Nitric oxide releasing wound treatment materials composed of metal particles and methods for making and using the same

Abstract

In accordance with the purpose(s) of the present disclosure, as embodies and broadly described herein, the disclosure, in one aspect, relates to wound treatment materials and methods for making and using the same. In one aspect, the would treatment material comprises a first layer adjacent to a second layer, wherein (a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and (b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.

Description

T|H Docket: 222105-2440NITRIC OXIDE RELEASING WOUND TREATMENT MATERIALS COMPOSED OF METAL PARTICLES AND METHODS FOR MAKING AND USING THE SAMESTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under HT9425-23-1-0955 awarded by the Defense Health Agency, Medical Research and Development Branch. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 750,333, filed on January 28, 2025, the contents of which are incorporated by reference herein in their entireties.BACKGROUND

[0003] T raumatic injuries range from automobile accidents to gunshots, shrapnel, and any injuries that require immediate attention and care. Every year, more than 5 million deaths happen globally due to trauma injuries. Uncontrollable hemorrhages and lacerations, the common aftermath of trauma, are the primary causes of deaths within the first 6 hours and 4 hours, respectively, among patients who are admitted into medical facilities. Uncontrollable hemorrhages contribute to approximately 50% of deaths in the first couple of days amongst both civilian and military soldiers. Excessive blood loss is responsible for nearly 30% of deaths after traumatic injuries. Infection is another leading cause of fatalities in trauma patients; indeed, it has become the second most common cause of death in patients who have experienced trauma more than 72 hours prior. Wounded sites that have not been properly treated are at a higher risk of infections. When the immune system concentrates on maintaining homeostasis while anti-inflammatory mediators focus on inhibiting the inflammation of the wounded area(s), the diversion of attention results in constant exposure of the wounded area to pathogens. This, therefore, impedes the process of wound healing while simultaneously increasing the immune disorder that can potentially cause multiple organ failures. Currently available wound dressings with antibiotics and silver ions are toxic to bacteria but at the same time are cytotoxic to mammalian cells, which is highly undesirable. There remains a need for wound dressings that overcome the aforementioned deficiencies.SUMMARY

[0004] In accordance with the purpose(s) of the present disclosure, as embodies and broadly described herein, the disclosure, in one aspect, relates to wound treatment materialsT|H Docket: 222105-2440and methods for making and using the same. In one aspect, the would treatment material comprises a first layer adjacent to a second layer, wherein (a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and (b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.

[0005] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.

[0007] FIGS. 1 and 2 show exemplary wound treating material described herein.

[0008] FIG. 3 shows NO release rates from nitric oxide-releasing wound dressings composed of Ag or Cu interface under conditions mimicking wound environment.

[0009] FIGS. 4A-4D show 24-h studies of microbial adhesion to silicone contact layers of nitric oxide-releasing wound dressings. Data shown as mean ± SD ( / V > 3 repeats per group). Significant comparisons shown for NO+Metal materials (p < 0.05).

[0010] FIG. 5 shows ISO 10993-5 studies of biocompatibility with nitric oxide-releasing wound dressings. Samples retained >70% cellular viability compared to silicone contact layer controls after 24 h. Significant comparisons shown (p < 0.05, N > 3 repeats / group).

[0011] The drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope described herein, as other equally effective embodiments are within the scope and spirit of this disclosure. The elements and features shown in the drawings are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the principles of the embodiments. Additionally, certain dimensions may be exaggerated to helpT|H Docket: 222105-2440visually convey certain principles. In the drawings, similar reference numerals between figures designate like or corresponding, but not necessarily the same, elements.DETAILED DESCRIPTION

[0012] Before the present compounds, compositions, articles, devices, and / or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, synthetic methods, or uses as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0013] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0014] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0015] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0016] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0017] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0018] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise,T|H Docket: 222105-2440all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0019] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions and abbreviations

[0020] In describing and claiming the disclosed subject matter, the following terminology will be used in accordance with the definitions set forth below.

[0021] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

[0022] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a solvent” includes, but are not limited to, mixtures or combinations of two or more such solvents, and the like.

[0023] It should be noted that ratios, concentrations, amounts, rates, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed and “about 5 to about 15” is also disclosed.T|H Docket: 222105-2440

[0024] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0025] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0026] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0027] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order.T|H Docket: 222105-2440Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0028] Disclosed are the components to be used to prepare the compositions disclosed herein as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0029] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0030] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance and instances where it does not.T|H Docket: 222105-2440

[0031] The term "alkyl group" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkylsubstituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.

[0032] In some embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g. have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0033] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, having from one to ten carbons, or from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In embodiments described in the present application, preferred alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0034] In some embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer.

[0035] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.T|H Docket: 222105-2440Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.

[0036] The term “alkylene aryl” as used herein is a group that contains an alkylene group substituted with an aryl group defined herein. For example, an alkylene aryl group can be represented by the formula -(CH2)n-Ar, where n is an integer from 1 to 20 and Ar is an aryl group as defined herein. An example of an alkylene aryl group is -(CH2)2-Ph, which is called phenethyl.

[0037] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA1— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0038] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0039] As used herein, the term “biocompatible,” with respect to a substance or fluid described herein, indicates that the substance or fluid does not adversely affect the short-term viability or long-term proliferation of a target biological particle within a particular time range.

[0040] The terms “antimicrobial” and “antimicrobial characteristic” refer to the ability to kill and / or inhibit the growth of microorganisms. A substance having an antimicrobial characteristic may be harmful to microorganisms or microbes (e.g., bacteria, fungi, virus, protozoans, algae, and the like). A substance having an antimicrobial characteristic can kill the microorganism and / or prevent or substantially prevent the growth or reproduction of the microorganism.

[0041] The terms “bacteria” or “bacterium” include, but are not limited to, gram positive and gram negative bacteria. Bacteria can include, but are not limited to, Abiotrophia, Achromobacter, Acidaminococcus, Acidovorax, Acinetobacter, Actinobacillus, Actinobaculum, Actinomadura, Actinomyces, Aerococcus, Aeromonas, Afipia, Agrobacterium, Alcaligenes, Alloiococcus, Alteromonas, Amycolata, Amycolatopsis, Anaerobospirillum, Anabaena affinis and other cyanobacteria (including the Anabaena, Anabaenopsis, Aphanizomenon, Camesiphon, Cylindrospermopsis, Gloeobacter Hapalosiphon, Lyngbya, Microcystis,T|H Docket: 222105-2440Nodularia, Nostoc, Phormidium, Planktothrix, Pseudoanabaena, Schizothrix, Spirulina, Trichodesmium, and Umezakia genera) Anaerorhabdus, Arachnia, Arcanobacterium, Arcobacter, Arthrobacter, Atopobium, Aureobacterium, Bacteroides, Balneatrix, Bartonella, Bergeyella, Bifidobacterium, Bilophila Branhamella, Borrelia, Bordetella, Brachyspira, Brevibacillus, Brevi bacterium, Brevundimonas, Brucella, Burkholderia, Buttiauxella, Butyrivibrio, Calymmatobacterium, Campylobacter, Capnocytophaga, Cardiobacterium, Catonella, Cedecea, Cellulomonas, Centipeda, Chlamydia, Chlamydophila, Chromobacterium, Chyseobacterium, Chryseomonas, Citrobacter, Clostridium, Collinsella, Comamonas, Corynebacterium, Coxiella, Cryptobacterium, Delftia, Dermabacter, Dermatophilus, Desulfomonas, Desulfovibrio, Dialister, Dichelobacter, Dolosicoccus, Dolosigranulum, Edwardsiella, Eggerthella, Ehrlichia, Eikenella, Empedobacter, Enterobacter, Enterococcus, Erwinia, Erysipelothrix, Escherichia, Eubacterium, Ewingella, Exiguobacterium, Facklamia, Filifactor, Flavimonas, Flavobacterium, Francisella, Fusobacterium, Gardnerella, Gemella, Globicatella, Gordona, Haemophilus, Hafnia, Helicobacter, Helococcus, Holdemania Ignavigranum, Johnsonella, Kingel la, Klebsiella, Kocuria, Koserella, Kurthia, Kytococcus, Lactobacillus, Lactococcus, Lautropia, Leclercia, Legionella, Leminorella, Leptospira, Leptotrichia, Leuconostoc, Listeria, Listonella, Megasphaera, Methylobacterium, Microbacterium, Micrococcus, Mitsuokella, Mobiluncus, Moellerella, Moraxella, Morganella, Mycobacterium, Mycoplasma, Myroides, Neisseria, Nocardia, Nocardiopsis, Ochrobactrum, Oeskovia, Oligella, Orientia, Paenibacillus, Pantoea, Parachlamydia, Pasteurella, Pediococcus, Peptococcus, Peptostreptococcus, Photobacterium, Photorhabdus, Phytoplasma, Plesiomonas, Porphyrimonas, Prevotella, Propionibacterium, Proteus, Providencia, Pseudomonas, Pseudonocardia, Pseudoramibacter, Psychrobacter, Rahnella, Ralstonia, Rhodococcus, Rickettsia Rochalimaea Roseomonas, Rothia, Ruminococcus, Salmonella, Selenomonas, Serpulina, Serratia, Shewenella, Shigella, Simkania, Slackia, Sphingobacterium, Sphingomonas, Spirillum, Spiroplasma, Staphylococcus, Stenotrophomonas, Stomatococcus, Streptobacillus, Streptococcus, Streptomyces, Succinivibrio, Sutterella, Suttonella, Tatumella, Tissierella, Trabulsiella, Treponema, Tropheryma, Tsakamurella, Turicella, Ureaplasma, Vagococcus, Veillonella, Vibrio, Weeksella, Wolinella, Xanthomonas, Xenorhabdus, Yersinia, and Yokenella. Other examples of bacterium include Mycobacterium tuberculosis, M. bovis, M. typhimurium, M. bovis strain BCG, BCG substrains, M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium subspecies paratuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus equi, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Listeria ivanovii, Bacillus anthracis, B. subtilis, Nocardia asteroides, and other Nocardia species, Streptococcus viridans group, Peptococcus species, Peptostreptococcus species, Actinomyces israelii and otherT|H Docket: 222105-2440Actinomyces species, and Propionibacterium acnes, Clostridium tetani, Clostridium botulinum, other Clostridium species, Pseudomonas aeruginosa, other Pseudomonas species, Campylobacter species, Vibrio cholera, Ehrlichia species, Actinobacillus pleuropneumoniae, Pasteurella haemolytica, Pasteurella multocida, other Pasteurella species, Legionella pneumophila, other Legionella species, Salmonella typhi, other Salmonella species, Shigella species Brucella abortus, other Brucella species, Chlamydi trachomatis, Chlamydia psittaci, Coxiella burnetti, Escherichia coli, Neiserria meningitidis, Neiserria gonorrhea, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Yersinia pestis, Yersinia enterolitica, other Yersinia species, Escherichia coli, E. hirae and other Escherichia species, as well as other Enterobacteria, Brucella abortus and other Brucella species, Burkholderia cepacia, Burkholderia pseudomallei, Francisella tularensis, Bacteroides fragilis, Fudobascterium nucleatum, Provetella species, and Cowdria ruminantium, or any strain or variant thereof. The gram-positive bacteria may include, but is not limited to, gram positive Cocci (e.g., Streptococcus, Staphylococcus, and Enterococcus). The gram-negative bacteria may include, but is not limited to, gram negative rods (e.g., Bacteroidaceae, Enterobacteriaceae, Vibrionaceae, Pasteurellae and Pseudomonadaceae).

[0042] The terms “fungus” or “fungi” include, but are not limited to yeasts such as, for example, Candida albicans or other Candida spp. including C. glabrata, C. rugosa, C. parapsilosis, C. tropicalis, or C. dubliniensis Fungi can also include dermatophytes such as, for example, Trichophyton spp. and Microsporum spp. (e.g., T. rubrum, T. interdigitale, T. tonsurans, T. violaceum, T. concentricum, T. schoenleinii, T. soudanense, T. mentagrophytes, T. equinum, T. erinacei, T. verrucosum, M. audouinii, M. ferrugineum, M. canis, M. gypseum, M. nanum, and / or M. cookie).

[0043] The term “antimicrobial effective amount” as used herein refers to that amount of the compound being administered / released that will kill microorganisms or inhibit growth and / or reproduction thereof to some extent (e.g. from about 5% to about 100%). In reference to the compositions or articles of the disclosure, an antimicrobial effective amount refers to that amount which has the effect of diminishment of the presence of existing microorganisms, stabilization (e.g., not increasing) of the number of microorganisms present, preventing the presence of additional microorganisms, delaying or slowing of the reproduction of microorganisms, and combinations thereof. Similarly, the term “antibacterial effective amount” refers to that amount of a compound being administered / released that will kill bacterial organisms or inhibit growth and / or reproduction thereof to some extent (e.g., from about 5% to about 100%). In reference to the compositions or articles of the disclosure, an antibacterial effective amount refers to that amount which has the effect of diminishment of the presence of existing bacteria, stabilization (e.g., not increasing) of the number of bacteria present,T|H Docket: 222105-2440preventing the presence of additional bacteria, delaying or slowing of the reproduction of bacteria, and combinations thereof.

[0044] As used herein, the term “subject” includes humans, mammals (e.g., cats, dogs, horses, etc.), birds, and the like. Typical subjects to which embodiments of the present disclosure may be administered will be mammals, particularly primates, especially humans. For veterinary applications, a wide variety of subjects will be suitable, e.g., livestock such as cattle, sheep, goats, cows, swine, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals will be suitable subjects, including rodents e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.

[0045] The terms “treat”, “treating”, and “treatment” are an approach for obtaining beneficial or desired clinical results. Specifically, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (e.g., not worsening) of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, and remission (partial or total) whether detectable or undetectable.

[0046] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

[0047] As used herein, the term “reduce” or “reducing” refers to deceasing the degree or amount of an event. For example, reducing biofilm formation can mean lower the amount of biofilm formation when using the compositions described herein when compared to the amount of biofilm formation when the compositions described herein are not used.Nitric Oxide Releasing Wound Treatment Materials

[0048] In accordance with the purpose(s) of the present disclosure, as embodies and broadly described herein, the disclosure, in one aspect, relates to a wound treatment material comprising a first layer adjacent to a second layer, wherein (a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and (b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.

[0049] FIG. 1 provides a non-limiting schematic of the wound treatment materials described herein. Referring to FIG. 1, the wound treatment material 100 has a first layer 110 and a second layer 120. The first layer 110 and the second layer 120 are adjacent to one another at interface 130. Here the first layer and second layer are in intimate contact with oneT|H Docket: 222105-2440another. In the first layer 110, a nitric oxide releasing compound 140 is homogeneously dispersed throughout the first layer. In the second layer 120, metal particles 150 are homogeneously dispersed throughout the second layer.

[0050] In one aspect, the wound treatment material is produced by applying the second layer to the first layer or, in the alternative, applying the first layer to the second layer. In one aspect, the first layer is cast into a mold of desired dimensions, and the second layer is subsequently cast onto the first layer to produce the wound treatment material. In another aspect, the second layer is cast into a mold of desired dimensions, and the first layer is subsequently cast onto the second layer to produce the wound treatment material.

[0051] In one aspect, the wound treatment material is produced by the method comprising (a) admixing a first polymer and a nitric oxide releasing compound to produce a first composition, wherein the nitric oxide releasing compound is homogeneously dispersed throughout the first polymer;(b) curing the first composition to produce a first layer;(c) admixing a second polymer and metal particles selected from the group consisting of silver, copper, strontium, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer to produce a second composition; (d) applying to at least one surface of the first layer the second composition; and(e) curing the second composition to produce the wound treatment material.

[0052] FIG. 2 provides another non-limiting schematic of the wound treatment materials described herein. Referring to FIG. 2, the wound treatment material 200 has a first layer 210, a second layer 220, and a third layer 230. The first layer 210 and the second layer 220 are adjacent to one another at interface 221. Here the first layer and second layer are in intimate contact with one another. In the first layer 210, a nitric oxide releasing compound 240 is homogeneously dispersed throughout the first layer. The second layer 220 is a barrier layer. By varying the polymer used to produce the barrier layer and the thickness of the barrier layer, the release kinetics of nitric oxide from the nitric oxide releasing compound can be modified and tuned. In one aspect, barrier layer comprises a thermoplastic silicone-polycarbonate-urethane, silicone-polyether-urethane, polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, poly(lactic-co-glycolic acid), or any combination thereof.

[0053] The second layer 220 and the third layer 230 are adjacent to one another at interface 231. Here the second layer and third layer are in intimate contact with one another. In the third layer 230, the metal particles 250 are homogeneously dispersed throughout the third layer.

[0054] In one aspect, the wound treatment material as depicted in FIG. 2 is produced by the method comprisingT|H Docket: 222105-2440(a) admixing a first polymer and a nitric oxide releasing compound to produce a first composition, wherein the nitric oxide releasing compound is homogeneously dispersed throughout the first polymer;(b) curing the first composition to produce a first layer;(c) applying to at least one surface of the first layer a third polymer;(d) curing the third polymer to produce a barrier layer;(e) admixing a second polymer and metal particles, or a combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer to produce a second composition;(f) applying to at least one surface of the barrier layer the second composition; and (g) curing the second composition to produce the wound treatment material.

[0055] Prior to curing, the first and second compositions are prepared by mixing the nitric oxide releasing compound and metal particles, respectively, with the first and second polymer to ensure the components are homogeneously dispersed throughout the polymer. In one aspect, components of the first and second compositions are agitated including, but not limited to, stirring, centrifugation, or sonication. In one aspect, an organic solvent can be used to produce the first and second compositions. In one aspect, the organic solvent is an alcohol, (e.g., methanol, ethanol), acetone, or tetrahydrofuran.

[0056] Once the first and second compositions have been prepared, they can be individually and sequentially cured to produce the wound treating materials described herein. In one aspect, the first and second composition is cured at a temperature from about 20 °C to about 50 °C.

[0057] The thickness of each layer of the wound treatment material can vary depending upon the application of the material. In one aspect, each layer of the wound treatment material has a thickness of about 0.3 nm to about 0.5 nm. In another aspect, the wound treatment material has a thickness of about 1.2 nm to about 1.5 nm. The Examples provide non-limiting procedures for making the wound treating materials described herein.

[0058] The polymers used to produce the first and second layers of the wound treating materials described herein can vary. In one aspect, the first polymer and the second polymer are the same polymer. In another aspect, the first polymer and the second polymer are different polymers.

[0059] In one aspect, the first polymer and the second polymer are a thermoplastic silicone-polycarbonate-urethane, a polyester, a polyamide, a polyalkylene glycol (e.g., polyethylene glycol, polypropylene glycol, ora polyethylene / polypropylene glycol copolymer), polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, or any combination thereof.T|H Docket: 222105-2440

[0060] In one aspect, the first polymer and the second polymer are a polysiloxane. In one aspect, the polysiloxane is a linear or branched polysiloxane. In another aspect, the first polymer and the second polymer are the same polysiloxane

[0061] In one aspect, the polysiloxane with one or more epoxide reactive groups has the structure Iwherein each R1is independently selected from alkyl, aryl, alkenyl, hydrogen, alkoxy;m is an integer from 1 to 10; andn is from about 2,500 to about 27,000.

[0062] In one aspect, each R1in structure I is a methyl group. In another aspect, each m in structure I is 3. In another aspect, n in structure I is 2,500, 5,000, 7,500, 10,000, 12,500, 15,000, 17,500, 20,000, 22,500, 25,00, or 27,000, where any value can be a lower and upper endpoint of a range (e.g., 5,000 to 17,500).

[0063] In one aspect, the polysiloxane comprises a polydimethylsiloxane, a polydiethylsiloxane, a polydipropylsiloxane, or a polydiphenylsiloxane. In another aspect, the first polymer and the second polymer are each polydimethylsiloxane

[0064] In one aspect, the nitric oxide releasing compound present in the first layer of the wound treating materials described herein is a compound that possesses one or more nitric oxide groups, wherein nitric oxide can be released from the compound.

[0065] In one aspect, the nitric oxide releasing compound is an S-nitrosothiol (RSNO) compound. In a further aspect, the nitric oxide compound is S-nitroso- / V-acetylpenicillamine, S-nitroso-glutathione, S-nitroso- / V-acetylcysteine, S-nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B, D-glucose, S-nitrosocaptopril, S-nitrosocysteamine, S-nitroso-3-mercapto-propanoic acid, S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-N-acetyl-L-methionine, S-nitrosomercaptoethanol, or any combination thereof. In another aspect, the nitric oxide releasing compound can be S-nitrosothiol conjugated polymers, S-nitrosothiol modified-dendrimers, S-nitrosothiol modified polysaccharides, S-nitrosothiol modified nano / microparticles, or S-nitrosothiol modified-proteins. The nitric oxide releasing compound can also include other NO-donors such as, for example, nitrates and N-diazeniumdiolates (NONOates).T|H Docket: 222105-2440

[0066] In other aspects, the nitric oxide releasing compound includes a modified antibiotic compound including a nitric oxide release agent covalently attached to an antibiotic molecule. Having a single molecule with the combined functionalities of both of a stable NO donor and an antibiotic can be a very efficient approach for combating and preventing biofilm related infections. The modified antibiotic compound can be a synthetic RSNO covalently attached to an antibiotic molecule to create a novel dual functional antimicrobial agent, also referred to as a modified antibiotic compound. In other aspects, the nitric oxide releasing agent is S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-glutathione, S-nitroso- / V-acetylcysteine, S-nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B, D-glucose, S-nitrosocaptopril, S-nitrosocysteamine, S-nitroso-3-mercapto-propanoic acid, or any combination thereof. In other aspects, the antibiotic molecule can be ampicillin, vancomycin, gentamicin, cephalexin, or any combination thereof. In further aspects, the modified antibiotic compound includes SNAP covalently bonded to ampicillin, referred to herein as SNAPicillin. SNAP can be represented by the following structure:SNAPicillin can be represented by the following structure:

[0067] In one aspect, the modified antibiotic compound can be formed by covalently attaching a nitric oxide release agent to an antibiotic molecule. The attachment can be formed by mixing the nitric oxide release agent and the antibiotic molecule in a solvent and then nitrosating the mixture. The nitrosation can occur through the excess addition of t-butyl nitrite or an acidified sodium nitrite solution to the mixture. The excess addition can be about a 3T|H Docket: 222105-2440times molar excess of t-butyl nitrate with respect to the quantity of the antibiotic molecule, such as ampicillin. Methods for producing the modified antibiotic compound useful as nitric oxide releasing compounds are described in US Patent No. 11,220,516, which is incorporated by reference in its entirety.

[0068] The amount of the nitric oxide releasing compound incorporated into the first layer of the wound treating materials described herein can vary. In one aspect, the nitric oxide releasing compound is from about 7 weight percent to about 30 weight percent of the first layer. In another aspect, the nitric oxide releasing compound is about 7 weight percent, 8 weight percent, 9 weight percent, 10 weight percent, 11 weight percent, 12 weight percent, 13 weight percent, 14 weight percent, 15 weight percent, 16 weight percent, 17 weight percent, 18 weight percent, 19 weight percent, 20 weight percent, 21 weight percent, 22 weight percent, 23 weight percent, 24 weight percent, 25 weight percent, 26 weight percent, 27 weight percent, 28 weight percent, 29 weight percent, or 30 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 9 weight percent to 20 weight percent).

[0069] The second layer of the wound treating materials described herein includes metal particles homogeneously dispersed throughout the second polymer. In one aspect, metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof. Not wishing to be bound by theory, the metal particles release monovalent ions that can catalyze NO release from the nitric oxide releasing compound. Incorporation of a metal particle interface on the nitric oxide releasing layer enables interaction and catalytic generation of NO, achieving enhanced NO release equating to therapeutic levels of NO for wound healing.

[0070] In one aspect, when the second layer includes metal particles from about 0.1 weight percent to about 10 weight percent of the second layer. In another aspect, when the second layer includes metal particles at about 0.1 weight percent, 0.5 weight percent, 1 weight percent, 2 weight percent, 3 weight percent, 4 weight percent, 5 weight percent, 6 weight percent, 7 weight percent, 8 weight percent, 9 weight percent, or 10 weight percent of the second layer, where any value can be a lower and upper endpoint of a range (e.g., 2 weight percent to 5 weight percent, of the second layer).

[0071] In one aspect, the metal particles are nanoparticles. In one aspect, the nanoparticles have an average particle diameter of about 10 nm to about 900 nm. In another aspect, the metal particles are silver nanoparticles having an average particle diameter of about 20 nm to about 800 nm, or about 20 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, or 800 nm, where any value can be a lower and upper endpoint of a range (e.g., 50 nm to 150 nm). In another aspect, the metal particles are copper nanoparticles having an average particle diameter of about 5 nm to about 500 nm, or about 5 nm, 10 nm, 50 nm, 100 nm, 150 nm, 200T|H Docket: 222105-2440nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm, where any value can be a lower and upper endpoint of a range (e.g., 10 nm to 100 nm).

[0072] In one aspect, the second layer includes an antifibrinolytic agent homogeneously dispersed throughout the second polymer. In one aspect, the antifibrinolytic agent is any compound that inhibits fibrinolysis. In one aspect, the antifibrinolytic agent is tranexamic acid or epsilon amino caproic acid (Amicar). In one aspect, when the second layer includes an antifibrinolytic agent, it is from about 1 milligram per milliliter to about 15 milligrams per milliliter of the second layer. In another aspect, when the second layer includes an antifibrinolytic agent, it is about 1 milligram, 2 milligrams, 3 milligrams, 4 milligrams, 5 milligrams, 6 milligrams, 7 milligrams, 8 milligrams, 9 milligrams, 10 milligrams, 11 milligrams, 12 milligrams, 13 milligrams, 14 milligrams, or 15 milligrams per milliliter of the second layer, where any value a lower and upper endpoint of a range (e.g., 6 milligrams to 10 milligrams per milliliter of the second layer).

[0073] In another aspects, depending upon the application of the wound treatment material, the material can include one or more bioactive agents. The bioactive agent can be incorporated in any layer of the wound treatment materials described herein. In one aspect, the bioactive material includes, but is not limited to, an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, an anti-angiogenic agent, a receptor antagonist, a nucleic acid, or any combination thereof. The bioactive agent can be incorporated into the wound treatment material during any phase of production (e.g., mixing the with nitric oxide releasing compound and the first polymer, metal particles with the second polymer, etc.).

[0074] The wound treatment materials described herein are useful in promoting the healing of a number of different wounds. Proper wound management requires multi-faceted healing platforms that regulate inflammation, stimulate tissue growth, promote blood flow, and prevent infection. Microbial burden becomes a major issue in wound management, especially in delayed healing and the development of chronic wounds (e.g., diabetic foot, venous leg, and pressure ulcers).

[0075] Skin and soft tissue infections (SSTIs) result from microbial contamination of the skin, tissue, or muscles and is common to open wounds resulting from cuts, punctures, or burns. SSTIs can range from mild infections to complicated, severe infections depending on the patient’s state and opportunistic microorganisms. Improper care of an open wound can lead to microbial invasion of community-acquired methicillin-resistant Staphylococcus aureus or streptococci, resulting in difficult-to-treat SSTIs. Involvement of such antibiotic-resistant Gram-positive strains increases the difficulty of treatment, and can significantly affect patient outcomes, leading to increased costs for chronic wound treatment and extendedT|H Docket: 222105-2440hospitalization. In this sense, initial wound care and management is critical to prevent the incidence of SSTIs.

[0076] Chronic wounds, common in the elderly population, do not progress through a normal process of repair, often remaining open for an extended period. Normally, the wound healing process is hindered by microorganisms and / or necrotic tissue by producing proinflammatory cytokines, elevating matrix metalloproteinases, and attracting excessive neutrophils. Thus, destroying or inactivating the building blocks necessary for normal wound healing. This also allows bacteria to proliferate and colonize the wound by constructing protected colonies or biofilms. More than 90% of chronic wounds contain bacteria existing within a biofilm construct. Biofilms prevent antibiotics and immune cells from penetrating the bacteria colony, giving added resistance power to bacteria to tolerate harsh conditions. Chronic wounds become more complicated with biofilm formation resulting in wounds that may take several years to heal. Therefore, early diagnosis can allow proper wound care treatment to avoid the incidence of chronic wounds.

[0077] SSTIs remain a broad clinical challenge to clinicians where antibiotic use is also heavily debated for its benefits / drawbacks to wound repair. Reducing bioburden is a key component to wound recovery through the normal phases of healing (i.e., hemostasis, inflammation, proliferation, and remodeling). However, avoiding chronic wound development is key in diverse patient groups (e.g., diabetes, poor circulation, malnutrition, etc.) wherein these technologies can have broad limitations (e.g., infiltration of inflammatory cells, lack of fibroblast migration, and low amounts of extracellular matrix components).

[0078] In one aspect, the wound treatment materials described herein are effective in reducing or preventing bacterial infection (e.g., Pseudomonas aeruginosa and Methicillin Resistant Staphylococcus aureus) when applied to the wound. In another aspect, the wound treatment materials described herein are effective in reducing or preventing biofilm formation, which can prevent antibiotics and immune cells from penetrating the bacteria colony in the wound.

[0079] In one aspect, the wound treatment materials described herein are effective in reducing or preventing blood loss when applied to the wound. Hemorrhage is the leading cause of preventable death in trauma patients. If not efficiently managed, bleeding is often associated with further morbidities, including infection and organ dysfunction / failure. In another aspect, the wound treatment materials described herein can promote blood flow in a wound, which is another important factor in wound care and healing.

[0080] In one aspect, the wound treatment materials described herein can reduce or prevent inflammation at or near the wound. Not wishing to be bound by theory, nitric oxide released from the wound treatment materials described herein can promote M2 macrophage polarization, leading to healing, fixing, antiinflammation.T|H Docket: 222105-2440

[0081] The wound treatment materials are effective in treating a number of significant wounds. In one aspect, the wound is the result of a traumatic injury. Traumatic injury is the leading cause of death for Americans up to the age of 45 years and the fourth leading cause of death overall. Uncontrolled trauma-related hemorrhage is the leading cause of death among critically injured patients. Infectious complications often result from extensive wound contamination in traumatic injury patients, and can lead to sepsis and organ failure.

[0082] In one aspect, the wound is the result of a surgical procedure or intervention. Surgical intervention often results in trauma to tissues and organs. Up to 3% of patients undergoing surgery will experience infection at or adjacent to the surgical site, extending hospitalization by more than a week on average.

[0083] In one aspect, the wound is a chronic wound. Chronic wound management is a broad challenge, with the mainstay of treatment being the TIME principle: tissue debridement, infection control, moisture balance, and edges of wound. More than 4.5 million Americans are affected by chronic lower extremity ulcers and related chronic wounds annually, with these ulcers typically lasting 12 to 13 months and having a high risk of recurrence. In one aspect, the chronic wound is a skin ulcer such as, for example, a diabetic ulcer, pressure ulcer, or venous ulcer. In another aspect, the wound is a burn.

[0084] The wound treatment materials described herein can provide sustained release of nitric oxide. In one aspect, the wound treatment materials described herein can release nitric oxide for at least 24 hours. In another aspect, the wound treatment materials described herein can release nitric oxide from 24 hours to 21 days, or 24 hours, 3 days, 6 days, 9 days, 12 days, 15 days, 18 days, or 21 days, where any value can be a lower and upper endpoint of a range (e.g., 3 days to 9 days). In another aspect, the wound treatment materials described herein can release nitric oxide at a concentration of less than or equal to 300 nM for a sustained period of time (e.g., 24 hours to 21 days), or 50 nM, 100 nM, 150 nM, 200 nM, 250 nM, or 300 nM, where any value can be a lower and upper endpoint of a range (e.g., 100 nM to 250 nM).

[0085] Depending upon the nature of the wound, the wound treatment materials described herein can be used alone (e.g., a wound packing) or incorporated into other wound dressing articles such as, for example, a bandage, gauze, pad, a gel, or a foam. When applied to the wound, the second layer of the wound treatment material is in contact with the wound.

[0086] In another aspect, the wound treatment materials described herein can be applied to a coating on an implantable device such as, for example, catheters (e.g., urinary or vascular), cannulas, tubing, sutures, an artificial heart valve, a graft (e.g., vascular graft), a stent (e.g., coronary stent), or circuitry (e.g., extracorporeal membrane oxygenation circuit).

[0087] In other aspects, the wound treatment materials described herein described herein can be used as a component to fabricate a medical device. For example, the wound treatmentT|H Docket: 222105-2440materials described herein can be used to produce cannulas, catheters, heart valves, endovascular stents, and joint prostheses, and other medical devices. In one aspect, the wound treatment materials described herein can be formulated in a solvent alone or in combination with one or more additional components then subsequently poured into a mold. The solvent then can be removed to produce a molded article composed of the wound treatment material. In another aspect, a molded article composed of a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer can be produced, and one or more surfaces of the molded article can subsequently coated with first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer.Aspects

[0088] Aspect 1. A wound treatment material comprising a first layer adjacent to a second layer, wherein(a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and(b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.

[0089] Aspect 2. The material of Aspect 1, wherein the first polymer and the second polymer are the same polymer.

[0090] Aspect 3. The material of Aspect 1 , wherein the first polymer and the second polymer are different polymers.

[0091] Aspect 4. The material of Aspect 1, wherein the first polymer and the second polymer are a thermoplastic silicone-polycarbonate-urethane, silicone-polyether-urethane, a polyester, a polyamide, a polyalkylene glycol, polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, poly(lactic-co-glycolic acid), or any combination thereof.

[0092] Aspect 5. The material of Aspect 1 , wherein the first polymer and the second polymer are a polysiloxane.

[0093] Aspect 6. The material of Aspect 5, wherein the polysiloxane comprises a linear or branched polysiloxane.

[0094] Aspect 7. The material of Aspect 5 or 6, wherein the polysiloxane comprises a polydimethylsiloxane, a polydiethylsiloxane, a polydipropylsiloxane, ora polydiphenylsiloxane.

[0095] Aspect 8. The material of Aspect 1 , wherein the first polymer and the second polymer are each polydimethylsiloxane.T|H Docket: 222105-2440

[0096] Aspect 9. The material of any one of Aspects 1 -8, wherein the nitric oxide releasing compound is a modified antibiotic compound comprising a nitric oxide release agent covalently attached to an antibiotic molecule

[0097] Aspect 10. The material of any one of Aspects 1-8, wherein the nitric oxide release agent is S-nitroso- / V-acetylpenicillamine, S-nitroso-glutathione, S-nitroso- / V-acetylcysteine, S-nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B, D-glucose, S-nitrosocaptopril, S-nitrosocysteamine, and S-nitroso-3-mercapto-propanoic acid.

[0098] Aspect 11. The material of Aspect 9 or 10, wherein the antibiotic molecule is ampicillin, vancomycin, gentamicin, or cephalexin.

[0099] Aspect 12. The material of Aspect 11, wherein the modified antibiotic compound comprises S-nitroso- / V-acetylpenicillamine covalently attached to ampicillin.

[0100] Aspect 13. The material of any one of Aspects 1-8, wherein the nitric oxide releasing compound is a S-nitrosothiol compound.

[0101] Aspect 14. The material of any one of Aspects 1-8, wherein the nitric oxide releasing compound is S-nitroso- / V-acetyl-penicillamine, S-nitroso-N-acetylcysteine, S-nitroso-N-acetyl cysteamine, S-nitrosoglutathione, S-nitrosocysteamine-glutathione, methyl S-nitrosothioglycolate, nitrosated cysteine, S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-L-homocysteine, S-nitroso-L-cysteine, S-nitroso-albumin, S-nitrosocaptopril, or any combination thereof.

[0102] Aspect 15. The material of any one of Aspects 1-8, wherein the nitric oxide releasing compound is S-nitroso- / V-acetyl-penicillamine.

[0103] Aspect 16. The material of any one of Aspects 1-15, wherein the nitric oxide releasing compound is from about 7 weight percent to about 30 weight percent of the first layer.

[0104] Aspect 17. The material of any one of Aspects 1-16, wherein the metal particles are from about 0.1 weight percent to about 10 weight percent of the second layer.

[0105] Aspect 18. The material of any one of Aspects 1-17, wherein the metal particles are nanoparticles.

[0106] Aspect 19. The material of any one of Aspects 1-17, wherein the metal particles comprise silver nanoparticles having an average particle diameter of about 20 nm to about 800 nm.

[0107] Aspect 20. The material of any one of Aspects 1-17, wherein the metal particles comprise copper nanoparticles having an average particle diameter of about 5 nm to about 500 nm.

[0108] Aspect 21. The material of any one of Aspects 1-20, wherein the second layer further comprises an antifibrinolytic agent homogeneously dispersed throughout the second polymer.T|H Docket: 222105-2440

[0109] Aspect 22. The material of Aspect 21, wherein the antifibrinolytic agent is from about 1 milligram per milliliter to about 15 milligrams per milliliter of the second layer.

[0110] Aspect 23. The material of Aspect 21, wherein the antifibrinolytic agent is tranexamic acid or epsilon amino caproic acid (Amicar).

[0111] Aspect 24. The material of any one of Aspects 1-23, wherein the first layer and the second layer has a thickness of about 0.3 nm to about 0.5 nm.

[0112] Aspect 25. A wound treatment material comprising a first layer, a barrier layer, and a second layer, wherein the barrier layer is positioned between the first layer and the second layer, wherein(a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and(b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.

[0113] Aspect 26. The material of Aspect 25, wherein the barrier layer comprises thermoplastic silicone-polycarbonate-urethane, silicone-polyether-urethane, polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, poly(lactic-co-glycolic acid), or any combination thereof.

[0114] Aspect 27. A wound treatment material produced by the method comprising (a) admixing a first polymer and a nitric oxide releasing compound to produce a first composition, wherein the nitric oxide releasing compound is homogeneously dispersed throughout the first polymer;(b) curing the first composition to produce a first layer;(c) admixing a second polymer and metal particles selected from the group consisting of silver, copper, strontium, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer to produce a second composition; (d) applying to at least one surface of the first layer the second composition; and(e) curing the second composition to produce the wound treatment material.

[0115] Aspect 28. The material of Aspect 27, wherein the curing steps are conducted at a temperature from about 20 °C to about 50 °C.

[0116] Aspect 29. The material of Aspect 27 or 28, wherein the first composition is produced by agitating a mixture comprising the nitric oxide releasing compound and the first polymer.

[0117] Aspect 30. The material of any one of Aspects 27-29, wherein the second composition is produced by agitating a mixture comprising the metal particles and the second polymer.T|H Docket: 222105-2440

[0118] Aspect 31. The material of any one of Aspects 27-30, wherein agitation comprises stirring, centrifugation, or sonication.

[0119] Aspect 32. A wound dressing comprising the wound treatment material of any one of Aspects 1-31.

[0120] Aspect 33. The wound dressing of Aspect 32, wherein the dressing comprises a bandage, gauze, pad, a gel, or a foam.

[0121] Aspect 34. An article comprising at least one surface, wherein the at least one surface is coated with the wound treatment material of any one of Aspects 1-31.

[0122] Aspect 35. An article comprising one or more components fabricated with the wound treatment material of any one of Aspects 1-31.

[0123] Aspect 36. The article of Aspect 34 or 35, wherein the article comprises a medical device.

[0124] Aspect 37. The article of Aspect 34 or 35, wherein the article is an implantable device.

[0125] Aspect 38. The article of Aspect 34 or 35, wherein the article is a catheter, a cannula, tubing, a suture, an artificial heart valve, a graft, a stent, circuitry, or a joint prostheses.

[0126] Aspect 39. A method for treating a wound, the method comprising applying the wound treatment material of any one of Aspects 1-31 to the wound, wherein the second layer of the wound treatment material is in contact with the wound.

[0127] Aspect 40. The method of Aspect 39, wherein the wound treatment material reduces or prevents the growth of microbes in the wound.

[0128] Aspect 41. The method of Aspect 39, wherein the wound treatment material reduces or prevents a bacterial infection in the wound.

[0129] Aspect 42. The method of Aspect 39, wherein the wound treatment material reduces or prevents biofilm formation at or near the wound.

[0130] Aspect 43. The method of Aspect 39, wherein the wound treatment material reduces or prevents blood loss from the wound.

[0131] Aspect 44. The method of Aspect 39, wherein the wound treatment material reduces or prevents inflammation at or near the wound.

[0132] Aspect 45. The method of any one of Aspects 39-44, wherein the wound is the result of a traumatic injury or surgical intervention.

[0133] Aspect 46. The method of any one of Aspects 39-44, wherein the wound is a chronic wound.

[0134] Aspect 47. The method of Aspect 46, wherein the chronic wound is a diabetic ulcer, pressure ulcer, or venous ulcer.T|H Docket: 222105-2440

[0135] Aspect 48. The method of any one of Aspects 39-44, wherein the wound is a burn to the skin.EXAMPLES

[0136] Now having described the embodiments of the disclosure, in general, the examples describe some additional embodiments. While embodiments of the present disclosure are described in connection with the example and the corresponding text and figures, there is no intent to limit embodiments of the disclosure to these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.

[0137] MATERIALS AND METHODS

[0138] Materials

[0139] Polydimethylsiloxane (PDMS) / Silicone was obtained from Kradyen (Denver, CO, USA). Tetrahydrofuran (THF) was purchased from Sigma-Aldrich (St. Louis, MO, USA). Silver nanoparticles and Copper nanoparticles were purchased from SkySpring Nanoparticles (Huston, TX, USA). Teflon blocks were purchased from Grainger (Athens, GA, USA) and were carved into 3.5 cm x 3.5 cm molds.

[0140] Silver-NO Wound Construct Fabrication

[0141] Wound dressings were made using a layer-by-layer casting method with PDMS-SNAP on the bottom layer and PDMS-Ag on the top layer. In the first layer, 10 wt% or 20 wt% SNAP was added to a 300 mg / mL PDMS-THF solution. 5 mL of the PDMS-SNAP solution was cast into a 3.5 cm x 3.5 cm Teflon Mold and cured at room temperature for 48 hours in the fume hood. Then the constructs were placed in the desiccator for vacuum drying for 24 hours. In the second layer, 1 wt% or 3 wt% Ag nanoparticles were dissolved in 300 mg / mL PDMS-THF solution. 1 mL of the PDMS-Ag solution was added to the constructs. The films were cured at room temperature for 48 hours in the fume hood, followed by vacuum drying for 24 hours in the desiccator.

[0142] Copper-NO Wound Construct Fabrication

[0143] Wound dressings were made using a layer-by-layer casting method with PDMS-SNAP on the bottom layer and PDMS-Cu on the top layer. In the first layer, 10 wt% or 20 wt% SNAP was added to a 300 mg / mL PDMS-THF solution. 5 mL of the PDMS-SNAP solution was cast into a 3.5 cm x 3.5 cm Teflon Mold and cured at room temperature for 48 hours in the fume hood. Then the constructs were placed in the desiccator for vacuum drying for 24 hours. In the second layer, 1 wt% or 3 wt% Cu nanoparticles were dissolved in 300 mg / mL PDMS-THF solution. 1 mL of the PDMS-Cu solution was added to the constructs. The filmsT|H Docket: 222105-2440were cured at room temperature for 48 hours in the fume hood, followed by vacuum drying for 24 hours in the desiccator.

[0144] SNAP Leaching

[0145] SNAP leaching was continuously monitored throughout the 3-day period from the PDMS-SNAP, PDMS-SNAP-Ag and PDMS-SNAP-Cu samples by keeping them in PBS at 37°C. The incubated samples were taken out periodically to record absorbance readings at 340 nm, the peak wavelength of SNAP, using a UV-Vis spectrophotometer.

[0146] RESULTS

[0147] S-nitroso-N-acetylpenicillamine (SNAP) Incorporation into Silicone Contact Layers with a Metal Nanoparticle-Doped Interface Enables Sustained Therapeutic Levels of NO Release

[0148] Silicone contact layers prepared with 20 wt% of SNAP with a 3 wt% Ag or Cu-NP top layer exhibited tunable levels of NO release through 72-h (i.e. , typical changing timeframe for silicone contact layers) (Fig. 3). These levels are consistent with levels of NO accumulation that would facilitate wound healing without triggering pro-inflammatory response (i.e., M1 macrophage polarization).

[0149] Catalyzed NO Release Enhances Antimicrobial Effects and is Complementary to Ag / Cu Antimicrobial Effects

[0150] The antimicrobial efficacy of silicone contact layers developed with catalytic NO release via either Ag or Cu-NPs was evaluated for resistance to viable bacteria adhesion over 24-h against Escherichia coli (ATCC 25922) and Methicillin-resistant Staphylococcus aureus (MRSA BAA41) strains, demonstrating over 3-log reduction in viable adhered bacteria compared to silicone control dressings (CTRL) (Figs. 4A-4D). The catalyzed NO release and antimicrobial metal ions exert a bactericidal effect on both Gram-positive and Gram-negative bacteria present at a wound site, including antibiotic-resistant strains, reducing microbial bioburden at the site of wound repair.

[0151] Catalytic Nitric Oxide Releasing Wound Dressings Exhibit Strong Biocompatibility in Pilot ISO 10993-5 Studies

[0152] The general biocompatibility of catalytic NO-releasing silicone contact layers was assessed through International Organization for Standardization (ISO) 10993-5 standards for biocompatibility of medical devices, challenged against human fibroblast cells (CRL-2522) in 24-h studies of indirect contact (leachate) screening (Fig. 5). Both NO+Ag and NO+Cu silicone contact layers were exposed to complete cell culture medium for 24 h at 37 °C. Afterwards, extracts were exposed to monolayers of fibroblasts for 24 h. Following incubation, cell numbers were determined, demonstrating >70% retention in cellular viability with respect to the silicone control. These results support the general biocompatibility of NO+Ag and NO+Cu contact layers in short-term models (24 h).T|H Docket: 222105-2440

[0153] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations and are set forth only for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure.

Claims

T|H Docket: 222105-2440CLAIMS1. A wound treatment material comprising a first layer adjacent to a second layer, wherein (a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and(b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, selenium, zinc, iron, nickel, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.2 The material of claim 1, wherein the first polymer and the second polymer are the same polymer.3 The material of claim 1, wherein the first polymer and the second polymer are different polymers.4 The material of claim 1, wherein the first polymer and the second polymer are a thermoplastic silicone-polycarbonate-urethane, silicone-polyether-urethane, a polyester, a polyamide, a polyalkylene glycol, polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, poly(lactic-co-glycolic acid), or any combination thereof.5 The material of claim 1, wherein the first polymer and the second polymer are a polysiloxane.6 The material of claim 5, wherein the polysiloxane comprises a linear or branched polysiloxane.7 The material of claim 5, wherein the polysiloxane comprises a polydimethylsiloxane, a polydiethylsiloxane, a polydipropylsiloxane, or a polydiphenylsiloxane.8 The material of claim 1, wherein the first polymer and the second polymer are each polydimethylsiloxane.9 The material of claim 1 , wherein the nitric oxide releasing compound is a modified antibiotic compound comprising a nitric oxide release agent covalently attached to an antibiotic molecule10 The material of claim 1, wherein the nitric oxide release agent is S-nitroso- / V- acetylpenicillamine, S-nitroso-glutathione, S-nitroso- / V-acetylcysteine, S-nitrosocysteine, S-nitrosopenicillamine, S-nitroso-B, D-glucose, S-nitrosocaptopril, S-nitrosocysteamine, and S-nitroso-3-mercapto-propanoic acid.11 The material of claim 9, wherein the antibiotic molecule is ampicillin, vancomycin, gentamicin, or cephalexin.T|H Docket: 222105-244012. The material of claim 11, wherein the modified antibiotic compound comprises S-nitroso- / V-acetylpenicillamine covalently attached to ampicillin.

13. The material of claim 1, wherein the nitric oxide releasing compound is a S-nitrosothiol compound.

14. The material of claim 1 , wherein the nitric oxide releasing compound is S-nitroso- / V-acetyl- penicillamine, S-nitroso-N-acetylcysteine, S-nitroso-N-acetyl cysteamine, S- nitrosoglutathione, S-nitrosocysteamine-glutathione, methyl S-nitrosothioglycolate, nitrosated cysteine, S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET), S-nitroso-L- homocysteine, S-nitroso-L-cysteine, S-nitroso-albumin, S-nitrosocaptopril, or any combination thereof.

15. The material of claim 1 , wherein the nitric oxide releasing compound is S-nitroso- / V-acetyl- penicillamine.

16. The material of claim 1 , wherein the nitric oxide releasing compound is from about 7 weight percent to about 30 weight percent of the first layer.

17. The material of claim 1, wherein the metal particles are from about 0.1 weight percent to about 10 weight percent of the second layer.

18. The material of claim 1 , wherein the metal particles are nanoparticles.

19. The material of claim 1, wherein the metal particles comprise silver nanoparticles having an average particle diameter of about 20 nm to about 800 nm.

20. The material of claim 1 , wherein the metal particles comprise copper nanoparticles having an average particle diameter of about 5 nm to about 500 nm.

21. The material of claim 1, wherein the second layer further comprises an antifibrinolytic agent homogeneously dispersed throughout the second polymer.

22. The material of claim 21, wherein the antifibrinolytic agent is from about 1 milligram per milliliter to about 15 milligrams per milliliter of the second layer.

23. The material of claim 21, wherein the antifibrinolytic agent is tranexamic acid or epsilon amino caproic acid (Amicar).

24. The material of claim 1, wherein the first layer and the second layer has a thickness of about 0.3 nm to about 0.5 nm.

25. A wound treatment material comprising a first layer, a barrier layer, and a second layer, wherein the barrier layer is positioned between the first layer and the second layer, wherein (a) the first layer comprises a first polymer and a nitric oxide releasing compound homogeneously dispersed throughout the first polymer; and(b) the second layer comprises a second polymer and metal particles selected from the group consisting of silver, copper, strontium, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer.T|H Docket: 222105-244026. The material of claim 25, wherein the barrier layer comprises thermoplastic silicone- polycarbonate-urethane, silicone-polyether-urethane, polyvinyl alcohol, polyurethane, sodium alginate, chitosan, cellulose, collagen, chondroitin, gelatin, silk fibroin, eggshell membrane, albumin, wheat bran, arabinoxylan, poly(lactic-co-glycolic acid), or any combination thereof.

27. A wound treatment material produced by the method comprising(a) admixing a first polymer and a nitric oxide releasing compound to produce a first composition, wherein the nitric oxide releasing compound is homogeneously dispersed throughout the first polymer;(b) curing the first composition to produce a first layer;(c) admixing a second polymer and metal particles selected from the group consisting of silver, copper, strontium, and any combination thereof, wherein the metal particles are homogeneously dispersed throughout the second polymer to produce a second composition;(d) applying to at least one surface of the first layer the second composition; and(e) curing the second composition to produce the wound treatment material.

28. The material of claim 27, wherein the curing steps are conducted at a temperature from about 20 °C to about 50 °C.

29. The material of claim 27, wherein the first composition is produced by agitating a mixture comprising the nitric oxide releasing compound and the first polymer.

30. The material of claim 27, wherein the second composition is produced by agitating a mixture comprising the metal particles and the second polymer.

31. The material of claim 27, wherein agitation comprises stirring, centrifugation, or sonication.

32. A wound dressing comprising the wound treatment material of any one of claims 1-31.

33. The wound dressing of claim 32, wherein the dressing comprises a bandage, gauze, pad, a gel, or a foam.

34. An article comprising at least one surface, wherein the at least one surface is coated with the wound treatment material of any one of claims 1-31.

35. An article comprising one or more components fabricated with the wound treatment material of any one of claims 1-31.

36. The article of claim 34, wherein the article comprises a medical device.

37. The article of claim 34, wherein the article is an implantable device.

38. The article of claim 34, wherein the article is a catheter, a cannula, tubing, a suture, an artificial heart valve, a graft, a stent, circuitry, or a joint prostheses.

39. A method for treating a wound, the method comprising applying the wound treatment material of any one of claims 1-31 to the wound, wherein the second layer of the wound treatment material is in contact with the wound.T|H Docket: 222105-244040. The method of claim 39, wherein the wound treatment material reduces or prevents the growth of microbes in the wound.

41. The method of claim 39, wherein the wound treatment material reduces or prevents a bacterial infection in the wound.

42. The method of claim 39, wherein the wound treatment material reduces or prevents biofilm formation at or near the wound.

43. The method of claim 39, wherein the wound treatment material reduces or prevents blood loss from the wound.

44. The method of claim 39, wherein the wound treatment material reduces or prevents inflammation at or near the wound.

45. The method of claim 39, wherein the wound is the result of a traumatic injury or surgical intervention.

46. The method of claim 39, wherein the wound is a chronic wound.

47. The method of claim 46, wherein the chronic wound is a diabetic ulcer, pressure ulcer, or venous ulcer.

48. The method of claim 39, wherein the wound is a burn to the skin.

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