pressure to the wound. For example, one or more nitric oxide generating layers may have a thickness of about 1 mm to 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, one or more nitric oxide generating layers may have a thickness of about 2 mm.

[0046] In some embodiments, the absorbent material layer 221 is provided above the permeable layer 226. The absorbent material, which may include foam or nonwoven, natural or synthetic materials and optionally include superabsorbent materials, forms a reservoir for fluid, specifically liquid to be removed from the wound site. In some embodiments, the layer 221 may also help draw the fluid toward the backing layer 220.

[0047] The material of the absorbent layer 221 may also prevent the fluid collected within the wound dressing 100 from flowing freely within the dressing, preferably acting to contain any collected fluid within the dressing. The absorbent layer 221 also helps distribute the fluid throughout the layer by suction, drawing the fluid away from the wound site and storing it throughout the absorbent layer. This helps prevent aggregation in areas of the absorbent layer. The capacity of the absorbent material must be sufficient to control the flow rate of wound exudate when negative pressure is applied. Since the absorbent layer experiences negative pressure during use, the material of the absorbent layer is selected to absorb fluid under such conditions. There are several materials that can absorb fluid under negative pressure, such as superabsorbent materials. The absorbent layer 221 can typically be manufactured from ALLEVYN® foam, Freudenberg 114-224-4, or Chem-Posite® 11C-450. In some embodiments, the absorbent layer 221 may include a composite material comprising superabsorbent powder, fibrous material such as cellulose, and binding fibers. In preferred embodiments, the composite material is an air-laid, heat-bonded composite material.

[0048] In some embodiments, the absorbent layer 221 is a layer of nonwoven cellulose fibers having a superabsorbent material in the form of dry particles dispersed throughout the layer. The use of cellulose fibers introduces a high-speed suction element that helps to quickly and evenly distribute the liquid absorbed by the coating material. The parallel arrangement of numerous twisted fibers leads to a strong capillary action of the fiber pad that helps to disperse the liquid. In this way, the liquid is efficiently supplied to the superabsorbent material. The suction action also helps to bring the liquid into contact with the upper cover layer in order to help increase the evaporation rate of the coating material.

[0049] Preferably, an opening, hole, or orifice 227 is provided in the backing layer 220 to allow negative pressure to be applied to the wound dressing 100. The fluid connector 110 is preferably mounted on or sealed over the orifice 227 fabricated in the wound dressing 100, on top of the backing layer 220, and transmits negative pressure through the orifice 227. A long pipe may be coupled at a first end to the fluid connector 110 and at a second end to a pump unit (not shown) to allow fluid to be drawn from the wound dressing. If the fluid connector is bonded to the upper layer of the wound dressing, the long pipe may be coupled at the first end of the fluid connector such that the pipe or conduit extends away from the fluid connector parallel to it or substantially to the top surface of the wound dressing. The fluid connector 110 may be bonded and sealed to the backing layer 220 using an adhesive such as acrylic, cyanoacrylate, epoxy, UV-curable, or hot-melt adhesive. The fluid connector 110 may be formed from a soft polymer having a hardness of 30 to 90 on the Shore A scale, such as polyethylene, polyvinyl chloride, silicone, or polyurethane. In some embodiments, the fluid connector 110 may be made from a soft material or a suitable material.

[0050] Optionally, the absorbent layer 221 includes at least one through-hole 228 positioned beneath the fluid connector 110. In some embodiments, the through-hole 228 may be the same size as, or larger than, the opening 227 in the backing layer, or smaller than. As shown in Figure 2C, a single through-hole may be used to provide an opening beneath the fluid connector 110. It will be understood that multiple openings may be available as alternatives. Furthermore, if one or more ports are to be utilized according to a particular embodiment of the present disclosure, one or more openings may be fabricated in the absorbent layer to align with each respective fluid connector. Although not essential to some embodiments of the present disclosure, the use of through-holes in the superabsorbent layer may provide an unobstructed fluid path, particularly when the absorbent layer is near saturation.

[0051] As shown in Figure 2C, the opening, or through-hole 228, is preferably provided in the absorbent layer 221 below the orifice 227 so that the orifice is directly connected to the permeable layer 226. This allows the negative pressure applied to the fluid connector 110 to be transmitted to the permeable layer 226 without passing through the absorbent layer 221. This ensures that even if the absorbent layer absorbs wound exudate, the negative pressure applied to the wound site is not obstructed by the absorbent layer. In other embodiments, the opening may not be provided in the absorbent layer 221, or alternatively, multiple openings may be provided below the orifice 227. In further alternative embodiments, an additional layer, such as another permeable layer, or a concealing layer, such as that described in International Patent Application Publication WO2014 / 020440, which is incorporated herein in whole by reference, may be provided above the absorbent layer 221 and below the backing layer 220.

[0052] The backing layer 220 is preferably gas-impermeable but breathable and may extend across the width of the wound dressing 100. For example, it may be a polyurethane film (e.g., Elastollan SP9109) having a pressure-sensitive adhesive on one side. The backing layer 220 is gas-impermeable and therefore acts to cover the wound and seal the wound cavity on which the wound dressing is placed. In this way, an effective chamber is created between the backing layer 220 and the wound site, where negative pressure can be established. The backing layer 220 is preferably sealed to the wound contact layer 222 within the boundary region around the dressing, for example, by 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 (bacterial barrier) and allows fluid from wound exudate to move through the layer and evaporate from the outer surface of the film. The backing layer 220 preferably comprises two layers, namely a polyurethane film and an adhesive pattern spread on this film. The polyurethane film may preferably be made from a material that is permeable to moisture and whose water permeability increases when wet. In some embodiments, the permeability of the backing layer increases when the backing layer is wet. The permeability of the wet backing layer may be up to about 10 times that of the dry backing layer.

[0053] The absorbent layer 221 may have a larger area than the permeable layer 226 so that the absorbent layer overlaps with the edge of the permeable layer 226, thereby ensuring that the permeable layer does not come into contact with the backing layer 220. This provides an outer channel of the absorbent layer 221 that comes into direct contact with the wound contact layer 222, facilitating more rapid absorption of exudate into the absorbent layer. Furthermore, this outer channel ensures that fluid does not accumulate around the periphery of the wound cavity, which could otherwise seep out from the seal around the dressing and lead to leakage. As shown in Figure 2C, the absorbent layer 221 may have a smaller periphery than the periphery of the backing layer 220 so that a boundary line, or boundary region, is defined between the edge of the absorbent layer 221 and the edge of the backing layer 220.

[0054] As shown in Figure 2C, one embodiment of the wound dressing 100 includes an opening 228 in an absorbent layer 221 located below 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 therefore come into contact with the permeable layer 226, and thus can help transmit negative pressure to the wound site, even when the absorbent layer 221 is filled with wound fluid. Some embodiments may have a backing layer 220 that is at least partially adhered to the permeable layer 226. In some embodiments, the opening 228 is at least 1 to 2 mm larger than the diameter of the wound-facing portion of the fluid connector 11 or the orifice 227.

[0055] In particular, in embodiments with a single fluid connector 110 and a through-hole, it may be preferable that the fluid connector 110 and the through-hole be located off-center, as shown in Figure 2B. Such a position may allow the dressing 100 to be positioned on the patient such that the fluid connector 110 is elevated relative to the rest of the dressing 100. When positioned in this manner, the fluid connector 110 and the filter 214 may be less likely to come into contact with the wound fluid, which could cause premature occlusion of the filter 214 in order to prevent the transmission of negative pressure to the wound site.

[0056] Similar to the embodiments of wound dressings described above, some wound dressings include a perforated wound contact layer with a silicone adhesive on the skin contact surface and an acrylic adhesive on the back surface. In some embodiments, the wound contact layer may be constructed from polyurethane, polyethylene, or polyester. Above this boundary layer is a permeable layer. Above the permeable layer is an absorbent layer. The absorbent layer may include a superabsorbent nonwoven (NW) pad. The absorbent layer may be in contact with the permeable layer for approximately 5 mm beyond its periphery. The absorbent layer may have an opening or through-hole directed toward one end. The opening may be approximately 10 mm in diameter. Above the permeable layer and the absorbent layer is a backing layer. The backing layer may be a high water vapor permeability (MVTR) film, which is a pattern coated with acrylic adhesive. The high MVTR film and the wound contact layer encapsulate the permeable layer and the absorbent layer, creating a periphery boundary of approximately 20 mm. The backing layer may have a 10 mm opening that overlaps the opening in the absorbent layer. Above the opening, a fluid connector may be connected, comprising a liquid-impermeable, gas-permeable, semi-permeable membrane (SPM) or filter that overlaps the aforementioned opening.

[0057] Figure 2D shows an embodiment of a wound dressing similar to the wound dressings of Figures 2A-2C. Referring to Figure 2D, the masking, or concealing layer 2107 may be positioned beneath at least a portion of the backing layer 2140. In some embodiments, the concealing layer 2107 may have any of the same features, materials, or other details as any other embodiment of the concealing layer disclosed herein, including, but not limited to, having any viewing windows or holes. An example of a wound dressing having a concealing layer and a viewing window is described in International Patent Publication WO2014 / 020440, which is incorporated in its entirety by reference. Furthermore, the concealing layer 2107 may be positioned adjacent to the backing layer or adjacent to any other dressing layer as desired. In some embodiments, the concealing layer 2107 may be bonded to the backing layer or formed integrally with the backing layer. Preferably, the concealing layer 2107 has substantially the same size and shape as the absorption layer 2110 and is configured to overlay it. Thus, in these embodiments, the concealing layer 2107 has a smaller area than the backing layer 2140.

[0058] Preferably, the absorption layer 2110 and the concealment layer 2107 include at least one through-hole 2145 positioned below the port 2150. Naturally, each hole through these various layers 2107, 2140, and 2110 may be of different sizes relative to one another. As shown in Figure 2D, a single through-hole may be used to create an opening below the port 2150. In certain embodiments, the port may be replaced by or used in combination with a fluid connector, as shown in Figure 2C. It will be understood that multiple openings may be available as alternatives. Furthermore, if one or more ports are to be utilized according to a particular embodiment of the present disclosure, one or more openings may be fabricated in the absorption layer and the concealment layer, aligned with each respective port. Although not essential in some embodiments of the present disclosure, using through-holes in the superabsorbent layer may provide an unblocked fluid path, particularly when the absorption layer 2110 is near saturation.

[0059] An opening, or through-hole, 2144 may be provided in the absorbent layer 2110 and the concealing layer 2107 below the orifice 2144, so that the orifice is directly connected to the permeable layer 2105. This allows the negative pressure applied to the port 2150 to be transmitted to the permeable layer 2105 without passing through the absorbent layer 2110. This ensures that even if the absorbent layer absorbs wound exudate, the negative pressure applied to the wound site is not obstructed by the absorbent layer. In other embodiments, the opening may not be provided in the absorbent layer 2110 and / or the concealing layer 2107, or alternatively, a plurality of openings may be provided below the orifice 2144.

[0060] In some embodiments, the concealing layer 2107 may help reduce the unsightly appearance of the dressing during use by using a material that provides partial concealment or masking of the dressing surface. In one embodiment, the concealing layer 2107 only partially conceals the dressing to allow the clinician to access necessary information by observing the spread of exudate across the dressing surface. The partial masking properties of this embodiment of the concealing layer allow the clinician to perceive different colors caused by exudate, blood, by-products, etc., on the dressing, enabling visual assessment and monitoring of the extent of the spread across the dressing. However, since the change in the color of the dressing from its clean state to its exudate-containing state is only a slight change, the patient is 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, for example, by reducing stress.

[0061] In some embodiments, the concealment layer may be formed from a nonwoven fabric (e.g., polypropylene) and may be thermally bonded using a diamond pattern having a bonding area of ​​19%. In various embodiments, the concealment layer may be hydrophobic or hydrophilic. Depending on the application, in some embodiments, a hydrophilic concealment layer may provide additional moisture permeability. However, in some embodiments, a hydrophobic concealment layer may still provide sufficient moisture permeability (i.e., through appropriate material selection and thickness of the concealment layer), while also allowing for better retention of dyes or colors in the concealment layer. Thus, dyes or colors may be trapped beneath the concealment layer. In some embodiments, this may allow the concealment layer to be colored with a light color or white. In preferred embodiments, the concealment layer is hydrophobic. In some embodiments, the concealment layer material may be sterilizable using ethylene oxide. In other embodiments, sterilization may be performed using gamma irradiation, electron beam, steam, or other alternative sterilization methods. Furthermore, in various embodiments, the concealment layer may be colored or tinted with, for example, medical blue. The concealing layer may also be constructed from multiple layers, including a colored layer laminated or fused to a stronger uncolored layer. Preferably, the concealing layer is odorless and exhibits minimal fiber shedding.

[0062] Multilayer covering material for use without negative pressure Figures 3A to 3D show various embodiments of wound dressings 500 that can be used to heal wounds without negative pressure. Figure 3E shows a cross-section of the wound dressings of Figures 3A to 3D. As shown in the dressings of Figures 3A to 3E, the wound dressings may have multiple layers similar to the dressings described with reference to Figures 2A to 2D, except that the dressings of Figures 3A to 3E do not include ports or fluid connectors. The wound dressings of Figures 3A to 3E may include a cover layer 501 and an optional wound contact layer 505, as described herein. In some embodiments, the cover layer 501 may be permeable to moisture and / or air. The wound dressings may include various layers positioned between the wound contact layer 505 and the cover layer 501. For example, the dressings may include one or more absorbent layers or one or more permeable layers, as described herein with reference to Figures 2A to 2D.

[0063] As shown in Figures 3A to 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 a selected specific dressing size. An optional layer of activated charcoal cloth (not shown), similar in size to or slightly smaller than layer 504, may be provided to allow odor control. An absorbent layer 502, such as a layer of superabsorbent foam material containing cellulose fibers and superabsorbent polyacrylate particles, is provided on top of layer 504 and is slightly larger in size than layer 504, allowing for overlapping of the superabsorbent material and acting as a leak-proof layer. On top of layer 502, a masking or concealing layer 503 is provided, such as a layer of three-dimensional knitted spacer cloth, to provide protection from pressure, while allowing partial masking of the top surface of the superabsorbent material, to which colored exudate remains. In this embodiment, this is smaller in dimension than layer 502 (plan view) and allows visualization of the edge of the absorbent layer, which can be used by clinicians to evaluate whether the covering material needs to be changed.

[0064] The wound dressing 500 may incorporate or include one or more nitric oxide generating layers (e.g., nitrite delivery layer, acid group providing layer) as described in this section of this specification or elsewhere. Those skilled in the art will understand that the wound dressing 500 may incorporate any of the one or more nitric oxide generating layers as disclosed in this section of this specification or elsewhere. Those skilled in the art will also understand that one or more nitric oxide generating layers may be incorporated as part of all constituent layers or as part of constituent layers. In some embodiments, the nitric oxide generating layers may be provided below the cover layer 501. In some embodiments, one or more nitric oxide generating layers may be provided above the wound contact layer 505. In certain embodiments, the wound contact layer 505 may be omitted so that one of the nitric oxide generating layers is the bottom layer and in contact with the wound surface. In some embodiments, one or more nitric oxide generating layers may be provided below the foam layer 504. In some embodiments, one or more nitric oxide generating layers may replace the foam layer 504. In some embodiments, the dressing 500 may consist only of the cover layer 501 and one or more nitric oxide generating layers. In some embodiments, one or more nitric oxide generating layers, or their components (e.g., nitrite-providing layers as described herein), may be separated from the wound dressing 500. For example, one or more nitric oxide generating layers, or their components, may be provided as separate layers that can be placed on the wound, and the wound dressing 500 may be placed on top of them.

[0065] As described above, one or more nitric oxide generating layers may be incorporated into or used with commercially available wound dressings such as ALLEVYN® form, ALLEVYN® Life, ALLEVYN® Adhesive, ALLEVYN® Gentle Border, ALLEVYN® Gentle, ALLEVYN® Ag Gentle Border, ALLEVYN® Ag Gentle, Opsite Post-Op Visible. In some embodiments, the wound dressing 500 may include a cover layer 501, a wound contact layer 505, and a nitric oxide generating layer sandwiched between them. In some embodiments, the wound dressing 500 may include a cover layer 501, an absorbent layer 502, a nitric oxide generating layer beneath the absorbent layer 502, and a wound contact layer 505.

[0066] Further details relating to wound dressings that may be used in combination with or in addition to the embodiments described herein are found in U.S. Patent No. 9,877,872 issued on January 30, 2018, entitled "Wound Dressing and Method of Treatment," which is incorporated herein by reference in its entirety, including further details relating to embodiments of wound dressings, components and principles of wound dressings, and materials used in wound dressings.

[0067] Multilayer wound dressing with integrated negative pressure supply In some embodiments, some or all other components of the TNP system, such as a negative pressure source (e.g., a pump), and power supplies, sensors, connectors, and user interface components (e.g., buttons, switches, speakers, screens), may be integrated with wound dressings, such as those described above in relation to Figures 1 to 3D. Furthermore, several embodiments relating to wound treatment comprising wound dressings described herein may also be used in combination with, or in addition to, the embodiments described in International Application No. WO2016 / 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 disclosure of which is incorporated herein by reference in whole, further details relating to embodiments of wound dressings, wound dressing components, and principles, as well as materials used in wound dressings and wound dressing components.

[0068] In some embodiments, the pump and / or other electronic components may be configured to be positioned adjacent to or next to the absorbent and / or permeable layer of the wound dressing, such that the pump and / or other electronic components are positioned away from the wound site, while the pump and / or other electronic components are still part of a single device that will be applied to the patient.

[0069] Nitric oxide production layer Figures 4-5 show wound dressings 12000 including a nitric oxide generating layer according to several embodiments. In the illustrated embodiments, the wound dressing 12000 may include a cover layer 12200, an activator layer 12400, and a 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 various sections of the dressing may be referred to as “layers,” but such sections may be of other preferred shapes or configurations. As will be understood by those skilled in the art, wound dressings and / or nitric oxide delivery embodiments described in this section of this specification, or elsewhere in this specification, may be applied over a wound and / or over surrounding skin such as the area surrounding the wound.

[0070] The cover layer 12200 is gas-impermeable but may be breathable and may extend across the width of the wound dressing 12000. For example, the cover layer 12200 may be a polyurethane film having a pressure-sensitive adhesive on one side (e.g., Elastollan SP9109 or Elastollan SP806), and may be gas-impermeable, so that it can cover the wound and seal the wound cavity on which the wound dressing is placed. Thus, a chamber, or sealed wound space, is created between the cover layer 12200 and the wound site. In some embodiments, negative pressure may be established within the chamber, or sealed wound space, created between the cover layer 12200 and the wound site. The cover layer 12200 protects the wound from external bacterial contamination (bacterial barrier) and allows fluid from wound exudate to move through the layer and evaporate from the outer surface of the film. The cover layer 12200 may include two or more layers, for example, a polyurethane film and an adhesive pattern spread on the film. In certain examples, the polyurethane film may be permeable and may be made from a material whose water permeability increases when wet. In some embodiments, the permeability of the cover layer increases when the cover layer is wet. The permeability of the wet cover layer may be up to about 10 times that of the dry cover layer. In some embodiments, the cover layer 12200 may be replaced or supplemented with additional wound dressings as described elsewhere in this specification, thereby positioning the additional wound dressings above the nitric oxide generating layer. The cover layer may also be waterproof so that the dressings incorporating such a cover layer can be used in a shower. The cover layer may be configured so that nitric oxide does not immediately leak through the cover layer, meaning that the cover layer is nitric oxide impermeable or semi-impermeable, thereby trapping nitric oxide against the tissue so that nitric oxide can interact with the user's body. Those skilled in the art will understand that the cover layer can be fabricated to be vapor-permeable but nitric oxide-impermeable.

[0071] The nitric oxide source layer 12600 may provide one or more nitric oxide release agents to the wound site. The nitric oxide release agent may include any chemical entity that produces nitric oxide at the wound site when activated or otherwise stimulated to produce nitric oxide at the wound site. In some embodiments, the nitric oxide release agent may include nitrite ions, nitrites, organic and inorganic nitrites, or any pharmacologically acceptable nitrite source, thereby reducing the amount of nitrite ions required to produce nitric oxide at the wound site. For example, the nitric oxide source layer 12600 and / or elements may include one or more of ammonium nitrite, lithium nitrite, calcium nitrite, sodium nitrite, and potassium nitrite. In some embodiments, the nitric oxide source layer may be a suitable material layer or element containing alkali metal nitrites and / or alkaline earth metal nitrites. In certain embodiments, the nitrite may include LiNO2, NaNO2, KNO2, RbNO2, CsNO2, FrNO2, Be(NO2)2, Mg(NO2)2, Ca(NO2)2, Sr(NO2)2, Ba(NO2)2, Ra(NO2)2, or any other suitable nitrite. In some embodiments, precursors of nitrite ions, such as nitrite, nitrate ions, nitroprusside ions, or any pharmacologically acceptable salts thereof, may be used as the source of the nitrite. In some embodiments, the nitric oxide release agent may include nitrites, such as nitro-functionalized compounds.For example, nitric oxide-releasing agents include nitroglycerin, isoamyl nitrite, isobide mononitate, N-(ethoxycarbonyl)-3-(4-morpholinyl)sidenimine, 3-morpholinosidenimine, 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-di-chlorophenyl)-chloride, 1,2,3,4-oxatriazolium, 5-amino-3-(chloro-2-methylphenyl)chloride, 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl) It may contain the internal salt of (l)-5-[[[cyanomethylamino]carbonyl]amino]-hydroxydo, S-nitroso-N-acetyl-(D,L)-penicillamine, l-[(4',5'-bis(carboxymethoxy)-2l-nitrophenyl)methoxy]-2-oxo-3,3,diethyl-l-triazenipotassium salt, and [l-(4',5'-bis(carbomethoxy)-2'-nitrophenyl)methoxy]-2-oxo-3,3-diethyl-1-triazinediacetoxymethyl ester.

[0072] In some embodiments, the nitric oxide release agent of the nitric oxide source layer 12600 may include diazenium diolates, including O-alkylated diazenium diolates, O-derivativeated diazenium diolates, and non-O-derivativeated diazenium diolates. For example, the nitric oxide release agent may include diethylamine / NO, V-PYRRO / NO, and / or spermine / NO. In some embodiments, the nitric oxide release agent of the nitric oxide source layer 12600 may include S-nitrosothiols, such as S-nitro-glutathione, S-nitroso-N-acetylcysteine, and S-nitroso-acetylpinicillamine. In some embodiments, the nitric oxide release agent of the nitric oxide source layer 12600 may include silica or silica nanoparticles modified with nitric oxide. In some embodiments, the nitric oxide release agent may be a polymer modified with nitric oxide to contain nitric oxide. For example, polyethyleneimines, polypropyleneimines, polybutyleneimines, polyurethanes, or polyamides can be modified with nitric oxide to form diazenium diolates. In some embodiments, the nitric oxide source layer 12600 can be constructed from such polymers modified with nitric oxide. Further examples of nitric oxide-releasing agents are provided in International Publication No. WO2006 / 058318 and Liang et al., "Nitric oxide generating / releasing materials," Future Science OA, 1(1)(2015), which are incorporated herein by reference in their entirety.

[0073] In some embodiments, the nitric oxide source layer 12600 may contain a nitric oxide release agent (e.g., sodium nitrite) in an aqueous solution. For example, the nitric oxide source layer 12600 may contain a material immersed in a solution of a nitric oxide release agent (e.g., sodium nitrite). In some embodiments, the nitric oxide source layer 12600 may contain a dry nitric oxide release agent (e.g., sodium nitrite) in solid form.

[0074] The nitric oxide source layer 12600 may comprise a mesh, foam, gel, or any other material suitable for containing a nitric oxide release agent. For example, the nitric oxide source layer 12600 may comprise a mesh impregnated with a solution of a nitric oxide release agent (e.g., sodium nitrite). The mesh may be knitted, woven, or nonwoven. The mesh may be made from polymer materials, such as viscose, polyamide, polyester, polypropylene, or a combination thereof. In some embodiments, the nitric oxide source layer 12600 may comprise 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 that release nitric oxide. In some embodiments, the nitric oxide source layer 12600 may be constructed from a colored material so that it can be visible during application to a wound to assist in the positioning of the wound dressing 12000 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 completely or semi-permeable to the diffusion of nitric oxide.

[0075] In some embodiments, the nitric oxide source layer 12600 is the bottom layer of the dressing 12000 so that the nitric oxide source layer 12600 can come into contact with the wound. In some embodiments, the nitric oxide source layer 12600 may be located within and / or on the wound. The nitric oxide source layer may be constructed so that the nitric oxide source layer 12600 does not substantially adhere to the skin or the wound, or does not cause damage to the wound when it comes into contact with the wound. In some embodiments, the dressing 12000 may include one or more layers beneath the nitric oxide source layer 12600, for example, a wound contact layer. In some embodiments, the wound dressing 12000 may include two or more nitric oxide source layers. For example, the wound dressing 12000 may include two, three, four, five, six, seven or more nitric oxide source layers. In some embodiments, the nitrite supply layer 12600 may be separate from the wound dressing 12000. For example, the nitrite-providing layer 12600 may be provided as a separate layer that can be placed on the wound, and the wound dressing 12000 may be placed on it. The nitric oxide-releasing agent may be incorporated into the nitrite-providing layer to provide a dose of nitrite (e.g., a dose of sodium nitrite) in M ​​(moles) of about 0.01 to 5.0, 0.5 to 4.5, 1.0 to 3.0, 1.0 to 2.0, and / or 1.0 to 1.5. For example, the dose may be about 0.50 M, about 0.01 M, about 1.5 M, about 2 M, or about 2.5 M.

[0076] The activator layer 12400 may contain chemical agents, functional groups, or functional moieties that can activate and / or facilitate the release of nitric oxide from the nitric oxide release agent. For example, protons or an acidic environment may promote the reduction of nitrite to nitric oxide, and the activator layer 12400 may contain acidic groups or acidic moieties that can provide protons in an aqueous environment, thereby lowering the pH at the application site. In certain embodiments, the acidic groups or moieties are immobilized in the activator layer 12400, for example, on the surface of the activator layer 12400. The acidic groups or acidic moieties may be covalently bonded in the activator layer 12400. In some embodiments, the activator layer 12400 may contain an acidic solution. The activator layer 12400 may contain a mesh, foam, gel, or any other material suitable for containing acidic groups or acidic moieties. In some embodiments, the activator layer 12400 may be located above the nitric oxide source layer 12600, or below the nitric oxide source layer 12600. In some embodiments, the activator layer 12400 may contain water, a proton source such as methanol, ethanol, propanol, butanol, pentanol, hexanol, phenol, naphthol, or polyol, an acid such as phosphate, succinate, carbonate, acetate, or formate, an acidic buffer such as propionate, butanoate, fatty acid, amino acid, or ascorbic acid, or any suitable enzymatic or catalytic compound. In some embodiments, body fluids such as blood, lymph, bile, or wound exudate may function as activators and assist the activator layer 12400. In some embodiments, the wound dressing 12000 may not contain the activator layer 12400, and a wound fluid or wound exudate may function as an activator. Further examples of activators for nitric oxide release agents are provided in International Publication No. WO2006 / 058318 and Liang et al., "Nitric oxide generating / releasing materials," Future Science OA, 1(1)(2015), which are incorporated herein by reference in their entirety.

[0077] In some embodiments, the wound dressing 12000 may include two or more nitric oxide source layers and / or two or more activator layers. For example, the wound dressing 12000 may include two, three, four, five, six, seven or more nitric oxide source layers and / or activator layers.

[0078] In some embodiments, the activator layer 12400 includes a hydrogel so that the activator layer 12400 can absorb wound exudate. In certain examples, the activator layer 12400 may be constructed from a xerogel. The activator layer 12400 may be constructed from any suitable material disclosed herein. The gel of the activator layer 12400 may be presented in different physical formats. For example, the activator layer 12400 may foam during curing. The hydrogel may be poured into a foam and then cured within the foam. In some embodiments, the activator layer 12400 may be perforated through its thickness. The perforations may be sized to allow fluid absorption and to release a desired therapeutic dose of nitric oxide from the wound dressing. For example, the perforations may have diameters of approximately 0.1mm–10mm, 0.15mm–7mm, 0.2mm–5mm, 0.5mm–4mm, or 0.7mm–3mm. The perforations may be circular, square, triangular, or any other suitable shape. The foamed structure and / or perforations may contribute to the fluid handling capacity of the activator layer.

[0079] In some embodiments, the active substance for the activator layer may be provided as a dispensable composition, for example, a prepolymer solution, or in an otherwise moldable form, instead of being provided as an activator layer such as activator layer 12400, so that it can be applied more freely to the wound and / or around the wound. For example, the active substance may be provided as a gel prepolymer solution so that it can be applied by a clinician to or in close proximity to a wound having an irregular shape and size. In some embodiments, the active substance, 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 substance may also be formulated to cure rapidly and, once applied to or around the wound, no longer flow. The active substance may contain an evaporative solvent, such as isopropanol. The active substance may have a suitable secondary curing mechanism, such as a photoinitiated acrylate functional group. In some embodiments, the active substance may be provided as a reactive two-subsystem. For example, the first and second parts may be provided to be mixed so as to result in polymer formation immediately before dispensing. In some embodiments, the first and second parts may be oppositely charged fluid gels, thereby interacting upon mixing to provide a substantially non-flowing gel. In some embodiments, the active substance may include a material such as a gel that changes in response to changes in the environment. For example, the active substance may include a material such as a specific Pluronic so as to harden when the temperature changes as it is applied to the skin from a dispenser or syringe. The active substance may be applied so as to interact with nitrite from the nitric oxide source layer 12600 (which may provide nitrite) to produce nitric oxide. Once the active substance is applied and hardened or otherwise non-flowing, the cover layer 18200 may be applied.

[0080] When the coating material 12000 is activated, for example, by placing the activator layer 12400 in contact with the nitric oxide source layer 12600, the nitric oxide release agent from the nitric oxide source layer 12600 releases nitric oxide. For example, in some embodiments, nitrites can be reduced to nitric oxide in the presence of the acidic environment provided by the activator layer 12400, as shown below.

[0081] [ka]

[0082] The activator layer 12400 and the nitric oxide source layer 12600 may be positioned such that a nitric oxide-releasing agent reacts to provide nitric oxide. For example, the activator layer 12400 and the nitric oxide source layer 12600 may be in contact with each other within the coating 12000 during use. In some embodiments, one or more additional layers may be positioned between the activator layer 12400 and the nitric oxide source layer 12600. In some embodiments, the activator layer 12400 and the nitric oxide source layer 12600 may be fluidically separated from each other before the coating 12000 is applied to the patient to prevent premature release of nitric oxide. For example, the nitric oxide source layer 12600 may be supplied in separate packaging from the rest of the coating 12000. Once the coating 12000 is activated, the nitric oxide-releasing agent from the nitric oxide source layer 12600 may be dispersed within the coating 12000. In some embodiments, the nitric oxide-releasing agent may be dissolved in the wound exudate, which can facilitate the dispersion of the nitric oxide-releasing agent. At least a portion of the nitric oxide-releasing agent will react to release nitric oxide in the presence of the activator in the activator layer 12400. The generated nitric oxide can diffuse into the wound or be delivered to the wound by any preferred 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, thereby preventing or killing microbial growth within the dressing.

[0083] In some embodiments, the wound dressing 12000 may contain a reducing agent that facilitates the reduction of a nitric oxide-releasing agent (e.g., nitrite ion) to nitric oxide. Physiologically acceptable examples of such reducing agents include, but are not limited to, iodide anions, ascorbic acid, ascorbates (e.g., sodium ascorbate), isoascorbic acid (e.g., sodium isoascorbate), hydroquinone, butylated quinone, tocopherol, butylated hydroquinone, hydroquinone variants, butylated hydroxyanisole, butylated hydroxytoluene, beta-carotene, potassium iodide, ascorbic acid variants, isoascorbic acid variants, any other suitable reducing agent, and / or antioxidants and / or reducing agents as described herein. The reducing agent may be contained in one or more layers of the wound dressing 12000. For example, the reducing agent may be included in the cover layer 12200, the activator layer 12400, the 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 containment, physical mixing, coating, covalent bonding, or any other suitable method. The reducing agent may be incorporated into the dressing in a suitable layer, such as a hydrogel activator layer, in w / w% of about 0.01–5.0%, 0.1–4.5%, 1.0–3.0%, 1.0–1.5%, and / or 1.5–2.5%. For example, the w / w% may be about 0.02%, about 0.03%, about 0.8%, about 1.2%, about 1.4%, or about 2.43%. Higher levels of reducing agents can lead to increased nitric oxide production, however, very high levels of reducing agents can be toxic.

[0084] As described herein, the nitric oxide source layer may contain a nitrite and may be referred herein to as a nitrite delivery layer or nitrite supply layer. As described herein, the activator layer may contain an acid and may be referred herein to as an acid supply layer or acid delivery layer. The nitric oxide source layer / nitrite delivery layer / nitrite supply layer and the activator layer / acid supply layer may be referred herein to as a nitric oxide generating layer, collectively or individually. As will be understood by those skilled in the art, the nitrite supply layer disclosed herein may be prepared and provided separately from the wound dressing. For example, the nitrite supply layer may be applied to a wound, and the wound dressing may be applied on top of the nitrite supply layer.

[0085] Nitric oxide coating materials and structures As will be understood by those skilled in the art, the materials and covering structures described above in relation to the nitric oxide delivery covering 1200 in Figures 4-5 and elsewhere in this specification may include several suitable structures and different types of materials. For example, the uppermost layer furthest from the wound may be an upper layer or cover film layer, such as a polyurethane material, as disclosed herein. Such an upper layer or cover film may be constructed from the material used for the cover layer of RENASYS drapes, sold by Smith+Nephew. For example, in some embodiments, the cover layer may be an IV3000 top film. Below the upper layer or cover film layer may be a masking or fabric layer, which may be constructed from any suitable material disclosed herein as a masking or fabric layer. The masking layer may be constructed from stretchable and non-stretchable polyester, polyethylene, polypropylene, polypropylethylene, and nonwoven fabrics and suitable mixtures thereof. For example, in some embodiments, the masking layer may be a 17gsm polypropylene masking layer. More preferable nonwoven fabrics and mixtures may also be available. In certain embodiments, the masking layer may be a foam. Beneath the masking layer, or fabric layer, is an activator layer similar to the activator layers described herein and throughout this specification. Such an activator layer may be constructed from a hydrogel adhesive, optionally containing a central polyester support mesh and / or a support release liner. For example, in some embodiments, the activator layer may be in a DURAFIBER format, loaded with hydrogel as described herein. As will be understood by those skilled in the art, DURAFIBER is a cellulosic material manufactured by Smith+Nephew. In such embodiments, depending on the size of the covering material, an equivalent of approximately 6 grams of hydrogel can be loaded onto a 10.8 cm × 10.8 cm DURAFIBER piece, which can then be cut into 10 cm × 10 cm pieces, resulting in approximately 5.14 grams of hydrogel on each 10 cm × 10 cm DURAFIBER piece.The activator layer may be constructed from any suitable hydrogel material disclosed herein, such as acrylic acid hydrogel and / or sulfonic acid hydrogel. Beneath the activator layer may be a water-absorbing partitioning layer, which may be constructed from any suitable water-absorbing partitioning layer material disclosed herein, such as those related to Figures 2C-2D. For example, the water-absorbing partitioning layer may be constructed from 3D knit, gauze and / or stretch polyester fibers woven in a net form, similar to the material used in Acticoat Flex by Smith+Nephew, but silver is optional. In some embodiments, the water-absorbing partitioning layer may be constructed from a prepolymer solution having a mixture of water, a surfactant and polyethylene glycol, such as the foam used in Allevyn foam by Smith+Nephew. The masking layer and the water-absorbing partitioning layer may use the same material and be interchangeable. In certain embodiments, the water-absorbing partitioning layer may be pressed into the activator layer and / or cured within the activator layer. Curing the water absorption and distribution layer within the activator layer may improve the rate of nitric oxide formation due to faster transport. Below the water absorption and distribution layer, there may be a wound contact layer, which may be constructed from any suitable material disclosed herein, such as the one related to Figure 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 so that the nitric oxide source layer is direct to the wound or other tissue. In some embodiments, the nitric oxide source layer may be in other locations, such as above the activator layer and / or elsewhere within the coating. For example, in some embodiments, the nitrite supply layer may be a separate 17gsm polypropylene mesh saturated with a sodium nitrite solution. In certain embodiments, the ALLEVYN, or PICO coating, disclosed in Figures 2-3, may be placed directly above the activator layer and the underlying nitric oxide source layer. Direct placement of a nitric oxide source layer on the wound, surrounding area, and / or other tissues may allow for increased direct release of nitric oxide into the tissue.As will be understood by those skilled in the art, the wound dressings and / or nitric oxide delivery embodiments described in this section of this specification, or elsewhere in this specification, may be applied to a wound and / or to the surrounding skin, such as the area surrounding the wound.

[0086] Chemiluminescence Figure 6 shows an exemplary configuration 600 for a chemiluminescence protocol for testing nitric oxide delivery coatings, such as those disclosed above in relation to Figures 4 and 5. The protocol may include a sample 602, a desiccant 604, an air source 606, a chemiluminescence detector 608, a nitrogen supply unit 610, an air pump 612, a mass flow meter 614, and a T-piece connector 616. In certain embodiments, a ThermoFisher 42i-HL detector may be used as the chemiluminescence detector 608. After warming the instrument with an airflow under atmospheric pressure, the sample box 602 and the nitrogen supply unit may be connected to the instrument. The nitrogen flow through the mass flow controller may be set to a preferred value, such as about 1 to 100, 10 to 90, 25 to 75, 40 to 60, or about 50 mL / min. After flushing the system (e.g., for about 1-60, 10-50, 20-40, or about 30 minutes), a nitric oxide source layer (such as a nitrite mesh) and an activator layer (such as an acid-providing hydrogel) may be placed in the sample chamber 602. In some embodiments, the nitrite mesh has a smaller total area than the activator layer. In certain embodiments, the nitric oxide source layer and / or activator layer may have lengths and / or widths 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 × 2.5 cm, while the activator layer may be 3 cm × 3 cm.

[0087] The NO / NO2 emission concentration may be measured at an appropriate rate by a chemiluminescence detector, checking the concentration in ppb or ppm units and monitoring it periodically, such as every 1, 2, 5, 10, 30, 60, or 90 seconds. In certain embodiments, the NO / NO2 concentration may be checked in ppm units.

[0088] As will be understood by those skilled in the art, for coatings disclosed herein, such as those described in relation to Figures 4-5, it is desirable to maximize NO above NO2. Nitric oxide (NO2) can exhibit antimicrobial properties, but NO2 does not possess the vasodilatory properties or cell proliferation-activating ability of NO. Therefore, it is generally desirable to reduce the generation of NO2 as much as possible during nitrite acidification, such as by means of reducing the oxidation of dissolved nitric oxide (NO) by removing oxygen from the hydrogel body where nitrite acidification occurs. Nitric oxide delivery coatings disclosed herein can generate both NO and NO2. In some embodiments, nitric oxide coatings disclosed herein can generate NO and NO2 in NO / NO2 ratios such as about 0.5:1 to 500:1, 1:1 to 400:1, 10:1 to 300:1, 20:1 to 200:1, and 50:1 to 100:1. For example, the ratio could be approximately, or at least approximately 0.5:1, 1.01:1, 1.1:1, 1:1, 2:1, 5:1, 10:1, 20:1, 30:1, 50:1, 100:1, 200:1, or 500:1.

[0089] Figure 7 shows an example of an experimental configuration 700 and subsequent results 750 demonstrating nitric oxide delivery from a combination of an activator layer and a nitric oxide source layer while under negative pressure, similar to the dressings described in relation to Figures 4 and 5. As shown in Figure 7A, a negative pressure wound therapy pump 702 is connected to a negative pressure wound therapy dressing 704, such as those described herein in Figures 2A–2D. The dressing is sealed over a chamber 706 containing a nitrite test solution 708 that changes color in the presence of NO. In some embodiments (data not shown), the test solution did not change color before negative pressure was applied (750). After running negative pressure for a period of time to ensure that no background color change occurred, as shown in 760, an activator layer 710 (such as an acid-providing hydrogel), such as those 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 generate nitric oxide even under negative pressure.

[0090] As will be understood by those skilled in the art, negative pressure can be applied to any of the nitric oxide delivery dressings disclosed herein, such as dressings, as shown in Figures 4-5 and elsewhere in this specification. Dressings, such as those shown in Figures 2A-2D, may be placed on an activator layer and a nitric oxide source layer placed within the wound, thereby delivering nitric oxide to the wound while simultaneously applying negative pressure wound therapy.

[0091] Figures 8A–8C show examples of chemiluminescence experiments using protocols similar to those described above. As will be understood by those skilled in the art, these measurements obtained in these experimental runs are merely illustrative, and the disclosure herein is not limited to such values. Figure 8A shows experimental results when testing a dry sodium nitrite mesh embodiment with the arrangement shown in Figure 8A, which includes a polyurethane cover layer superimposed on a stretchable polyester ADL layer, positioned on a hydrogel activator layer sandwiched between another stretchable polyester ADL layer on a dry sodium nitrite mesh, as shown in the figure. In this experimental run, after the addition of DI water, the dry sodium nitrite mesh released approximately 550 ppm NO and 75 ppm NO2 at its peak at the 25-minute mark, and the concentrations gradually decreased to approximately 80 ppm NO and 10 ppm NO2 at the 50-minute mark.

[0092] Figure 8B shows experimental results when testing the entire coating design with a pull-out tab and a self-sealing boundary. The pull-out tab is initially used to separate the nitric oxide source layer from the activator layer; therefore, once the tab is removed and the coating is wet, the interaction between the nitric oxide source layer and the activator layer generates nitric oxide. In this experimental run, after the addition of DI water, the entire coating design with the pull-out tab and self-sealing boundary released approximately 84 ppm NO and 15 ppm NO2 at its peak at the 17-minute mark, and the concentrations gradually decreased to approximately 25 ppm NO and 5 ppm NO2 at the 50-minute mark.

[0093] Figure 8C shows an example of experimental results for a coating containing a biodegradable film. Here, the biodegradable film was placed between the activator layer and the nitric oxide source layer, thereby generating nitric oxide once the biodegradable layer decomposed. In this experiment, after the addition of DI water, the coating containing the biodegradable film released approximately 1000 ppm NO and 45 ppm NO2 at the 25-minute mark, with a peak, and the concentrations gradually decreased to approximately 225 ppm NO and 20 ppm NO2 at the 50-minute mark. The experimental protocol was also used to test an activator layer containing sodium isoascorbate. In this experimental run, after the addition of DI water, the activator layer containing sodium isoascorbate released approximately 52 ppm of NO and 4 ppm of NO2 at its first peak at the 80-minute mark, 66 ppm of NO and 5 ppm of NO2 at its second and largest peak at the 110-minute mark, and gradually decreased in concentration to approximately 45 ppm of NO and 2 ppm of NO2 at the 160-minute mark.

[0094] Figure 9 shows various gsm (g / m 2 Examples of relative peak output in ppm for activator hydrogels (acid provided) with or without a water absorption partition layer, including a water absorption partition layer made of polypropylene, polypropylethylene, or stretch polyester, are shown. Without the water absorption partition layer, the peak NO and NO2 concentrations were approximately 55 ppm and 10 ppm, respectively; however, those skilled in the art will understand that the water absorption partition layer can enable improved fluid distribution and handling over a larger area, such as in a coating. For a 17 gsm polypropylene press-fitted water absorption partition layer, the peak NO and NO2 concentrations were approximately 20 ppm and 2 ppm, respectively. For a 17 gsm polypropylene cured water absorption partition layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. As described above, curing the water absorption partition layer can enable increased fluid transport and increased nitric oxide formation rates. (Polypropylene 30 g / m²) 2In the pressure-absorbing water distribution layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. (Polypropylene 30 g / m²) 2 In the water absorption distribution layer, the peak NO and NO2 concentrations were approximately 40 ppm and 5 ppm, respectively. (Polypropylene 40 g / m²) 2 In the pressure-absorbing water distribution layer, the peak NOk and NO2 concentrations were approximately 30 ppm and 2 ppm, respectively. (Polypropylene 40 g / m²) 2 In the cured water absorption partition layer, the peak NO and NO2 concentrations were approximately 38 ppm and 5 ppm, respectively. (Polypropylethylene 30 g / m²) 2 In the pressure-absorbing water distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. (Polypropylethylene 30 g / m²) 2 In the cured water absorption distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. In the stretchable polyester pressure water absorption distribution layer, the peak NO and NO2 concentrations were approximately 35 ppm and 3 ppm, respectively. In the FLEX pressure water absorption distribution layer, the peak NO and NO2 concentrations were approximately 55 ppm and 8 ppm, respectively.

[0095] Figures 10A–10D show examples of NO and NO2 concentrations over time for several embodiments incorporating an activator layer and a nitric oxide donor layer. As shown in Figures 10A–10B, activator layers containing approximately 2–3% sodium isoascorbate were tested with or without different pressed or cured water-absorbing partitioning layers. Gels without a water-absorbing partitioning layer produced pNO=785 ppm and pNO2=78 ppm (p indicates the peak). Activator layers with stretch polyester pressed into the gel produced pNO=506 ppm and pNO2=24 ppm. With stretch polyester cured on the activator layer, pNO=625 ppm and pNO2=50 ppm. With polypropylene pressed into the gel, pNO=508 ppm and pNO2=26 ppm. In polypropylene cured within the gel, pNO = 624 ppm and pNO2 = 26 ppm.

[0096] Figures 10C-10D show examples of NO and NO2 concentrations over time in an activator layer containing approximately 1-2% sodium isoascorbate, with or without different pressed or cured water-absorbing partitioning layers. The activator layer without ADL produced pNO=334 ppm and pNO2=40 ppm. The stretchable polyester water-absorbing partitioning layer pressed within the activator layer produced pNO=211 ppm and pNO2=10 ppm. The stretchable polyester water-absorbing partitioning layer cured within the activator layer produced pNO=247 ppm and pNO2=14 ppm. The polypropylene water-absorbing partitioning layer pressed within the activator layer produced pNO=112 ppm and pNO2=5 ppm. The polypropylene water-absorbing partitioning layer cured within the activator layer produced pNO=184 ppm and pNO2=8 ppm. As described elsewhere in this specification, curing the water absorption and distribution layer within the activator layer can improve fluid handling and nitric oxide generation compared to nitric oxide generation.

[0097] Xerogel and hydrogel constructs In this specification, xerogels may be used as references. Xerogels can be formed from gels by drying under unhindered shrinkage conditions. As will be understood by those skilled in the art, xerogels are gels having a very low free water content, such a low water content that the minimum reaction to form nitric oxide occurs without the addition of further water and / or liquid. For example, xerogels may be substantially water-free in their dry state. Drying can be completed by any preferred means known in the art (e.g., freeze-drying).

[0098] In certain cases, the hydrogel (which may then become a xerogel after drying) may be produced with or without glycerol and may contain, as necessary, a standard amount or two, three, or four times the required amount of the crosslinking agent PEG diacrylate. A solution of sodium 2-acrylamido-2-methyl-1-propanesulfonic acid may be present in the xerogel. The hydrogel and xerogel may be prepared by converting 2-acrylamido-2-methyl-1-propanesulfonic acid (SA), stabilized in as-supplied MEHQ, to a sodium salt by dissolving it in water, and then neutralizing it with 50% NaOH to pH 7.0 while cooling from a 10°C water bath to form a solution of neutralizing acid (NaAMPS). The hydrogel may contain approximately 5.393% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 1.0 SA), approximately 4.654% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.85 SA), approximately 2.839% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.5 SA), and / or ranges from approximately 1.457% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 0.25 SA) to approximately 7.704% by weight of 2-acrylamido-2-methyl-1-propanesulfonic acid (equivalent to 1.5 SA). The hydrogel prepolymer is prepared by pre-dispersing the 2-hydroxy-2-methylpropiophenone photoinitiator in PEG diacrylate with minimal light, and then mixing it with a 58% aqueous solution of sodium 2-acrylamido-2-methyl-1-propanesulfonate (NaAMPS), sodium isoascorbate, pre-pulverized 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS acid), and glycerol, and then adding 10- It can be prepared by mixing for 20 minutes. The AMPS acid may be completely dissolved in a stirred Na AMPS solution before glycerol is gradually added, and then the photoinitiator / diacrylate mixture may be completely dissolved in a water bath. In certain embodiments, the hydrogel may also be prepared using twice the usual amount of photoinitiator / crosslinker and / or omitting glycerol, and / or using three times the amount of prepolymer mixture in the mold to form a gel three times thicker.

[0099] Nitric oxide generating coating material utilizing anhydrous sodium nitrite Figures 11A–11D show embodiments of nitric oxide generating wound dressings having various layer arrangements. As will be understood by those skilled in the art, the nitrite-providing layer disclosed herein may be prepared and provided separately from the wound dressing. For example, the nitrite-providing layer may be applied to the wound, and the wound dressing may be applied on top of the nitrite-providing layer. Those skilled in the art will further understand that the various layers shown in Figures 11A–11D may be ordered in any preferred order, and the order shown in the figures is merely an example. In some embodiments, the top layer may be a cover layer 13002, which may have any of the same features, materials, or other details as the cover layer disclosed herein, such as being constructed from a film. The cover layer 13002 may be suitable for sealing the dressing over the wound, and for connecting to a negative pressure source and / or maintaining negative pressure at the wound site. In certain embodiments, the boundary region of the cover layer 13002 may be attached to the skin surrounding the wound to form a seal, so that wound exudate can be contained within the wound dressing 13000. Beneath the cover layer, a masking layer or concealing layer 13004 (hereinafter referred to as the “masking layer”) may be present to prevent or limit the visibility of the wound or wound exudate through the cover layer 13002. The masking layer 13004 may be located beneath at least a portion of the cover layer 13002. In some embodiments, the masking layer 13004 may have any of the same features, materials, or other details as any other embodiment of the masking layer disclosed herein, including, but not limited to, having any viewing windows or holes. Examples of wound dressings having a concealing layer and a viewing window are described in International Patent Publications WO2013 / 007973 and WO2014 / 020440, which are incorporated by reference in their entirety. Furthermore, the masking layer 13004 may be positioned adjacent to the cover layer or, if desired, adjacent to any other dressing layer. In the illustrated embodiment, the masking layer 13004 is positioned between the cover layer 13002 and the activator layer 13006.As described elsewhere in this specification and as will be understood by those skilled in the art, the activator layer may be an acid-providing layer or other preferred layer. In certain embodiments, the masking layer 13004 may be bonded to or integrally formed with the cover layer 13002. The masking layer 13004 may have substantially the same size and shape as the activator layer 13006 and be configured to overlay it. The masking layer 13004 may have a smaller area than the cover layer 13002. In certain embodiments, the masking layer 13004 may horizontally absorb the fluid and, similarly, function as a water absorption distribution layer.

[0100] In certain embodiments, the activator layer 13006 may have any of the same features, materials, or other details as any other embodiment of the activator layer disclosed herein. For example, the activator layer 13006 may be an adhesive and may be constructed from a hydrogel or xerogel configured to have a plurality of acidic groups or acidic moieties capable of providing protons in an aqueous environment. As described elsewhere in this specification, under such acidic conditions, nitrite ions from the nitric oxide source layer 13010 may be reduced to nitric oxide for delivery to wound or intact skin. As described elsewhere in this specification and as understood by those skilled in the art, the activator layer may be a nitrite supply layer or other preferred layer. The activator layer 13006 (e.g., a hydrogel layer) may include a plurality of perforations extending through the thickness of the activator layer, as described elsewhere in this specification. Multiple perforations may allow wound exudate beneath or around the activator layer to be transported to one or more additional absorbent and / or evaporative layers (e.g., cover layers) above the activator layer, thus enabling or facilitating the passage of wound exudate through the activator layer to prevent excessive accumulation of wound exudate beneath the activator layer 13006. Furthermore, multiple perforations may provide an increased surface area of ​​the activator layer, thereby increasing the absorption rate of the activator layer.

[0101] As shown in Figure 11A, in some embodiments, the water absorption distribution layer 13008 may be positioned between the activator layer 13006 and the nitrite supply layer 13010. In certain embodiments, the water absorption distribution layer 13008 may be constructed to advantageously draw up a fluid, such as wound exudate, horizontally as it is absorbed through the layers of the dressing 13000. Such lateral draw-up of the fluid may also allow for maximum distribution of the fluid through the activator layer 13006, enabling the activator layer 13006 to reach its full retention capacity. Furthermore, the water absorption distribution layer 13008 may facilitate the generation of nitric oxide because the nitrite ions dissolved in the fluid can spread more rapidly across the surface of the activator layer 13006. Some embodiments of the water absorption distribution layer 13008 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these materials, and the material may be needle-punched. Some embodiments of the water absorption and distribution layer 13008 may contain cellulose in the range of 40 to 160 gsm (or about 40 to about 160 gsm), for example, 80 (or about 80) gsm. Some embodiments of the water absorption and distribution layer 13008 may contain polyethylene in the range of 40 to 150 grams / square meter (gsm). In some embodiments, the water absorption and distribution layer 13008 may have a thickness of 1.2 mm or about 1.2 mm, or a thickness in the range of about 0.5 mm to 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 and distribution layer 13008 may be constructed from a material that resists compression at levels of negative pressure commonly applied during negative pressure therapy.

[0102] The water absorption and distribution layer 13008 may contain a plurality of loosely wrapped fibers that can be arranged within a substantially horizontal fibrous network. In some embodiments, the water absorption and distribution layer 13008 may consist of a mixture of two fiber types. One may be a flat fiber having a width of 20 μm to 50 μm, or about 20 μm to about 50 μm, and may contain a cellulose-based material. The other fiber may be a two-component fiber having an inner core with a diameter of 8 μm to 10 μm, about 8 μm to about 10 μm, 7 μm to 11 μm, 6 μm to 12 μm, or 5 μm to 13 μm, and an outer layer having a thickness of 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm. The two-component fiber may be a mixture of polyethylene (PE) type material and polyethylene terephthalate (PET). In some embodiments, the core of the two-component fiber may be PET, and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may contain about 60% to about 90% cellulose fibers, for example, about 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, for example, about 25% PE / PET fibers. In some embodiments, the water absorption distribution layer 13004 may contain segmented microfibers.

[0103] The majority of the fiber volume may extend horizontally (i.e., parallel to the top and bottom planes of the material), or substantially or nearly horizontally. In another embodiment, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In yet another embodiment, all or substantially all of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some embodiments, the majority of the fibers, 80% to 90% (or about 80% to about 90%) or more, or even all or substantially all of the fibers, extend over a distance (horizontal or transverse distance) perpendicular to the thickness of the water absorption distribution layer 13004, which is greater than the thickness of the water absorption distribution layer 13004. In some embodiments, the horizontal or transverse distance covered by such fibers is at least twice (or about twice), three times (or about three times), four times (or about four times), five times (or about five times), or ten times (or about ten times) the thickness of the water absorption distribution layer 13008. Such fiber orientation can promote the transverse suction of fluid through the water absorption distribution layer 13008. This allows for a more even distribution of fluids, such as wound exudate, across the entire water absorption distribution layer 13008. In some embodiments, the ratio of the amount of fluid suctioned transversely across the water absorption distribution layer 13008 to the amount of fluid suctioned vertically through the water absorption distribution layer 13008 under negative pressure may be 2:1 or about 2:1 or more, or in some embodiments, up to 10:1 or about 10:1 or more.

[0104] Continuing with Figure 11A, in an embodiment, the nitric oxide source layer 13010 may be provided beneath the water absorption and distribution layer 13004. Such a nitric oxide source layer 13010 may have any of the same features, materials, or other details as any other embodiment of the nitric oxide source layer disclosed herein, for example, the nitric oxide source layer 13010 may be a nitrite supply layer. For example, the nitric oxide source layer may be a wet mesh immersed in a sodium nitrite solution. In some embodiments, the nitric oxide source layer 13010 may be dry and may contain a dry nitrite source such as dry sodium nitrite. Such dry sodium nitrite may be loaded into a material layer, which is constructed from a suitable material such as any material disclosed herein. As will be understood by those skilled in the art, dry materials and / or substances are those that do not contain or contain relatively little liquid. For example, polypropylene, polyethylene, or melt-extrudeable fibers may be suitable materials for such a layer. In embodiments, such a nitric oxide source layer 13010 layer may need to be initially separated from the activator layer 13006 when the activator layer is a hydrogel, in order to avoid reaction and nitric oxide generation before application to the wound and / or skin. As shown in Figure 11A, a dry fluid absorption layer 13008 may serve to separate the nitric oxide source layer 13010 and the hydrogel activator layer 13004 before application. However, such a dry sodium nitrite supply layer may be adjacent to the xerogel activator layer 13006, as the xerogel would not be wetted. In the case of a xerogel, activation may occur when it comes into contact with a fluid such as wound exudate as the wound exudate is drawn up through the dressing. In the case of hydrogels, when a fluid such as wound exudate comes into contact with the water absorption and distribution layer 13008, nitrite ions may then come into contact with the acidic environment generated by the activator layer, thereby generating nitric oxide that can then move into the wound and / or skin. In some embodiments, each of the layers, such as the nitric oxide source layer, the activator layer, and any other suitable layer, may be dried and stored before use. Before application to the skin or wound, the layers may be moistened with a suitable liquid such as saline solution.

[0105] As illustrated in Figure 11B, to maintain nitric oxide release, several layers containing dry sodium nitrite may be present, for example, a first nitric oxide source layer 13010 and a second nitric oxide source layer 13012, which will be "activated" when the wound fluid reaches and wets the layer(s), allowing the sodium nitrite to come into contact with the acidic groups of the hydrogel or xerogel of the activator layer 13006, thereby generating nitric oxide. In certain embodiments, there may be two, three, four, five, six, or more layers containing dry sodium nitrite. As shown in Figure 11B, a masking layer 13004 may serve to prevent contact between the second nitric oxide source layer 13012 and the activator layer 13004. In certain embodiments, additional water absorption / distributing layers and / or masking layers may be sandwiched between the activator layers to provide additional nitric oxide sources.

[0106] As shown in Figures 11C to 11D, in the embodiment, the activator layer 13006 may be positioned below the nitric oxide source layer, thereby wetting the nitrite supply layer 13010 (from wound exudate) and enabling the dressing to be activated.

[0107] Nitric oxide coating material containing ADL Figures 12-13 show wound dressings 14000 having a nitric oxide generating layer. Wound dressing 14000 may be similar to wound dressing 12000. Wound dressing 14000 may include a cover layer 14200, an activator layer or acid-providing layer 14400, and a nitric oxide source layer or nitrite-providing layer 14600, each of which may be similar to the cover layer 12200, the activator layer or acid-providing layer 12400, and the nitric oxide source layer or nitrite-providing layer 12600, respectively. As will be understood by those skilled in the art, the nitrite-providing layer(s) 12600 disclosed herein may be prepared and provided separately from the wound dressing. For example, the nitrite-providing layer 12600 may be applied to the wound, and the wound dressing may be applied on top of the nitrite-providing layer.

[0108] The cover layer 14200 may be similar to the cover layer 12200. The cover layer 14200 may have a greater length and width than the other layers 14400, 14600, and 14800 so that the cover layer 14200 defines a boundary region extending between the outer periphery of the other layers and the outer periphery of the cover layer 14200. The boundary region of the cover layer 14200 may be attached to the skin surrounding the wound to form a seal so that wound exudate can be contained within the wound dressing 14000.

[0109] In the illustrated embodiment, the wound dressing 14000 further comprises an ADL (Aqueductive Distribution Layer) 14800. The ADL 14800 may be constructed to favorably draw up fluids, such as wound exudate, horizontally as they are absorbed through the layers of the dressing 14000. Such lateral drawup of the fluid may also allow for maximum dispersion of the fluid through the acid-providing layer 14400, enabling the acid-providing layer 14400 to reach its full retention capacity. Furthermore, the ADL 14800 may facilitate the generation of nitric oxide because nitrite ions dissolved in the liquid can spread more rapidly across the surface of the acid-providing layer 14400. Some embodiments of the ADL 14800 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these materials, which may be needle-punched. Some embodiments of the water absorption and distribution layer 14800 may contain, for example, 80 (or about 80) gsm of cellulose in the range of 1 to 220 grams / m² (gsm) (or about 1 to about 220 gsm), 3 to 200 grams / m² (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). Some embodiments of the water absorption and distribution layer 14800 may include polyethylene in the range of 3–200 gsm (or about 3–200 gsm), 5–190 gsm (or about 5–190 gsm), 10–180 gsm (or about 10–180 gsm), 20–170 gsm (or about 20–170 gsm), or 40–150 gsm. In some embodiments, the water absorption and distribution layer 14800 may have a thickness of 1.2 mm or about 1.2 mm, or a thickness in the range of 0.07 mm–7.0 mm, 0.1 mm–5.0 mm, 0.5 mm–3.0 mm, 0.7 mm–2.5 mm, 0.9 mm–2.1 mm, or 1.1 mm–1.5 mm. The water absorption and distribution layer 14800 may be constructed from a material that resists compression at the level of negative pressure commonly applied during negative pressure therapy.

[0110] The water absorption and distribution layer 14800 may contain a plurality of loosely wrapped fibers that can be arranged within a substantially horizontal fibrous network. In some embodiments, the water absorption and distribution layer 14800 may consist of a mixture of two fiber types. One may be a flat fiber having a width of 20 μm to 50 μm, or about 20 μm to about 50 μm, and may contain a cellulose-based material. The other fiber may be a two-component fiber having an inner core with a diameter of 8 μm to 10 μm, about 8 μm to about 10 μm, 7 μm to 11 μm, 6 μm to 12 μm, or 5 μm to 13 μm, and an outer layer having a thickness of 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm. The two-component fiber may be a mixture of polyethylene (PE) type material and polyethylene terephthalate (PET). In some embodiments, the core of the two-component fiber may be PET, and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may contain about 60% to about 90% cellulose fibers, for example, about 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, for example, about 25% PE / PET fibers. In some embodiments, the water absorption distribution layer 14800 may contain segmented microfibers.

[0111] The majority of the fiber volume may extend horizontally (i.e., parallel to the top and bottom planes of the material), or substantially or nearly horizontally. In another embodiment, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In yet another embodiment, all or substantially all of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some embodiments, the majority of the fibers, 80% to 90% (or about 80% to about 90%) or more, or even all or substantially all of the fibers, extend over a distance (horizontal or transverse distance) perpendicular to the thickness of the water absorption distribution layer 14800, which is greater than the thickness of the water absorption distribution layer 14800. In some embodiments, the horizontal or transverse distance covered by such fibers is at least twice (or about twice), three times (or about three times), four times (or about four times), five times (or about five times), or ten times (or about ten times) the thickness of the water-absorbing distribution layer 14800. Such fiber orientation can promote the transverse suction of fluid through the water-absorbing distribution layer 14800. This can more evenly distribute fluids, such as wound exudate, throughout the water-absorbing distribution layer 14800. In some embodiments, the ratio of the amount of fluid suctioned transversely across the water-absorbing distribution layer 14800 to the amount of fluid suctioned vertically through the water-absorbing distribution layer 14800 under negative pressure may be 2:1 or about 2:1 or more, or in some embodiments, up to 10:1 or about 10:1 or more.

[0112] 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 top and bottom planes of the material), 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, substantially, or nearly vertically. Such fiber orientation may facilitate the vertical suction of fluid through the water absorption distribution layer 14800. In some embodiments, the ratio of the amount of fluid suctioned vertically across the water absorption distribution layer 14800 to the amount of fluid suctioned laterally through the water absorption distribution layer 14800 under negative pressure may be 2:1 or more, or about 2:1 or more, or in some embodiments, up to 10:1 or more, or about 10:1 or more.

[0113] In some embodiments, the water absorption and distribution layer 14800 may be located below the acid supply layer 14400, as shown in Figures 12-13. In some embodiments, the water absorption and distribution layer 14800 may be located above the acid supply layer 14400.

[0114] In some embodiments, a wound dressing having a nitric oxide generating layer may include two or more water-absorbing distribution layers. Figures 14-15 show a wound dressing 16000 having two water-absorbing distribution layers, a first water-absorbing distribution layer 16820 and a second water-absorbing distribution layer 16840. The wound dressing 16000 further includes a cover layer 16200, an acid-providing layer 16400, and a nitrite-providing layer 16600, which are similar to the cover layer 14200, the acid-providing layer 14400, and the nitrite-providing layer 14600, respectively. The first water-absorbing distribution layer 16820 and the second water-absorbing distribution layer 16840 are similar to the water-absorbing distribution layer 14800 of the wound dressing 14000.

[0115] As shown in Figures 14-15, the acid supply layer 16400 may be sandwiched between the first water absorption and distribution layer 16820 and the second water absorption and distribution layer 16840. In some embodiments, both the first and second distribution layers may be positioned above or below the acid supply layer 16400.

[0116] In some embodiments, one or more layers of the nitric oxide generating wound dressing may be transparent. For example, cover layers, e.g., cover layer 12200, cover layer 14200, and cover layer 16200, may be transparent. Furthermore, acid-providing layers, e.g., acid-providing layer 12400, acid-providing layer 14400, and acid-providing layer 16400, may be semi-transparent when the hydrogel material is wet, for example, from contact with wound exudate. In some embodiments, a masking layer may be positioned within the wound dressing to prevent the visibility of the wound or wound exudate through the cover layers or acid-providing layers.

[0117] Wound dressing with composite layer In certain embodiments, an activating layer, such as a gel layer disclosed herein, may be integrated with another material to form a composite layer. In embodiments, the gel layer may be a hydrogel. Such integration may be achieved through curing of a gel polymer (such as a hydrogel) or other preferred techniques. As will be described in more detail below, for example, the gel may be integrated with an ADL layer, such as any ADL layer described herein, to form a composite water absorption and distribution layer. In certain embodiments, the gel may be integrated with a SLIMCORE or other nonwoven water absorption and distribution layer manufactured by Libeltex, as will be described further herein. For example, the ADL may be an air-bonded web multilayer water absorption and distribution layer. In certain embodiments, the ADL may include hydrophilic PET and / or binary fibers. In further embodiments, the gel may be integrated with an absorbent material to form a composite absorbent layer, as will be described in more detail below, including a material such as a fibrous gelling material, such as cellulose fibers. For example, the cellulose / cellulose ethyl sulfonate fibers found in DURAFIBER are manufactured by Specialty Fibres and Materials Ltd and incorporated into the product by Smith+Nephew. DUREFIBER is a commercially available absorbent nonwoven material made from cellulose. Further examples of absorbents include gelled fibers, such as AQUACEL's Hydrofiber, manufactured by Convatec. Such integrated composite layers may also serve to provide improved fluid handling, thereby directing nitrites into the composite structure for improved interaction with the activator layer, thereby generating and delivering nitric oxide. As will be understood by those skilled in the art, the nitrite-providing layers(s) disclosed herein may be prepared and provided separately from wound dressings. For example, the nitrite-providing layer may be applied to the wound, and the wound dressing may be applied on top of the nitrite-providing layer.

[0118] In some embodiments, gel layers and / or composite layers, as described herein, may include interleaves within the gel layer. The interleaves may be in the form of thin meshes positioned within the gel layer for structural support and may be constructed from polypropylene or any suitable polymer disclosed herein. The interleaves may be constructed from porous structural materials that provide greater integrity to otherwise less cohesive gels. The interleaves may be positioned in the center of the gel slab to induce cohesiveness for thicker samples. However, those skilled in the art will understand that the interleaves may be positioned at any suitable location within the gel, such as near the top or bottom. Furthermore, the interleaves may be configured so as not to impede the passage of fluid through the thickness of the gel.

[0119] Composite water absorption distribution layer As described above, in certain embodiments, an activator layer, such as a hydrogel layer, may be embedded in a water-absorbing / distributing layer to form a composite layer. Figure 16A shows a wound dressing 19000 similar to the wound dressings shown in Figures 11A-15, however, here the wound dressing 19000 includes a composite water-absorbing / distributing layer (ADL) 19002. The composite ADL may be formed by applying an activator gel in liquid form (including any preferred activator layer material described herein) to an ADL (such as any preferred ADL described herein), or vice versa. As described elsewhere in this specification, the activator gel may be constructed from a hydrogel or xerogel configured to have multiple acidic groups or acidic moieties that can provide protons in an aqueous environment. In the case of a xerogel, the ADL may be embedded while drying within the xerogel. In the case of a hydrogel, the hydrogel may be applied in liquid and / or gel form. The activator hydrogel material can then be cured to form composite ADL 19002. The activator layer can be cured by any suitable technique, such as by applying energy to the system in the form of UV light, irradiation (such as gamma), or heat (optionally in combination with a suitable initiator such as a photoinitiator and / or thermal initiator). Curing chemical additives can also be used for curing. A cover layer 19004 (as described herein) may be applied on top of the composite ADL, and a nitrite supply layer 19006 may be provided below the composite ADL layer or above the composite ADL layer below the cover layer. The nitrite supply layer 19006 may be provided as part of the covering or applied separately. Furthermore, as described elsewhere herein, a wound contact layer (not shown) may be positioned below the covering and above the wound. As will be understood by those skilled in the art, the activator gel in liquid form may be applied in any preferred manner such that the ADL encompasses the bottom portion, the top portion, or the central portion of the composite ADL layer. In some embodiments, the ADL may encompass the entire dimensions of the composite ADL layer. In some embodiments, the ADL may be coated with a hydrophilic agent before the addition of the activator layer in liquid gel form.In certain embodiments, the activator gel in liquid form may be cast directly onto the ADL layer to form a composite ADL, and / or the ADL may be pressed onto the top of the activator layer before the activator layer is cured into a gel. As will be understood by those skilled in the art, the activator gel material and the ADL material may be fused together in any preferred arrangement.

[0120] In certain embodiments, the ADL may be made more rigid before being cast into the composite ADL by any preferred means such as coating or temperature treatment. Further preferred methods may include bonding methods such as thermal bonding or adhesive bonding. Additional preferred methods may include thermal setting, increasing thickness / basis weight, increasing fiber stiffness / thickness, lamination, and / or annealing. A more rigid ADL may play a role in improving fluid uptake within the composite ADL by increasing the surface area. Further methods for curing and forming the composite ADL layer are described below.

[0121] The cover layer 19004 may be similar to the cover layers disclosed elsewhere in this specification. The cover layer 19004 may have a greater length and width than the other layers so that it defines a boundary region extending between the outer periphery of the other layers and the outer periphery of the cover layer 19008. The boundary region of the cover layer 19010 may be attached to the skin surrounding the wound to form a seal so that wound exudate can be contained within the wound dressing 19000.

[0122] In certain embodiments, the composite ADL 19002 may be constructed to favorably draw up fluids such as wound exudate horizontally and / or vertically when absorbed by the wound dressing 19000. Such fluid draw-up may allow for maximum distribution of the fluid through the composite ADL layer 19002, thereby allowing the composite ADL 19002 to reach or be close to its full holding capacity. Furthermore, because nitrite ions dissolved in the fluid can spread across and throughout the composite ADL 19002 more quickly than the activator gel alone, the composite ADL 19002 may promote nitric oxide production. Some embodiments of the ADL within the composite ADL layer 19002 may include viscose, polyester, polypropylene, cellulose, or a combination of some or all of these materials, and the material may be needle-punched. Furthermore, the composite ADL layer may include fibers such as polyethylene, polyamide, and / or a preferred blend thereof. Additional suitable materials may include copolymers of any polymer disclosed herein with core / sheath fibers having two or more materials per fiber. Any suitable ADL material disclosed herein may be used. Some embodiments of the ADL in the composite ADL layer 19002 may include, for example, 80 (or about 80) gsm of cellulose in the range of 1 to 220 grams / m² (gsm) (or about 1 to about 220 gsm), 3 to 200 grams / m² (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). Some embodiments of the composite water absorption and distribution layer 19002 may include polyethylene in the range of 3–200 gsm (or about 3–200 gsm), 5–190 gsm (or about 5–190 gsm), 10–180 gsm (or about 10–180 gsm), 20–170 gsm (or about 20–170 gsm), or 40–150 gsm.In some embodiments, the ADL may have a thickness of 1.2 mm or about 1.2 mm, or may have a thickness in the range of 0.07 mm to 7.0 mm, 0.1 mm to 5.0 mm, 0.5 mm to 3.0 mm, 0.7 mm to 2.5 mm, 0.9 mm to 2.1 mm, or 1.1 mm to 1.5 mm. The ADL may be constructed from a material that can withstand compression at the levels of negative pressure commonly applied during negative pressure therapy, as described herein.

[0123] Composite ADL19002 may include multiple loosely wrapped fibers that can be arranged within a substantially horizontal fibrous network. In some embodiments, the ADL in composite ADL19002 may consist of a mixture of two or more fiber types. One may be a flat fiber having a width of 20 μm to 50 μm, or about 20 μm to about 50 μm, and may include a cellulose-based material. In certain embodiments, the fiber shape may include star-shaped, elliptical, or other preferred shapes. The other fiber may be a two-component fiber having an inner core with a diameter of 8 μm to 10 μm, about 8 μm to about 10 μm, 7 μm to 11 μm, 6 μm to 12 μm, or 5 μm to 13 μm, and an outer layer having a thickness of 1 μm to 2 μm, about 1 μm to about 2 μm, 1 μm to 2.3 μm, 0.8 μm to 2.5 μm, or 0.5 μm to 3 μm. The two-component fiber may be a mixture of polyethylene (PE) type material and polyethylene terephthalate (PET). In some embodiments, the core of the two-component fiber may be PET, and the outer layer may be PE. PE / PET fibers may have a smooth surface morphology, while cellulose fibers may have a relatively rough surface morphology. In some embodiments, the ADL material may contain about 60% to about 90% cellulose fibers, for example, about 75% cellulose fibers, and about 10% to about 40% PE / PET fibers, for example, about 25% PE / PET fibers. In some embodiments, the ADL may include segmented microfibers.

[0124] The majority of the fiber volume within the composite ADL may extend horizontally (i.e., parallel to the top and bottom planes of the material), or substantially or nearly horizontally. In another embodiment, 80% to 90% (or about 80% to about 90%) or more of the fiber volume may extend horizontally, or substantially or nearly horizontally. In some 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, extend over a distance (horizontal or lateral distance) perpendicular to the thickness of the composite water absorption distribution layer, which is greater than the thickness of the water absorption distribution layer 19002. In some embodiments, the horizontal or transverse distance covered by such fibers is at least twice (or approximately twice), three times (or approximately three times), four times (or approximately four times), five times (or approximately five times), or ten times (or approximately ten times) the thickness of the composite ADL19002. The orientation of such fibers promotes the transverse suction of fluid through the composite ADL, thereby allowing for a more uniform distribution of fluids such as wound exudate throughout the composite ADL19002. In some embodiments, the ratio of the amount of fluid suctioned transversely across the composite ADL19002 to the amount of fluid suctioned vertically through the composite ADL19002 under negative pressure may be 2:1 or approximately 2:1 or more, or in some embodiments, up to 10:1 or approximately 10:1 or more.

[0125] In some embodiments, at least a portion of the fiber volume of composite ADL19002 may extend vertically (i.e., perpendicular to the top and bottom planes of the material), substantially, or nearly vertically. In certain 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, substantially, or nearly vertically. Such fiber orientation may facilitate the vertical suction of fluid through composite ADL19002. In some embodiments, the ratio of the amount of fluid suctioned vertically across composite ADL19002 to the amount of fluid suctioned laterally through composite ADL19002 under negative pressure may be 2:1 or more, or about 2:1 or more, or in some embodiments, up to 10:1 or more, or about 10:1 or more.

[0126] In some embodiments, as shown in Figure 16B, another separate ADL 19012, as described herein, may be positioned below the composite ADL to further facilitate fluid suction and nitrite distribution throughout the composite ADL. As will be understood by those skilled in the art, ADLs may instead be positioned above the composite ADL, or multiple ADLs may be positioned on top of and below the composite ADL. Those skilled in the art will also understand that nitrite supply layers may be duplicated so that one or more nitrite supply layers may be positioned elsewhere in the coating, such as above the composite ADL. Multiple ADLs, composite ADLs, and / or nitrite supply layers may be suitably incorporated into a single coating.

[0127] In some embodiments, fluid handling tests were performed on composite ADL20000, such as the composite ADL described above in relation to Figures 16A-16B (data not shown). Some embodiments show fluid suction through composite ADL20000, represented by the red liquid. In some embodiments, after 1 minute, the fluid is distributed almost throughout the entire coating. Such rapid fluid distribution facilitates the interaction between hydrogen ions from the activator layer gel and nitrite passing through the coating. Some embodiments show composite ADL layer 20000, similar to the layers described above in relation to Figures 16A-16B. Here, squares of activator gel and squares of ADL were placed on a sheet of material, such as a cover layer material as described herein. The ADL and activator gel squares were arranged in an alternating checkerboard pattern to create a checkerboard composite ADL. Fluid distribution across the composite ADL was observed in 1 minute.

[0128] Composite absorption layer As described above, in further embodiments, the gel may be integrated with an absorbent material to form a composite absorbent layer. Such a composite absorbent layer may include materials such as fibrous gelling materials, such as cellulose fibers. For example, the cellulose / cellulose ethyl sulfonate fibers found in DURAFIBER are manufactured by Specialty Fibres and Materials Ltd and incorporated into products by Smith+Nephew. Further examples of absorbents include gelling fibers, such as AQUACEL's hydrofibers, manufactured by Convatec. In certain embodiments, the absorbent material may be a foam or another suitable material.

[0129] Figure 17 shows a wound dressing 19001 similar to the wound dressings shown in Figures 11A-15 and 16A-16B, however, here the wound dressing 19001 includes a composite absorbent layer 19003. The composite absorbent layer may be formed by applying an activator gel in liquid form (including any suitable activator layer material described herein) to an absorbent layer (such as any suitable absorbent described herein), or vice versa. As described elsewhere in this specification, the activator gel may be constructed from a hydrogel or xerogel configured to have multiple acidic groups or acidic moieties capable of providing protons in an aqueous environment. In the case of a xerogel, the absorbent may be embedded while drying within the xerogel. In the case of a hydrogel, the hydrogel may be applied in liquid and / or gel form. The activator hydrogel material may then be cured to form the composite absorbent layer 19003. The activator layer may be cured by any suitable technique, such as by applying energy to the system in the form of UV light, irradiation (such as gamma), or heat (optionally in combination with a suitable initiator such as a photoinitiator and / or thermal initiator). Curing chemical additives may also be used for curing. The cover layer 19005 (such as those described herein) may be applied on top of the composite absorbent layer, and the nitrite supply layer 19007 may be provided below the composite absorbent layer or on top of the composite ADL layer below the cover layer. The nitrite supply layer 19007 may be provided as part of the covering or applied separately. Furthermore, as described elsewhere in this specification, a wound contact layer (not shown) may be positioned below the covering and above the wound. As will be understood by those skilled in the art, the activator gel in liquid form may be applied in any preferred manner such that the absorbent covers the bottom of the composite absorbent layer, the top of the composite absorbent layer, or the central portion of the composite absorbent layer. In some embodiments, the absorbent material may encompass the entire dimensions of the composite absorbent layer. In some embodiments, the absorbent material may be coated with a hydrophilic agent before adding the activator layer in liquid gel form.In certain embodiments, the activator gel in liquid form may be cast directly onto the absorbent to form a composite absorbent layer, and / or the absorbent may be pressed onto the top of the activator layer before the activator layer hardens into a gel. As will be understood by those skilled in the art, the activator gel material and the absorbent material may be fused together in any preferred arrangement.

[0130] In some embodiments, foams may be used to form a composite absorption layer (also called a composite foam layer) having an activator gel, similar to the embodiments described above in relation to Figures 16A-17. As will be understood by those skilled in the art, the composite foam layer may be incorporated into a wound dressing in any manner, as described above in relation to the composite layers of Figures 16A-17. Furthermore, the composite foam layer may be used in combination with additional ADL layers, and other foam layers, similar to one or more nitrite-providing layers in Figure 16A, and nitrite-providing layers. In certain embodiments, before curing, an uncured activator gel material in liquid form may be poured into a foam and then cured in the foam to form a composite foam layer. In some embodiments (data not shown), a fluid handling test was performed using a composite foam layer 21000 in which an uncured activator layer material liquid was poured into a foam and cured. The composite foam layer 21000 absorbed all the fluid and the fluid distributed around the radius of the liquid source. Figure 18A shows a composite foam layer including foam portions 21002 embedded in the activator gel 21004. As will be understood by those skilled in the art, the foam portions may extend throughout the entire thickness of the composite foam layer or penetrate only partially through it. The foam portions may be rounded, square, disc-shaped, or any other preferred shape. The foam portions may be arranged in an array or in a random pattern, as shown herein.

[0131] In some embodiments, a composite foam layer similar to the composite foam layer in Figure 18A is considered; however, in contrast to Figure 18A, a portion of the activator gel material is cured within the foam layer. The activator gel 21102 may extend throughout the entire thickness of the foam 21104 or penetrate only partially through the foam. As will be understood by those skilled in the art, the activator gel 21102 may be arranged in an array, a random pattern, or any preferred arrangement. Furthermore, the activator gel 21102 may be rounded or have another preferred shape. In some embodiments, the activator gel may protrude from the foam layer 21106 or may be coplanar with the foam layer 21108. The activator gel may protrude from both sides or only one side, or may be coplanar with both sides or only one side. In certain embodiments, the activator gel is in the form of a disc placed within a punch-out of the foam.

[0132] Figure 18B shows a side view of a wound dressing 21101 including a composite foam layer 21100. Here, the cover layer 21110 overlaps the composite foam layer, which, like other cover layers disclosed herein, alternately includes activator layer gel portions 21102 and foam 21104. Figure 18C shows the same composite foam layer, here with a wound contact layer 21112 constructed from one of the materials described herein. In certain embodiments, the silicone wound contact layer may extend across the entire bottom of the wound dressing or only partially across the underside of the wound dressing to form a window 21012. As will be understood by those skilled in the art, the wound contact layer may be constructed from any suitable material disclosed herein. For example, the wound contact layer may be constructed from silicone, a skin-friendly pressure-sensitive adhesive, a gentle acrylic adhesive, a polyurethane adhesive, a hydrophilic colloid, or other suitable material. The window may facilitate the delivery of nitric oxide to the wound. Those skilled in the art will understand that the nitrite supply layer may be attached directly to the underside or topside of the composite foam layer, and / or may be provided separately and positioned below or above the composite foam layer.

[0133] In some embodiments, the composite layer, rather than the foam or ADL, may be formed of a superabsorbent material. The superabsorbent material may be embedded within the composite superabsorbent layer by any preferred means, such as a separate pattern or array of superabsorbents within the activator layer gel. In embodiments, the superabsorbents may be distributed throughout the composite absorbent layer such that the superabsorbent particles are evenly distributed throughout the composite absorbent layer or concentrated in specific areas of the composite absorbent layer. Such embodiments may function to absorb and trap more fluid within the superabsorbent portion. In certain embodiments, the composite superabsorbent layer may contain about 10-90% superabsorbents, such as 20-80%, 30-70%, 40-60%, or about 50% superabsorbents. In one embodiment, the gel may be completely removed, leaving only a superabsorbent layer with an embedded acid-providing portion.

[0134] Figure 19 shows a wound dressing 22000 having a cover layer 22002, an absorbent layer which may be a foam 22004, a perforated activator gel layer 22006, and a nitrite-providing layer 22008. Such an arrangement allows for rapid interaction between the nitrite-providing layer and the activator gel layer to generate nitric oxide, while still being able to absorb sufficient wound exudate and prevent leakage. In certain embodiments, the activator gel layer 22006 may be a composite ADL as disclosed herein.

[0135] Perforated composite ADL Figures 20A–20D show wound dressings and composite ADLs having perforations. Such composite ADLs are similar and can be prepared as described above in relation to the figures. In some embodiments, the amount of opening area of ​​a perforated ADL can range from about 25–75%, 35–65%, 40–60%, or about 50%. Perforations can be arranged and shaped to suit a particular embodiment, such as a pattern. For example, perforations in an ADL may be arranged linearly, with the perforations evenly spaced and positioned adjacent to one another. In some embodiments, the perforations may be arranged in a checkerboard-type pattern having parallel lines and rows of perforations, or the perforations may be offset or staggered relative to each adjacent perforation. Perforations may have an outer perimeter of any shape, e.g., circular, square, rectangular, triangular, rhombus, etc. Perforations may have different dimensions as they extend through the material or layer. For example, a perforation may have an overall pyramidal shape. In other words, a perforation may increase or decrease in cross-sectional area as it extends through layers or material. As will be understood by those skilled in the art, in certain embodiments, a perforation may be in the form of a slit, pit, recess, bump, or any preferred structure.

[0136] In the embodiment, the ADL within the composite ADL may include prongs, such as microneedles. Such microneedles may penetrate into the activator layer gel to promote capillary action on the gel.

[0137] Figure 20A shows a top view of one embodiment of a composite ADL 23002 having perforations in the ADL. Such a composite ADL may include an ADL 23004 embedded within an activator gel 23006. Perforations passing through the ADL layer allow the activator gel 23006 to directly interact with a nitrite-containing fluid passing through the nitrite-supplying layer above or below the composite ADL.

[0138] Figure 20B shows a side view of one embodiment of coating material 23000, which contains a perforated composite ADL 23002, which includes a perforated ADL 23004 and an activator gel 23006, covered by a cover layer. As described above, the perforated ADL includes perforations 23010, which allow for improved direct fluid flow to the activator gel 23006. In certain embodiments, coating material 23000 further includes mesh interleaves 23012. Figure 20C shows a side view of one embodiment of coating material 23000, similar to the coating material in Figure 20B, where the mesh interleaves 23012 include larger perforations to allow for more fluid flow. In some embodiments, the perforations of the interleaves may have an opening area of ​​about 25-75%, 35-65%, 40-60%, or about 50%. In some embodiments, the fluid is distributed within 1 minute after application across a composite ADL having a perforated ADL layer 23004.

[0139] Figure 20D shows a side view of one embodiment of wound dressing 23000, similar to the dressings in Figures 20A and 20B. Here, the composite ADL includes a first perforated ADL 23004 and a second perforated ADL 23014 on top of it. In certain embodiments, the second ADL 23014 may have the same opening area as the first ADL 23004, a larger opening area than the first ADL 23004, or a smaller opening area than the first ADL 23004. In certain embodiments, the ratio of the opening area of ​​the second ADL 23014 to that of the first ADL 23004 is approximately 0.25, 0.5, 1, 1.5, 2, 4, 6, or 10.

[0140] Figure 21 shows another embodiment of wound dressing 14001, similar to other wound dressings disclosed herein, such as Figures 16A to 20D. Wound dressing 14001 may include a cover layer 14002, an absorbent layer 14004, a gel-permeable perforating absorbent layer 14016 as described elsewhere herein, a gel material or gel layer 14006, and a tissue interface layer 14012. The cover layer 14002 may be positioned above the absorbent layer 14004. The gel-permeable perforating absorbent layer 14016 may be positioned below the absorbent layer 14004. The gel material or gel layer 14006 may be adhered to the wound-facing surface of the gel-permeable perforating absorbent layer 14016. An optional tissue interface layer 14012 may be positioned below the gel material or gel layer 14006 and adhered to the peripheral portion of the cover layer 14002.

[0141] The wound dressing 14001 in Figure 21 may include one or more nitrite-supplying layers that can be separated from the dressing. In some embodiments, the wound dressing 14000 may include a water-supplying distribution layer as described herein. The nitrite-supplying layer(s) as described herein may be located above the absorbent layer 14004, between the absorbent layer 14004 and the gel-permeable perforating absorbent layer 14016, between the gel material or gel layer 14006 and the gel-permeable perforating absorbent layer 14016, below the gel material or gel layer 14006, below the cover layer 14002, or between the cover layer 14002 and the absorbent layer 14004. In embodiments having a water absorption distribution layer, the water absorption distribution layer may be positioned between one or more nitrite supplying layers and the gel material or gel layer 14006, between the cover layer 14002 and the absorption layer 14004, or between the absorption layer 14004 and the gel material or gel layer 14006. As shown in Figure 21, the gel material or gel layer 14006 may have perforations 14010. The perforations may have any preferred arrangement, for example, as described herein in relation to Figures 20A-D.

[0142] In the manufacture of the wound dressing 14001, the gel material may be permeated into a perforated absorbent layer to form a gel-permeable perforated absorbent layer 14016. The gel-permeable perforated absorbent layer 14016 may then be cured, for example, by using UV light or heat. The gel material, or gel layer 14006, may then be adhered to the gel-permeable perforated absorbent layer 14016. The size of the perforations 14026 in the gel-permeable perforated absorbent layer 14016 may be sized to accommodate any expansion or enlargement caused by permeating the gel material into the perforated absorbent layer.

[0143] Two-piece wound dressing with combinable nitric oxide generating components Figures 22A–22D illustrate embodiments of wound dressings, including a two-piece application, which may include a mesh component embedded in a nitric oxide precursor, such as sodium nitrite, that can be inserted into a composite pocket composed of a fibrous substrate loaded with an acidic hydrogel. Those skilled in the art will understand that such embodiments may be combined with and / or incorporate components of embodiments disclosed elsewhere in this specification. In some embodiments, the opening of a composite pocket prepared from a 10 × 5 cm piece OPSITE POST-OP pad loaded with an acidic hydrogel may be formed when the two layers of the composite are folded together and / or bonded. In some embodiments, a nitrite-embedded mesh (such as a 70 gsm polypropylene mesh) may be inserted into the composite pocket using a pair of forceps. In some embodiments, alternative fibrous gelling substrates, such as DURAFIBER, may be used with the composite. Those skilled in the art will recognize that the rigidity and flexibility of the mesh components can be varied according to the ease of insertion into the pocket, and that alternative mesh compositions having sufficient rigidity to withstand insertion, such as meshes of 30 gsm or more, are possible substitutes. In certain embodiments, the mesh may be in the range of 10–50 gsm, 20–40 gsm, or about 30 gsm. In some embodiments, the mesh can be embedded in a sodium nitrite solution and can be constructed from alternative materials compatible with strong oxidizing agents, such materials may include polyethylene and fluorinated materials such as polyvinylidene fluoride (PVDF).

[0144] Figure 22A shows a cross-section of an example of an assembled, combinable wound dressing 23000. The wound dressing may include an upper, or cover film layer 23002, positioned on top of a composite pocket 23006. An insertable mesh 23004 may be positioned within the pocket. The wound contact layer may be opposite the upper layer, below the composite pocket 23006. In some embodiments, the composite pocket may provide a surface for improved adhesion of an upper film layer, such as the IV3000 upper film layer. The IV3000 upper layer is a translucent, stretchable, and breathable extruded film of about 33 gsm based on a polyurethane blend, which is highly breathable and pattern-diffused with an acrylic adhesive.

[0145] Figure 22B shows a cross-section of an example of an assembled, combinable wound dressing 23000. The wound dressing may include an upper or cover film layer 23002 positioned on top of a masking layer 23008. The masking layer 23008 may be positioned on top of a composite pocket 23006. An insertable mesh 23004 may be positioned inside the pocket. The wound contact layer may be on the opposite side from the upper layer below the composite pocket 23006. The masking layer 23008 may be configured to at least partially limit the visibility of the wound.

[0146] Figure 22C shows a vertical view of an example of a combinatorial wound dressing 23000. The wound dressing may include an upper or cover film layer 23002 placed on top of a masking layer 23008. The masking layer 23008 may be placed on top of a composite pocket 23006. An insertable mesh 23004 may be placed inside the pocket. The wound contact layer may be on the opposite side from the upper layer. The masking layer 23008 may act as a guide for inserting the mesh into the opening composite pocket.

[0147] Figure 22D shows a vertical view of an example of an assembled, combinatorial wound dressing 23000. The wound dressing may include an upper or cover film layer 23002 placed on top of a masking layer 23008. The masking layer 23008 may be placed on top of a composite pocket 23006. An insertable mesh 23004, embedded with a nitric oxide precursor such as sodium nitrite, may be placed inside the pocket. The wound contact layer may be on the opposite side from the upper layer. The masking layer 23008 may act as a guide for inserting the mesh into the opening of the composite pocket. In some embodiments, the fluids necessary for the nitric oxide generation reaction to proceed may be provided from a group consisting of an aqueous environment for the hydrogel, wound exudate, and separately provided ampoules of aqueous reagents. In some embodiments, the combination of the insertable mesh 23004 into the composite pocket 23006 in the presence of fluids enables the generation of nitric oxide.

[0148] Figures 23A-23B illustrate an example of a “pocket-in-pocket system,” in which an insertion tool may be used to guide an insertable mesh pocket component, embedded with a nitric oxide precursor such as sodium nitrite, into a gel composite pocket. In some embodiments, the folded mesh may be positioned on a disposable T-shaped insertion tool made of PET film. Alternatively, the tool may be made from any other suitable material, where suitable means having sufficient rigidity, being suitable for medical applications, being suitable for gamma sterilization, having the ability to release the mesh component once inserted, or being suitable in terms of cost and manufacturing procedure. Examples of such materials include wood, polypropylene, and high-density polyethylene (HDPE). The geometric shape of the tool may ensure the correct positioning of the mesh pocket and avoid over-insertion if only two sides of the gel composite pocket are sealed. Once insertion of the mesh pocket into the composite pocket is complete, the tool may be removed and discarded. In certain embodiments, the tool may be rectangular, elliptical, square, polygonal, or any other suitable shape. Alternatively, the mesh pocket may be inserted into the covering pocket by hand, with tweezers, or by any other preferred method.

[0149] Figure 23A shows one embodiment of a "pocket-in-pocket" system, in which an insertable mesh component 24000, embedded with a nitric oxide precursor such as sodium nitrite, can be folded around an insertion tool 24002. The mesh 24000 can then be guided into a composite pocket 24004 using the insertion tool 24002. Once the mesh 24000 is properly inserted into the composite pocket 24004, a combined wound dressing 24006 is produced, and the insertion tool 24002 can be removed and discarded.

[0150] Figure 23B shows an alternative embodiment of the “pocket-in-pocket” system, in which the insertable mesh component 24000 may be configured to position a nitric oxide precursor, such as sodium nitrate, or any other active component, on one side of the mesh pocket. The mesh component may be configured to position the active compound at the bottom of the wound site. The mesh component may characterize a receptacle 24008, such as a pouch, bag, or pocket, for containing the nitric oxide precursor and any other active component. Alternatively, the mesh component may be configured to embed the nitric oxide precursor and any other active component only on the bottommost side of the mesh at the wound site. The insertable mesh component 24000 may be folded around an insertion tool 24002. The mesh 24000 can then be guided into the composite pocket 24004 using the insertion tool 24002. Once the mesh 24000 is properly inserted into the composite pocket 24004, the combined wound dressing 24006 is generated, and the insertion tool 24002 can be removed and discarded.

[0151] In some embodiments, there is an opening or opening in the composite pocket that may allow insertion of an insertable mesh into the composite pocket. In some embodiments, the pocket opening is a narrow slit cut into the surface of the composite pocket. In some embodiments, the pocket opening is a larger slot or an eyelet cut into the surface of the composite pocket. The pocket may be rectangular, elliptical, square, polygonal, or any preferred shape. Those skilled in the art will understand that the wound dressings of Figures 22-24 may be configured to feature a slot or open pocket for insertion of a mesh component, but the embodiments of Figures 22-24 may feature any opening in the composite layer suitable for insertion of a mesh component. In some embodiments, insertion into the pocket may be achieved by an opening or an eyelet cut into the surface of the composite layer, thereby allowing access to the composite pocket. In some embodiments, if the composite pocket is covered by a masking layer and / or a top layer, insertion into the pocket may be achieved by an opening or an eyelet cut into the surface of the masking layer and / or the surfaces of the top layer and the composite layer, thereby allowing access to the composite pocket. In some embodiments, the opening may be equipped with a “trapdoor” system that can be used to mask and / or lift a portion of the upper layer to allow access to the composite pocket, and then close and reseal after the mesh has been inserted into the pocket. In some embodiments, the opening, or eyelet, may be covered by a removable handle before the mesh component is inserted.

[0152] In some embodiments, the combinatorial components of the wound dressing are configured to improve adhesion between the nitrite-embedded mesh and the composite material loaded with acidic hydrogel. In embodiments, the use of a pocket system can reduce direct exposure to the patient of sodium nitrite and / or other reagents coexisting on the mesh. In certain embodiments, a two-piece application system with a pocket and an insertable mesh offers advantages by providing a single means of activating the dressing system with less potential user error or misuse. In some embodiments, instead of mesh, an ampoule of reagent containing a nitric oxide precursor may be supplied, and the contents may be inserted into the pocket dressing to initiate the process.

[0153] Those skilled in the art will understand that while the wound dressing embodiments of Figures 22-24 may be configured to deliver nitric oxide to the wound and / or skin surface, the embodiments of Figures 22-24 may deliver any suitable type of active ingredient and are not limited to the delivery of nitric oxide. In particular, the embodiments of Figures 22-24 are suitable for the delivery of active ingredients that require a reaction to facilitate the generation 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. In some embodiments, the mesh components may further include antioxidants and / or reducing agents co-localized with the nitrite-providing layer. In some embodiments, the active ingredient gel may not further include antioxidants and / or reducing agents. In some embodiments, the mesh components may be embedded in a suspension comprising antioxidants and / or reducing agents, as well as the nitrite-providing layer, suspended in a water-miscible anhydrous carrier.

[0154] Antimicrobial activity results when the mesh layer is positioned on top of the composite material and does not come into contact with the test organism. Figures 24A–24E show the results of an exemplary experiment evaluating the antimicrobial efficacy of a wound dressing containing a sodium nitrite-embedded mesh placed on top of a composite hydrogel. In this experiment, Sabouraud dextrose agar (SDAB) was loaded onto a 120 mm × 120 mm plate, and a 75 mm × 75 mm steel insert was attached. Approximately 10 units were used to cover a 13 mm diameter membrane. 6 CFU of Candida albicans (CA) was directly inoculated and placed in the center of a steel insert. A composite hydrogel composed of a DURAFIBER substrate, loaded with 6 g of 1.0 SA gel further incorporating 0.8% sodium isoascorbate, was placed on top of the CA-loaded membrane. The 1.0 SA / 0.8% ISO gel can be prepared with the following components (parts by weight per 100 g batch): 62.82 g of AMPS sodium, 0.0320 g of piperazine diacrylamide, 0.794 g of sodium-D-isoascorbic acid monohydrate, 5.393 g of AMPS(H+), 30.94 g of glycerol, and 0.01616 g of 2-hydroxy-2-methylpropiophenone. In the experimental active arm, the mesh was loaded with 1.5 M sodium nitrite, while the negative control was characterized by a mesh without sodium nitrite. The IV3000 top film was placed on top to complete the dressing, and the inoculated dressing was incubated for 24 or 72 hours to evaluate the reduction of plankton CA from the initial inoculation. Figure 24A shows the orientation and dimensions of the layers used in the experimental dressing. Figure 24B shows an overhead view of the layers of the experimental dressing. Figure 24C shows the experimental results, demonstrating how the active dressing in this experiment, including a mesh embedded with 1.5 M sodium nitrite, successfully reduced CA growth over both 24 and 72-hour periods. A graphical representation of these results is shown in Figure 24D. Figure 24E further demonstrates that recovery of CA after treatment was impaired in the dressing featuring a mesh embedded with 1.5 M sodium nitrite. Thus, these results indicate that the antimicrobial activity of nitric oxide-generating wound dressings against CA is maintained when the mesh is placed on top of the composite and is not in physical contact with the inoculated film.

[0155] Integrated wound dressing with combinable nitric oxide generating components [Figure 25 shows an embodiment 27000 of a wound dressing, characterized by a combinable composite component and a mesh component within an integrated application. The embodiment may be characterized by a first handle component 27002 that allows the combination of the composite component 27004 and the mesh component 27010 when removed. A first adhesive layer may be located beneath the composite component 27006 and the mesh component 27012. Furthermore, a film layer 27008 may be located beneath the adhesive layer 27006 and the composite component 27004. A film layer 27014 may be located beneath the adhesive layer 27012 and the mesh component 27010. The film layer 27014 may be located above the second adhesive layer 27016. A second removable handle 27018 may be present. The dressing may be configured such that, upon removal of the first handle 27002, the dressing can be manipulated to bring the composite component 27004 and the mesh component 27010 into contact with each other. The dressing may be configured such that, when the mesh 27010 and the composite component 27004 are combined, the film 27008, originally positioned below the composite component 27004, becomes the upper layer of the dressing. The dressing may be configured such that, when the mesh 27010 and the composite component 27004 are combined, the mesh component 27010 is closer to the wound contact layer than the composite layer 27004. The dressing may be configured such that, after the combination of the mesh 27010 and the composite component 27004, the combined dressing 27000 can be applied to the wound site upon removal of the second handle layer 27018. The first adhesive layer 27012, the film layer 27014, and the second adhesive layer 27016, on the same side as the mesh component 27010, may be perforated before assembly. The covering material may be configured not to generate nitric oxide before the removal of the first handle 27002 and the subsequent assembly of the mesh component 27010 and the composite component 27004. In some embodiments, the fluids required for the nitric oxide generation reaction to proceed may be provided from a group consisting of the aqueous environment of the hydrogel, wound exudate, and separately provided ampoules of aqueous reagents.

[0156] Additional wound dressing embodiments 28000, characterizing the combinable composite material 28010 and mesh 28002 components within an integrated application, are shown in Figures 26A-26B. As shown in Figure 26A, the embodiment may feature an upper handle component 28008 that allows the combination of the composite material 28010 and mesh 28002 components when removed. A first adhesive layer 28004 may be located beneath the mesh component 28002. A first adhesive layer 28012 may be located beneath the composite component 28010. Furthermore, a film layer 28006 may be located beneath the adhesive layer 28004 on the same side as the mesh component 28002. A film layer 28014 may be located beneath the adhesive layer 28012 on the same side as the composite component 28010 before combination. A second removable handle 28016 may be present. The covering material may be configured so that, when the first handle 28008 is removed, the covering material can be manipulated to bring the composite component 28010 and the mesh component 28002 into contact with each other. The covering material may be configured such that, when the mesh 28002 and the composite component 28010 are combined, the film 28006 positioned below the mesh component 28002 becomes the upper layer of the covering material. The covering material may be configured such that, when the mesh 28002 and the composite component 28010 are combined, the composite component 28010 is closer to the wound contact layer than the mesh component 28002. The covering material may be configured so that, after the combination of the mesh 28002 and the composite component 28010, the combined covering material 28000 can be applied to the wound site when the second handle layer 28016 is removed. The adhesive layer 28012 and the film layer 28014, on the same side as the composite component 28010, may be perforated before being combined with the mesh component 28004. The adhesive layer 28022 may be present between the film layer 28014 and the handle 28016. The covering material may be configured not to generate nitric oxide before the removal of the first handle 28008 and the subsequent combination of the mesh component 28002 and the composite component 28010.In some embodiments, the fluids necessary for the nitric oxide generation reaction to proceed may be provided from a group consisting of the aqueous environment of the hydrogel, wound exudate, and separately provided ampoules of aqueous reagents.

[0157] As shown in Figure 26B, this embodiment of the wound dressing may feature the same design as the embodiment shown in Figure 26A, with the addition of an additional adhesive layer 28020 and a film layer 28018, such that the composite component 28010 is located between the two inner adhesive layers (28020 and 28012) and the two outer film layers (28018 and 28014). The adhesive layers 28020 and 28012, and the film layers 28018 and 28014, on the same side as the composite component 28010, may be perforated before combination with the mesh component 28004. The dressing may be configured not to generate nitric oxide before removal of the first handle 28008 and subsequent combination of the mesh component 28002 and the composite component 28010.

[0158] In some embodiments, the dressing may include combinable components and may be applied as a single component. In some embodiments, the dressing may feature a reduction in the amount of packaging material as a result of the application of a single component using combinable components. In some embodiments, the wound dressing may be applied and removed as a single component. In some embodiments, the combinable components of the wound dressing are configured to improve adhesion between the nitrite-embedded mesh and the composite material loaded with acid hydrogel.

[0159] Similar to other wound contact layers disclosed herein, a wound contact layer (not shown) may be positioned beneath the dressing and may include, but is not shown, handles, 27018, and 28016, which can be removed before the dressing is placed.

[0160] Those skilled in the art will understand that while the wound dressing embodiments of Figures 25 and 26 may be configured to deliver nitric oxide to the wound and / or skin surface, the embodiments of Figures 25 and 26 may deliver any suitable type of active ingredient and are not limited to the delivery of nitric oxide. In particular, the embodiments of Figures 25 and 28 are suitable for the delivery of active ingredients that require a reaction to facilitate the generation 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.

[0161] term The above-mentioned patents and specifications, as well as other references, including any that may be listed in the attached application documents, are incorporated herein by reference. Aspects of this disclosure may be modified, as necessary, to provide further embodiments using the systems, functions, and concepts of the various references described herein.

[0162] Features, materials, properties, or groups described in relation to a particular aspect, embodiment, or example should be understood to be applicable to any other aspect, embodiment, or example described herein, insofar as they do not conflict with such other aspects, embodiments, or examples. All features disclosed herein (including any appended claims, abstract, and drawings), or any methods or steps of any process disclosed herein, can be combined in any combination except for any combination in which at least some of such features or steps are mutually exclusive. The protection of this invention is not limited to the details of any embodiment described herein. The protection extends to any novel features or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or to any novel methods or steps of any process disclosed herein.

[0163] While certain embodiments are described, these embodiments are presented merely as examples and are not intended to limit the scope of protection. In fact, the novel methods and systems described herein can be embodied in a variety of other forms. Furthermore, various omissions, substitutions, and modifications are possible in the forms of the methods and systems described herein. Those skilled in the art will recognize that in some embodiments, the actual steps taken in the illustrated or disclosed processes may differ from the steps shown in the figures. In some embodiments, certain steps from the aforementioned steps may be omitted, or others may be added. For example, the actual steps taken in the disclosed process, or the order of the steps, may differ from those shown in the figures. In some embodiments, certain steps from the aforementioned steps may be omitted, or others may be added. Furthermore, the features and attributes of certain embodiments disclosed above may be combined in different ways to form additional embodiments, all of which remain within the scope of this disclosure.

[0164] This disclosure includes certain embodiments, examples, and applications, but those skilled in the art will understand that this disclosure extends beyond the scope of the specifically disclosed embodiments to other alternative embodiments or uses, as well as obvious variations and equivalents thereof, including embodiments that do not necessarily provide all of the features and advantages described herein. Therefore, the scope of this disclosure is not intended to be limited by the embodiments described, but may be defined by the claims presented herein or thereafter.

[0165] Conditional statements such as “can,” “could,” “might,” or “may,” unless otherwise specifically stated or interpreted within the context in which they are used, are typically intended to communicate that a particular embodiment includes a particular feature, element, or step, while other embodiments do not. Therefore, such conditional statements are generally not intended to suggest that a feature, element, or step is required to some extent in one or more embodiments, or that logic for determining whether or not these features, elements, or steps are included in any particular embodiment, or should be implemented in any particular embodiment, is necessarily included in one or more embodiments, with or without user input or instruction. Terms such as “comprising,” “including,” and “having” are synonyms and are used inclusively in an open-ended manner, not excluding additional elements, features, actions, and behaviors. Furthermore, the term “or” is used in an inclusive sense (rather than an exclusive sense), 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” refers to an enumeration of two or more items, encompassing all of the following interpretations of the word: any one of the items in the enumeration, all items in the enumeration, and any combination of items in the enumeration. In addition, the term “each” as used herein may, in addition to having its usual meaning, also mean any subset of the set of elements to which the term “each” applies. Furthermore, as used herein, “herein,” “above,” “below,” and similar terms mean, as used in this application, the entirety of this specification and not any particular part thereof.

[0166] Conjunctional phrases such as "at least one of X, Y, and Z" are to be interpreted separately, in the context generally used to indicate that an item, term, etc., can be either X, Y, or Z, unless otherwise specifically stated. Therefore, such conjunctional phrases are not typically intended to suggest that a particular embodiment must include at least one of X, at least one of Y, and at least one of Z.

[0167] As used herein, terms expressing degree, such as “approximately,” “about,” “generally,” and “substantially,” when used herein, represent values, quantities, or characteristics that still approximate the stated values, quantities, or characteristics that perform the desired function or produce the desired result. For example, the terms “approximately,” “about,” “generally,” and “substantially” may refer to quantities that are less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated quantity. As another example, in certain embodiments, the terms “generally parallel” and “substantially parallel” refer to values, quantities, or characteristics that deviate from being exactly parallel by 15 degrees or less, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degrees.

[0168] Any of the embodiments described herein may be used with or without a canister. Any of the dressing embodiments described herein may absorb and store wound exudate.

[0169] The scope of this disclosure is not intended to be limited by the description of any particular embodiment, but may be defined by the claims. The language of these claims should be interpreted broadly based on the language used herein, and not limited to the examples described herein or in the proceedings of this application, which should be interpreted non-exclusively.

[0170] Various modifications to the embodiments described herein may be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the spirit or scope of this disclosure. Therefore, the disclosure is not intended to limit itself to the embodiments shown herein, but should be given the broadest scope consistent with the principles and features disclosed herein. Certain embodiments of the disclosure are encompassed in the set of claims listed below or presented later.

[0171] Specific embodiments of this disclosure are included in the claims presented last in this specification or in any other claims presented at a later date.

Claims

1. A wound dressing for treating wounds, wherein the wound dressing is a two-piece application including combinable components, and the combinable components are A pocket composed of one or more composite layers, It comprises an insertable mesh component containing a nitrite supply layer, A wound dressing configured such that the insertion of the mesh component into the pocket generates nitric oxide.

2. The wound dressing according to claim 1, wherein the composite layer includes a gelled fiber substrate loaded with an activator gel.

3. The wound dressing according to claim 2, wherein the activating agent gel comprises a hydrogel.

4. The wound dressing according to claim 3, wherein the activator gel comprises an acidic group or a portion thereof.

5. The wound dressing according to any one of claims 1 to 4, wherein the wound dressing is configured to generate nitric oxide when the wound dressing interacts with a fluid.

6. The wound dressing according to claim 5, wherein the fluid is provided from the group consisting of the aqueous environment of the hydrogel, wound exudate, and a separately provided ampoule of aqueous reagent.

7. The wound dressing according to any one of claims 1 to 6, wherein the mesh component is embedded with a nitric oxide precursor.

8. The wound dressing according to claim 7, wherein the mesh component is embedded with sodium nitrite.

9. The wound dressing according to any one of claims 1 to 8, wherein the pocket is formed by attaching the sides of two composite layers together, or by attaching a composite layer to another layer of the dressing.

10. The wound dressing according to claim 9, wherein at least two sides of the two composite layers are attached together.

11. The wound dressing according to any one of claims 1 to 10, wherein the insertion of the mesh component into the pocket is achieved using an insertion device.

12. The wound dressing according to claim 11, wherein the insertion device is configured to control the depth to which the mesh component is positioned within the pocket, and to prevent excessive insertion or protrusion beyond the composite pocket.

13. The wound dressing according to claim 12, wherein the mesh component and the insertion device are configured such that the mesh component fits around the expansion tab of the insertion device, and when the mesh component is loaded into the composite pocket, the insertion device is removed from the mesh component and discarded.

14. The wound dressing according to any one of claims 1 to 13, wherein the dressing further comprises an upper layer.

15. The wound dressing according to any one of claims 1 to 14, wherein the dressing further comprises a masking layer.

16. The wound dressing according to any one of claims 14 or 15, wherein the upper layer or masking layer can function as a guide for inserting the mesh component into the pocket.

17. The wound dressing according to any one of claims 14 to 16, wherein the pocket is fixed to the upper layer or the masking layer.

18. The wound dressing according to any one of claims 1 to 17, wherein the pocket is configured to have an opening configured for the insertion of the mesh component.

19. The wound dressing according to any one of claims 1 to 18, wherein one or more composite layers of the pocket further comprises an antioxidant and / or a reducing agent.

20. The wound dressing according to any one of claims 1 to 18, further comprising an antioxidant and / or reducing agent colocalized with the nitrite-providing layer in the mesh component.

21. The wound dressing according to claim 20, wherein one or more composite layers of the pocket further do not contain antioxidants and / or reducing agents.

22. The wound dressing according to any one of claims 20 or 21, wherein the mesh component is embedded in a suspension comprising an antioxidant and / or reducing agent, and a nitrite-providing layer suspended in a water-miscible anhydrous carrier.

23. The wound dressing according to any one of claims 19 to 22, wherein the antioxidant and / or reducing agent is sodium isoascorbate.

24. A wound dressing for treating wounds, wherein the wound dressing is an integrated application including combinable components, and the combinable components are A composite component further comprising an activator gel, A mesh component further comprising a nitrite supply layer, By operating the aforementioned integrated application, the composite component and the mesh component can be combined before the application of the wound dressing. A wound dressing in which the combination of the composite component and the mesh component is configured to generate nitric oxide.

25. The wound dressing according to claim 24, wherein the composite component includes a gelled fiber substrate loaded with an activator gel.

26. The wound dressing according to claim 25, wherein the activating gel comprises a hydrogel.

27. The wound dressing according to claim 26, wherein the activator gel comprises an acidic group or a portion thereof.

28. The wound dressing according to any one of claims 24 to 27, wherein the wound dressing is configured to generate nitric oxide when the wound dressing interacts with a fluid.

29. The wound dressing according to claim 28, wherein the fluid is provided from the group consisting of the aqueous environment of the hydrogel, wound exudate, and a separately provided ampoule of aqueous reagent.

30. The wound dressing according to any one of claims 24 to 29, wherein the mesh component is embedded with a nitric oxide precursor.

31. The wound dressing according to claim 30, wherein the mesh component is embedded with sodium nitrite.

32. The wound dressing according to any one of claims 24 to 31, wherein the mesh components and the composite layer are separated from each other by a removable handle.

33. The wound dressing according to claim 32, wherein the removal of the handle allows for the combination of the mesh component and the composite layer.

34. The wound dressing according to any one of claims 24 to 33, wherein the wound dressing further comprises an upper layer.

35. The wound dressing according to any one of claims 24 to 34, wherein the wound dressing further comprises a masking layer.

36. The wound dressing according to any one of claims 24 to 35, wherein the wound dressing further comprises one or more adhesive layers.

37. The wound dressing according to any one of claims 24 to 36, wherein the wound dressing further comprises one or more film layers.

38. The wound dressing according to any one of claims 24 to 37, wherein the wound dressing is configured such that the mesh component is positioned in close proximity to the wound.

39. The wound dressing according to any one of claims 24 to 38, wherein the wound dressing is configured such that the composite component is positioned in close proximity to the wound.

40. The wound dressing according to any one of claims 24 to 39, wherein the activating gel further comprises an antioxidant and / or a reducing agent.

41. The wound dressing according to any one of claims 24 to 39, further comprising an antioxidant and / or reducing agent colocalized with the nitrite-providing layer in the mesh component.

42. The wound dressing according to claim 41, wherein the activator gel further contains no antioxidant and / or reducing agent.

43. The wound dressing according to any one of claims 41 or 42, wherein the mesh component is embedded in a suspension comprising an antioxidant and / or reducing agent, and a nitrite-providing layer suspended in a water-miscible anhydrous carrier.

44. The wound dressing according to any one of claims 40 to 43, wherein the antioxidant and / or reducing agent is sodium isoascorbate.

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