WO2020040783A1

WO2020040783A1 - Polyurethanes as oxygen delivery carriers

Info

Publication number: WO2020040783A1
Application number: PCT/US2018/047908
Authority: WO
Inventors: Phillip DENEN; Erik Edwards; Ramanathan S. Lalgudi
Original assignee: Avent, Inc.
Priority date: 2018-08-24
Filing date: 2018-08-24
Publication date: 2020-02-27

Abstract

An oxygen delivery dressing is provided. The oxygen delivery dressing releases or delivers oxygen to a tissue of a mammal and includes a substrate, a polyurethane carrier, and an oxygen producing compound. A method of forming an oxygen delivery dressing that includes an oxygen producing composition is also provided. The oxygen delivery dressing can directly contact the tissue of a mammal without contacting the skin with an oxygen producing compound, as the oxygen producing compound is contained within the polyurethane carrier until contacted with a catalyst.

Description

Polyurethanes as Oxygen Delivery Carriers

Statement of Government Support

This invention was made with government support under contract No. ONRBAA14-001 awarded by the Department of the Navy, Office of Naval Research. The government has certain rights in the invention.

Background of the Invention

The delivery of oxygen has many practical applications, but continues to suffer from challenges that inhibit applications for which current oxygen delivery solutions may be used. For instance, it is often difficult to find oxygen delivery methods that are capable of providing sufficient amounts of oxygen without compromising the stability of the composition or carrier, or the usability of the composition with the desired target.

Fields such as fermentation applications and microbial based remediation both require oxygen delivery, and particularly, there is a need in the field of wound care technology to deliver oxygen to severely injured limbs in austere environments, such as injuries that may require the application of a tourniquet for extended periods of time. Typically, in terms of wound care, the need often arises in military or disaster relief settings in which there may be a significant time lapse between the injury event and transportation of the patient to a treatment facility. Flowever, many wounds would benefit from a fast and more accessible oxygen delivery source, for example, when a tourniquet is required to treat the wound at the time of injury.

Many methods have been developed for oxygen delivery in biological settings, such as by using fluorocarbons, the use of modified hemoglobin, or hydrogen oxygen fuel cells. Flowever, none of these methods for oxygen delivery have been successful in forming an oxygen delivery system that was capable of generating a large amount of oxygen as compared to the system’s mass, or that were usable with, or in contact with, injured tissue.

Therefore, another solution has been to use solid peroxides, such as sodium percarbonate and calcium peroxide, which have the ability to degrade into hydrogen peroxide, which further degrades into oxygen, when exposed to water. These compounds have a large oxygen generating capacity for their mass. Flowever, high concentrations of the compounds may not directly contact a wound or tissue, limiting their use to applications in which the oxygen is generated in a separate area (such as a pump, and in bandages in which a barrier is used between the solid peroxide and the wound) or applications which utilize relatively small amounts of the solid oxygen generating compound. Therefore, in the wound care field, solid peroxides have been mainly used in external oxygen pumps rather than in skin contacting wound dressings.

However, for transport and storage in medical emergency situations, it would be beneficial to have an oxygen delivery dressing that does not require the use of a pump. It would be a further advantage to have an oxygen delivery dressing that may directly contact injured skin or tissue. It would be a further advantage if an oxygen producing compound could be incorporated into a wound dressing for delivery of oxygen and protection of injured tissue. It would also be advantageous to have an oxygen delivery composition that could remain in contact with the tissue even after the oxygen delivery composition has been activated or used. There is also a need for an easy-to-use product to apply oxygen to wounds to accelerate healing, begin healing or preserve tissue during the use of a tourniquet. Such a method and/or product should have relatively few components and be intuitive to use, without the need for special dressings or other requirements so as to be easily accessible in the field.

SUMMARY

The present disclosure may generally be directed to an oxygen delivery dressing for delivering oxygen to a tissue of a mammal. In one embodiment, the oxygen delivery dressing includes a substrate, a polyurethane carrier, and an oxygen producing compound. The polyurethane carrier is configured to contain the oxygen producing compound until the oxygen delivery dressing is contacted by a catalyst.

In an embodiment, the polyurethane carrier is comprised of an isocyanate component and a hydroxy functional component. In an additional embodiment, the isocyanate component comprises a polyisocyanate, a diisocyanate, or a combination thereof. Further, in an embodiment, the hydroxy functional component comprises a polyol. In an additional embodiment, the polyol comprises a polyethylene glycol, a polylcaprolactone, or a combination thereof. Additionally or alternatively, the hydroxy functional component, the isocyanate component, or both the hydroxy functional component and the isocyanate component are biodegradable.

In one embodiment, the oxygen producing compound comprises a

percarbonate. Furthermore, in an embodiment, the polyurethane carrier comprises a wrap or a plurality of microspheres. In one embodiment, the wrap forms all or a portion of the substrate. In an additional or alternative embodiment, the wrap is configured to be at least partially impermeable to oxygen produced by the oxygen producing compound. Moreover, in an embodiment, the plurality of microspheres are at least partially integrated into the substrate. In an additional embodiment, the plurality of

microspheres are separated from the wound dressing until the wound dressing is applied to a mammal.

In one embodiment, the catalyst comprises a wound exudate, water, saline, hydrogen peroxide, an enzyme, hemoglobin, sunlight, or a combination thereof.

The present disclosure may also be generally directed to a method to forming an oxygen delivery dressing for delivering oxygen to a tissue of a mammal. The method comprises forming a polyurethane carrier, dispersing an oxygen producing compound into the polyurethane carrier, and incorporating the polyurethane carrier containing the dispersed oxygen producing compound into a substrate. Further, the polyurethane carrier is configured to contain the oxygen producing compound until the oxygen delivery dressing is contacted by a catalyst.

In one embodiment, the formation of the polyurethane carrier comprises reacting an isocyanate component and a hydroxy functional component. In a further embodiment, the formation reaction of the polyurethane includes a solvent, where the solvent is removed from the polyurethane carrier after the oxygen producing compound has been dispersed into the polyurethane carrier.

In an additional or alternative embodiment, the polyurethane carrier is formed by an addition reaction comprising pre-polymerized prepolymers or by an in situ reaction of the isocyanate component and the hydroxy functional component. In one embodiment, the prepolymers comprise at least one prepolymer having a hydroxy functionality and at least a second prepolymer comprising an isocyanate.

In a further embodiment, the polyurethane carrier comprises a plurality of microspheres, wherein the oxygen producing compound is dispersed within the microspheres. In an embodiment, the plurality of microspheres are formed by dispersing the oxygen producing compound and the hydroxy functional component in a nonaqueous solvent, and then adding the isocyanate component.

Other features and aspects of the present disclosure are discussed in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and aspects of the present disclosure and the manner of attaining them will become more apparent, and the disclosure itself will be better understood by reference to the following description, appended claims and accompanying drawings, where:

Fig. 1 schematically illustrates the protective and oxygen delivery

characteristics of a wound dressing of the present disclosure

Fig. 2 illustrates a wound dressing of the present disclosure;

Fig. 3 schematically illustrates the protective and oxygen delivery

characteristics of a wound dressing of the present disclosure.

DETAILED DESCRIPTION

Reference will now be made in detail to one or more embodiments of the invention, examples of which are illustrated in the drawings. Each example and embodiment is provided by way of explanation of the invention, and is not meant as a limitation of the invention. For example, features illustrated or described as part of one embodiment may be used with another embodiment to yield still a further embodiment. It is intended that the invention include these and other modifications and variations as coming within the scope and spirit of the invention.

Generally speaking, the present disclosure is directed to an oxygen delivery dressing for the delivery of oxygen that produces oxygen upon contact with a catalyst. Particularly, an oxygen delivery dressing of the present disclosure may be beneficial for use with injured tissue or limbs, as the oxygen producing compound of the oxygen delivery dressing does not come into direct contact with the tissue or limb. Further, the oxygen delivery dressing of the present disclosure may not require a separate component for storing the oxygen producing compound, and, instead, the oxygen producing compound may be completely contained in the oxygen delivery dressing. Particularly, the present inventors have found that an oxygen producing compound may be dispersed within a polyurethane carrier for delivering oxygen to the tissue of a mammal, without needing an additional barrier between the polyurethane carrier and the tissue of the mammal. For instance, the present inventors have found that a polyurethane carrier that is formed from an isocyanate component and a hydroxy functional component forms a carrier that is able to contain the oxygen producing compound such that the oxygen producing compound does not contact the tissue of a mammal when applied, but the oxygen producing compound is still capable of producing and delivering oxygen when contacted with a catalyst. Thus, the present disclosure may teach compositions that have an unexpected result in that they may be used in direct contact with injured tissue, making the oxygen delivery compositions surprisingly useful and effective for the delivery of oxygen to injured tissue or a wound.

Therefore, a feature of the oxygen delivery composition of the present disclosure is that it may be incorporated into a wound dressing, or may serve as a wound dressing, and has the ability to generate oxygen, and then subsequently deliver this oxygen to the wound and the surrounding tissue. According to the present disclosure, a wound, tissue, or injured tissue may generally refer to the tissue of a mammal (e.g. a human), and the terms may be used interchangeably to refer to injuries to a mammal that would benefit from the delivery of oxygen.

Moreover, the term wound dressing is used herein to generally refer to a dressing that may be applied to a wound as defined above. For instance, without intending to be limited to the following and for example only, the term wound dressing may be used in reference to a bandage, a gauze, a wound covering, a wrap, a woven or nonwoven material, film, elastic, self-adhesive material, or a combination thereof, as well as other wound dressing substrates known in the art.

The oxygenation needs of the human skin are typically met by the

combination of direct oxygen uptake from the ambient air and by tissue oxygenation from the vasculature. Dissolved oxygen is essential at all stages of the wound healing process. Poor tissue oxygenation can result in impaired healing. Chronic wounds are notably hypoxic, with an oxygen tension of 5 to 20 mmHg, compared to an oxygen tension of 30 to 50 mmHg in healthy tissue. In healing tissue, oxygen is required as a substrate for the production of biological energy, resistance to infection, collagen synthesis, blood vessel formation, cell migration, and cell proliferation. In addition, oxygen also serves as a signaling molecule to initiate cell motility and enhance the expression of several pro-inflammatory and angiogenic growth factors. In the human skin, adequate oxygen supply is a balance between proper oxygen transport by the blood and direct uptake from the atmosphere.

Therefore, oxygen delivery to the wound is dependent on multiple factors including blood perfusion of the tissue, capillary density, arterial partial oxygen pressure (poxygen), the blood hemoglobin level, and local oxygen consumption. Oxygen is not stored in the tissue and several systemic conditions, including advancing age and diabetes, can endanger its availability. Consequently, it is imperative that upon injury, the healing tissue quickly adapts to continuously meet the oxygen

requirements for proper healing and repair. Although the wounded tissue demands high oxygen levels, the overall oxygen needs of a wound differ at the different stages of the wound healing process.

Healthy tissue needs to be able to adjust oxygen delivery when there is an increase in oxygen demand. In the human skin, oxygen delivery occurs by diffusion via direct uptake from the atmosphere and from the vasculature, where the oxygen moves from areas of high concentration to areas of low concentration. Satisfactory oxygen supply to the subcutaneous tissue is highly dependent on appropriate oxygen transport through the blood at a sufficient bulk flow rate. During tissue injury, blood supply decreases due to disruption of blood vessels. As a consequence, there is a marked decrease in oxygen delivery. Although the wounded tissue is equipped with all the necessary tools to repair the damage and restore blood supply, there are intrinsic and extrinsic factors that can impair this process, resulting in prolonged oxygen deficiency or chronic tissue hypoxia. Because adequate oxygen supply is essential for successful tissue repair, inability of the wounded tissue to meet oxygen demand can be pathological, resulting in cell death and tissue necrosis.

Therefore, the goal of an oxygen-based therapy for wound care is to fulfill the oxygen demand of the healing tissue and maintain an oxygen concentration near an oxygen tension of about 40 mmHg, which is the average oxygen tension found in healthy, well-perfused tissues. Delivery of oxygen as part of oxygen-based therapy has been used clinically as an effective therapy for wound healing since the 1960s with the administration of systemic hyperbaric oxygen (HBO).

Throughout the years, advancements have been made in the scientific field to improve oxygen-based therapies for wound healing. In recent years, new oxygen delivery technologies have emerged that aim to locally provide oxygen to the wounded tissue in a faster and more efficient way than HBO therapy via topical administration. Clinical results have shown that topical delivery of oxygen to the wounded tissue can enhance the rate of epithelialization, induce extracellular matrix protein synthesis, and the expression of angiogenic factors. It should be understood that topically-delivered oxygen only targets the wounded tissue and, as a result, it does not involve high pressure and does not risk the potential for systemic oxygen toxicity.

In furtherance of the development of oxygen-based therapies and oxygen delivery compositions, the present disclosure is directed to an oxygen delivery dressing that includes a polyurethane carrier and an oxygen producing compound that, unexpectedly, may directly contact a wound or injured tissue.

For instance, the present inventors have unexpectedly found that by using a biocompatible and/or biodegradable urethane as a carrier, the urethane may swell and/or partially degrade upon exposure to a catalyst. The swelling and/or partial degradation allows the catalyst to contact an oxygen producing compound contained in the urethane carrier, such that the oxygen producing compound may release oxygen to a tissue of a mammal. Particularly, the urethane carrier may contain the oxygen producing compound within the dressing such that the oxygen producing compound does not come into contact with a tissue of a mammal but is capable of producing and releasing oxygen to a tissue of a mammal when contacted by a catalyst.

In one embodiment, a urethane, such as a swellable urethane, according to the present disclosure, may have components with different functionalities. For instance, a urethane according to the present disclosure may have at least two components, such as at least three components, such as at least four components, such as at least five components or more. Regardless of the number of components, at least two of the components may be capable of forming at least one urethane, or carbamate ester, bond.

In such an embodiment, at least one of the components may include a component with hydroxy functionality. For instance, a component with hydroxy functionality may be any polymer forming unit that contains at least hydroxyl group or is capable of having such a functional group in the presence of a solvent. In one embodiment, for example, the hydroxy-functional polymer is a polyalkylene ether. Polyalkylene ethers may include polyalkylene glycols, such as, polyethylene glycols, polypropylene glycols, and/or polytetramethylene glycols, polyepichlorohydrins, polyoxetanes, polyphenylene ethers, polyether ketones, and so forth. Particularly suitable are polyethylene glycols. In a further embodiment the polymer forming unit may be a polycaprolactone, such as a polycaprolactone formed via a catalyzed ring opening of a caprolactone. A urethane according to the present disclosure may also include an isocyanate component. In a particular embodiment, the isocyanate component may be a diisocyanate. In one embodiment, the isocyanate may be an aliphatic isocyanate, such as isophorone diisocyanate, hexamethylene diisocyanate, or a combination thereof, for example, or alternatively, may be an aromatic isocyanate such as a tolylene diisocyanate. Regardless of the isocyanate selected, the isocyanate may be selected based upon the amount of crosslinking desired in the final urethane product. For instance, an isocyanate may be selected that is capable of forming crosslinking bonds with amine or hydroxy functionalities on other components in order to form a urethane having the desired strength and flexibility properties, which will be discussed in greater detail below.

For example, in one embodiment, one component of the urethane may be a polyol having at least two hydroxy functional groups and second component may be a diisocyanate. Regardless of the specific polyol and/or diisocyanate selected, the respective components may be chosen in order to form a urethane that may be flexible or stretchable. For instance, the length of the polyol segment may be selectively controlled to impart flexibility to the urethane, such as a polyol with a fairly long chain, and/or a diisocyanate may be selected that allows for an intermediate or high amount of crosslinking with the other components in order to impart sufficient stretch and strength to the urethane. For example, in one embodiment, the polyol may be polyethylene glycol and/or polycaprolactone, and the diisocyanate

component may be isophorone diisocyanate and/or hexamethylene diisocyanate, or other combinations of components selected according to the present disclosure that would form a flexible urethane while also providing a swellable or biodegradable component according to the present disclosure. In such an embodiment, a flexible or stretchable polyurethane may be formed that may be suitable to form all or part of a wound dressing that may serve as a barrier to keep generated oxygen from escaping and/or to prevent dirt or bacteria from contacting the tissue, such as an embodiment where the urethane may form a bandage or a wrap.

While the polyethylene glycol may have any size or number of units as generally known in the art, in an embodiment where polyethylene glycol is used as a component of the polyurethane, the polyethylene used may have a molar mass of from about 3,000 g/mol to about 20,000 g/mol, such as from about 5,000 g/mol to about 15,000g/mol, such as from about 7,500 to about 12,500 g/mol. In one embodiment, a polyurethane according to the present disclosure may be formed in situ. In such an embodiment, the urethane components may be added together and allowed to form via a catalyzed addition reaction as is generally known in the art. Alternatively, the polyurethane may be formed via a catalyzed addition reaction of two or more pre-polymerized prepolymers. In such an embodiment, the components may have already been reacted under appropriate conditions to form pre-polymerized prepolymer components. In such an embodiment, the pre- polymerized prepolymers may be combined and catalyzed to form a urethane carrier according to the present disclosure.

Regardless of the method of forming the urethane, such reactions may also include a solvent. While any suitable solvent may be used, in one embodiment the solvent may include at least one organic solvent. While any suitable solvent capable of dispersing or dissolving the components may be suitable, solvents may include: dimethylformamide, dimethyl sulfoxide, hydrocarbons, ethers, ketones and aldehydes, acids, or a combination thereof, for example. In one embodiment, the solvent may be an aldehyde or a ketone such as acetone or methyl ethyl ketone, for example. After the addition reaction of the components has proceeded to form the urethane, the solvent may be removed to form a urethane carrier.

Further, the reaction composition may also include any other additive known in the art such as surfactants, catalysts, and the like, for example.

Notwithstanding the solvent used, or lack of solvent, or the method of formation used, the oxygen delivery dressing of the present disclosure may also contain an oxygen producing compound. Particularly, after the urethane has been formed, an oxygen producing compound may be introduced or dispersed into the newly formed urethane. For instance, in embodiments where a solvent is used, the oxygen producing compound may be dispersed into the composition after the urethane has been formed but prior to removal of the solvent. Further, the oxygen producing compound may be introduced prior to placing the formed urethane in a mold, or allowing the urethane to set. In such a manner, the oxygen producing compound may become incorporated into the polyurethane carrier without undergoing conditions that would cause the oxygen producing compound to degrade during formation of the oxygen delivery dressing. Thus, the oxygen producing compound may be contained within the urethane carrier so as maintain separation between the oxygen producing compound and a tissue of a mammal when incorporated into the oxygen delivery dressing, and maintain a configuration such that the oxygen producing compound may produce oxygen when contacted with a catalyst.

In one embodiment, the oxygen producing compound according to the present disclosure may be a solid peroxygen species such as a peroxide or a solid percarbonate. Particularly, solid peroxygen species according to the present disclosure may include solid percarbonates and/or solid peroxides. In one example, the solid peroxygen species may be sodium percarbonate, calcium peroxide, or a combination thereof.

In yet a further embodiment, the oxygen delivery dressing may also include a silica. The silica may be included in the urethane dressing so as to control the hydrophobicity of the wrap. In one embodiment, a silica derived from an amino silane may be used. However, in a further embodiment, any silane or silica may be used that allows the hydrophobicity of the dressing to be adjusted. For instance, a hydrophobic silica may help to retard the infusion of water into the matrix delaying the release of the oxygen from the polymer.

In a further embodiment, the urethane carrier may encapsulate or form a shell around the oxygen producing compound, forming microspheres. In such an embodiment, the swellable and/or degradable urethane may partially or completely encapsulate the oxygen producing compound so as to contain the oxygen producing compound separated from a tissue of a mammal.

In one such embodiment, the oxygen producing compound and the hydroxy functional component may be dispersed within a solvent. In one embodiment, the solvent may be a non-aqueous solvent, such as toluene, hexane, mineral oil, or a combination thereof, for example. The isocyanate component may then be added to the dispersion of the hydroxy functional component and the oxygen producing compound. Regardless of the solvent, hydroxy functional component, and

isocyanate component selected, the urethane may begin to form a shell around the oxygen producing compound. Thus, in such an embodiment, the urethane carrier may be in the form of a plurality of microspheres, and may form a solid, or semi-solid shell around the oxygen producing compound, such that the shell may swell or be fully or partially degraded upon exposure to a catalyst, allowing the catalyst to contact the oxygen producing composition. While any catalyst generally known in the field may be used to degrade the oxygen producing compound in order to produce oxygen according to the present disclosure, in one embodiment, the catalyst may be a wound exudate or compound naturally present in a wound or tissue of a mammal. For instance, the catalyst may be an enzyme, hemoglobin, or another wound exudate. Additionally or alternatively, the catalyst may be a biocompatible catalyst such as water, saline, hydrogen peroxide, sunlight, etc. Furthermore, the catalyst may be a combination of a wound exudate or naturally occurring composition and a biocompatible catalyst.

Nonetheless, other catalysts may be selected that catalyze a reaction of the oxygen producing compound, such that the oxygen producing compound may degrade and produce oxygen, where such catalysts are also safe to contact a human tissue according to the present disclosure.

Regardless of the carrier and/or oxygen producing compound selected, the urethane carrier and the oxygen producing compound according to the present disclosure may also be used to form all or part of a wound dressing. In an embodiment which forms microspheres, after the microspheres have been formed, the microspheres can be loaded into a wound dressing, such as loaded into a substrate that forms all or a portion of a wound dressing. Thus, the microspheres may be contained in a wound dressing such that they may be catalyzed when the dressing is applied to injured tissue, and may be incorporated into any wound dressing known in the art that may be used for wounds, such as wounds present on severely injured limbs. Flowever, the microspheres may be incorporated into any suitable substrate, and do not need a barrier to separate the microspheres from the tissue of a mammal, as the microspheres themselves serve to prevent the tissue from being contacted by the hydroperoxide functional groups, while still allowing the functional groups to decompose upon exposure to a fluid.

In one embodiment, the microspheres may be incorporated into a flexible substrate such as a silicone. For instance, an example of a substrate may be a polydimethyl siloxane. Regardless of the substrate used, the substrate may form all or a portion of a wound dressing. For instance, in one embodiment, the silicone may form the entire wound dressing, such that the silicone may be a wrap, bandage, or the like, as discussed herein. Alternatively, the silicone may be incorporated into an existing wound dressing on the wound facing side, so as to allow the encapsulated particles to contact the tissue of a mammal when applied. For instance, one embodiment that utilizes microspheres may be generally shown by Fig. 1. The microspheres 114 may be contained in any suitable substrate 111. The microspheres 114 and substrate 111 may be incorporated into a wound dressing 300 such that the microspheres 114 and/or substrate 111 may contact a tissue or wound site 200 of a mammal when the wound dressing 300 is applied. The substrate 111 may also include an outer layer 102 that provides additional protection from dirt or bacteria 112, or that provides an additional benefit to the wound dressing 300, such as waterproofing, adhesion, or compression, as examples only. Of course, the substrate 111 may only be a single layer and may not include an outer layer 102 in certain embodiments, or may have the outer layer 102 integrally formed as part of the substrate 111.

Moreover, regardless of the reaction used or the final form of the urethane carrier, the urethane carrier may form all, or a part, of a substrate for a wound dressing, or may be incorporated into a substrate for a wound dressing, or may be incorporated with a substrate for a wound dressing either prior to, or after,

application of the urethane carrier to a wound site. For instance, any wound dressing according to the present disclosure, whether a microsphere embodiment as discussed above, or another embodiment, may generally include a substrate and the urethane carrier. In one embodiment, the substrate may be a material or base material, such as a bandage, gauze, woven or nonwoven material, film, elastic, self- adhesive material, combinations thereof, as well as other wound dressing substrates known in the art. In one embodiment, the substrate may be separate from the urethane carrier, and may be incorporated with the urethane carrier either prior to application to a wound site, such as an integrated wound dressing that may be applied as a substrate and a urethane carrier together to the wound site, or may be separated from the urethane carrier until after the urethane carrier has been applied to a wound site, and then the substrate may be applied over the urethane carrier. In a further embodiment, the urethane carrier may form all or a part of the substrate, such that the urethane carrier formed according to the present disclosure forms the substrate itself, such as an embodiment where the urethane carrier is in the form of a wrap.

In yet a further embodiment, the urethane carrier and/or substrate may further include a polymer that may be incorporated into the substrate prior to, or during processing, or after the substrate has been formed. Polymers may be selected based upon desired characteristics, such as water absorbency, elasticity, durability, self-adhesion, water-tightness, and the like as is known in the field. For instance, exemplary secondary polymers may include polyacrylic acid polymers, elastomers, polyethylene polymers, polypropylene polymers, polyethylene and polypropylene copolymers, as well as other polymers that are known in the art. Particularly, a polyacrylic acid polymer may be included in the substrate in order to improve water absorbance in the final substrate, improving the interaction of the fluid with the catalyst when applied to wound. Similarly, an elastomer such as polybutadiene for example, may be included with the substrate to provide greater elasticity to the oxygen delivery composition, or may be included in an outer layer that overlies the oxygen delivery composition. Thus, the wound dressing may also incorporate a polymer that may provide greater absorbency or elasticity, or other polymers as discussed above, in the carrier and thus, the final wound dressing.

In one embodiment, the substrate can be absorbent and can also have elastic properties that provide enhanced compression benefits by applying pressure to immobilize the wound site and minimize minor bleeding. The substrate can thus, in one embodiment, be formed from a multilayer nonwoven composite material that provides properties similar to woven LYCRA™ fabrics, with the durability and cost of a nonwoven material.

The components of one wound dressing contemplated by the present disclosure are illustrated in Fig. 2. For example, a wound dressing 400 according to the present disclosure can include a skin or mucosa contacting urethane carrier 107, and an outer protective layer or substrate 110, where the urethane carrier 107 contacts a wound site and the outer protective layer 110 is exposed to the outside environment upon application of the wound dressing 400 around a wound site. In further optional embodiments, the wound dressing 400 can also include a breathable barrier layer 108 and/or an elastic layer 109. However, the present disclosure also contemplates a wound dressing that only includes the urethane carrier 107, such as an embodiment wherein the urethane carrier forms a flexible wrap and/or bandage, which may optionally include an additional substrate and/or outer protective layer 110, or which may serve both as the oxygen delivery dressing and substrate or outer layer. Of course, as previously discussed, wound dressing 400 may include the urethane carrier as a wrap itself, or may include microspheres dispersed in, or on, a substrate. The various wound dressing 400 components and other components of the urethane carrier 107 and/or substrate 110 that can be used in conjunction with the wound dressing 400 are described in Table 1 below.

Table 1 : Description and Function of Multilayer Wound Dressing

An optional outer protective layer or substrate 110, and/or a wrap formed from a urethane carrier and an optional polymer(s) can provide tensile strength and tear and puncture resistance with adjustable coverage area. A wound dressing 400 may therefore also provide adjustable levels of compression force due to the retraction forces inherent in the elastic components of the web, as well as comfort and conformability to control bleeding, physically protect the wounded limb, and preserve injured tissue, in addition to providing an oxygen delivery composition. The outer protective layer or substrate 110 and/or a wrap formed from a urethane carrier and an optional polymer(s) further protects against bacteria and solid particle penetration through size exclusion, reducing the risk of infection from the environment and the spread of bacteria from the wound to the surrounding area. However, it is also contemplated by the present disclosure that a wrap formed solely by the urethane carrier 107 may provide these benefits. For instance, in such an embodiment, the flexible wrap may be able to completely cover the wound or tissue, acting as a barrier to prevent generated oxygen from escaping the wound dressing while also acting as a barrier to external contaminants. Meanwhile, the skin contacting urethane carrier layer 107 of the wound dressing, which is the layer of the wound dressing positioned adjacent the wound site that may be formed solely from the urethane carrier itself, may provide air and water vapor transport, both for wound care as well as providing sufficient fluid to contact the catalyst and begin decomposition of the oxygen producing compound to release free oxygen. However, in one embodiment, the urethane carrier layer 107 may be at least partially impermeable to oxygen, so as to contain the generated oxygen adjacent to a wound or tissue. Additionally, in an embodiment, the urethane carrier 107 can be optionally tailored such that it is non-stick to skin or mucosa.

Further, it is to be understood that both the outer protective layer or substrate 110 and the urethane carrier 107, and any layers positioned there between, can be impregnated with nanoparticle metal (e.g., nanoparticle silver) which can be employed as an additional catalyst to generate oxygen from the oxygen producing compound or to provide for protection against microbial contamination.

Additionally or alternatively, a further embodiment of a wound dressing according to the present disclosure is discussed in relation to Fig. 3. As shown in Fig. 3, a wound dressing 500 has been applied to a wound site 200. The

combination of the urethane carrier 115 in the form of a wrap or bandage, as well as an optional outer layer 102, allows the application of the wound dressing 500 around the wound site 200 that provides a barrier to prevent or reduce the introduction of microbes 112 or other contaminants into the wound and also provides free oxygen that can preserve damaged tissue. In one embodiment, the urethane carrier 115 may be applied as a wrap formed from a dispersed oxygen producing compound in a urethane carrier 115 and an outer layer 102 may optionally be applied over the oxygen delivery dressing 115, or alternatively, outer layer 102 and the urethane carrier 115 may be integrated prior to application as described above to form a wound dressing that may be applied together as an oxygen delivery composition and a wound dressing. In use, the wound dressing may also include, or be used with, a hemostatic agent, a biotoxin sequestrant, a broad spectrum antimicrobial, pain medication, compression, wound exudate absorbency, and a neutral surfactant system to enhance debridement of the wound site once care is rendered at an aid station.

For instance, the wound dressing may further include any of the following, or may be applied over or in conjunction with antimicrobials, hemostatic agents, toxin sequestration agents, pain medication, debridement agents, or a combination thereof.

Any suitable antimicrobial agent is contemplated for use with a wound dressing of the present disclosure. The use of antimicrobial agents is further demonstrated and described in the following documents, all of which are

incorporated by reference to the extent they do not conflict herewith: U.S. Patent Application Publication No. 2007/0048344 to Yahiaoui, et al.; U.S. Patent Application Publication No. 2007/0048345 to Huang et al.: U.S. Patent Application Publication No. 2007/0048356 to Schorr, et al., U.S. Patent Application Publication No.

2006/0140994 to Bagwell, et al.: U.S. Patent No. 8,203,029 to Gibbins, et al.: and U.S. Patent No. 8,551 ,517 to Hoffman, et al.

Hemostatic agents are also contemplated for use with a wound dressing of the present disclosure and can be used to deliver blood loss prevention and/or coagulation benefits. Useful hemostatic agents include polyacrylate polymers, modified clays, and CaCI₂ in a polyacrylate polymer matrix. The use of these and other hemostatic agents is further demonstrated and described in the following documents, all of which are incorporated by reference to the extent they do not conflict herewith: U.S. Patent No. 7,335,713 to Lang, et al.: and U.S. Patent No. 6,822, 135 to Soerens, et al.

Toxin sequestration agents are also contemplated for use with a wound dressing of the present disclosure. Toxin sequestration agents include modified clay technology, as well as any other agents that reduce or eliminate biotoxin interaction with the wound and the surrounding tissue. The use of these and other toxin sequestration agents is further demonstrated and described in the following documents, all of which are incorporated by reference to the extent they do not conflict herewith: U.S. Patent No. 6,551 ,607 to Minerath, III, et al.: U.S. Patent No. 6,521 ,241 to Minerath, III, et al.: U.S. Patent No. 6,485,733 to Huard, et al.: U.S. Patent No. 6,517,848 to Huard, et al.: and U.S. Patent No. 8,110,215 to Koenig, et al.

Pain medications are well known, and any suitable topical, local, or systemic pain medication known in the art can be used in the wound dressing of the present disclosure. Suitable examples include but are not limited to lidocaine, benzocaine, or prilocaine. The wound dressing of the present disclosure also contemplates the use of one or more debridement agents. Debridement upon reaching an aid station can be enhanced by using debridement agents. Classes of such debridement agents include structured surfactant technology and agents that allow cleaning and debridement of the wound and the surrounding tissue. The use of these and other debridement agents is further demonstrated and described in the following

documents, all of which are incorporated by reference to the extent they do not conflict herewith: U.S. Patent No. 7,268,104 to Krzvsik et al.; U.S. Patent No.

7,666,824 to Krzysik, et al.; U.S. Patent No. 8,545,951 to Yahiaoui, et al.: and U.S. Patent No. 6,764,988 to Koenig, et al.

In one example of the use of a wound dressing of the present disclosure, a severe limb injury (e.g., avulsion, amputation, laceration, compound fracture, severe burn, degloving, severe abrasion, and/or other injuries possibly requiring the use of a tourniquet)) occurs. A user (e.g., corpsman, medic, first responder, etc.) can then remove the oxygen delivery dressing that may optionally be incorporated with a substrate, or may remove a urethane wrap, or may remove an oxygen delivery dressing that contains urethane microspheres that encapsulate the oxygen

producing compound combined with an additional substrate. The user can then apply the wound dressing to the injury, and the fluid from the injury will catalyze the decomposition reaction such that oxygen is supplied to the injury.

The embodiments of the invention described above are intended to be exemplary only. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Furthermore, certain embodiments of the present disclosure may be better understood according to the following examples, which are intended to be non- limiting and exemplary in nature.

Example 1

A hydroxy functional prepolymer according to the present disclosure was prepared by placing 120g of 8000 g/mol polyethylene glycol, 121.68 grams of methyl ethyl ketone, and 0.1216 grams of a dibutyltin dilaurate catalyst into a flask, and heating the mixture to a temperature of 60° C. Once the mixture had been heated to a temperature of 60° C, 1.7 grams of isophorone diisocyanate was gradually added to the flask. The mixture was then allowed to hold overnight at 60° C. Completion of the reaction was confirmed by utilizing Infrared Spectroscopy to check for the disappearance of the NCO peak. Once the reaction was complete, the mixture was removed from heat.

An isocyanate functional prepolymer according to the present disclosure was prepared by placing 50 grams of a low molecular weight polyester diol derived from a caprolactone monomer, an example of which may be sold under the name CAPA™ 2054, 89.37 grams of methyl ethyl ketone, and 0.096 grams of dibutyltin dilaurate catalyst into a flask, and heating the mixture to a temperature of 60° C. Once the mixture was heated to a temperature of 60° C, 40.37 grams of isophorone

diisocyanate was gradually added to the flask. The mixture was then allowed to hold overnight at 60° C. Completion of the reaction was confirmed by utilizing Infrared Spectroscopy to check for the disappearance of the OH peak. Once the reaction was complete, the mixture was removed from heat.

Next, 7.97 grams of the hydroxy functional prepolymer were combined with 4.02 grams of methyl ethyl ketone and heated at 60° Celsius until molten, and mixed for thirty seconds. Then, 15.91 grams of the isocyanate functional prepolymer were introduced into the mixture and mixed for another thirty seconds. Next, 16 grams of sodium percarbonate were added to the mixture and mixed for a further thirty seconds. The mixture was then placed into a mold, and kept under heat at 60° C for four days. After heating for four days, the methyl ethyl ketone was removed under reduced pressure to form the polyurethane carrier.

Example 2

An example of a polyurethane used as a carrier according to the present disclosure was formed by placing 18.37 grams of 8000 g/mol polyethylene glycol,

1.22 grams of a low molecular weight polyester diol derived from a caprolactone monomer, an example of which may be sold under the name CAPA™ 2054, 0.02059 dibutyltin dilaurate catalyst, and 48.04 grams of toluene into a flask. The mixture was then heated to 60° C. Once the mixture was heated to 60° C, 1.0 gram of isophorone diisocyanate was gradually added to the mixture. The mixture was maintained under heat at 60° C overnight. Completion of the reaction was confirmed by utilizing Infrared Spectroscopy to check for the disappearance of the NCO peak. Once the reaction was complete, the mixture was removed from heat, yielding a polyurethane according to the present disclosure.

Example 3

An example of a polyurethane used as a carrier according to the present disclosure was formed by placing 23.97 grams of a low molecular weight polyester diol derived from a caprolactone monomer, an example of which may be sold under the name CAPA™ 2054, 0.0320 grams of a dibutyltin dilaurate, and 31.97 grams of methyl ethyl ketone to a flask. The mixture was then heated to 60° C. Once the mixture was heated to 60° C, 8.0 grams of hexamethylene diisocyanate was gradually added to the mixture. The mixture was maintained under heat at 60° C overnight. Completion of the reaction was confirmed by utilizing Infrared

Spectroscopy to check for the disappearance of the NCO peak. Once the reaction was complete, the mixture was removed from heat, yielding a polyurethane according to the present disclosure.

Example 4

An example of microspheres used as the polyurethane carrier for the oxygen producing compound of the present disclosure were formed by placing 15.16 grams of 8000 g/mol polyethylene glycol, 0.02 of a dibutyltin dilaurate catalyst, 0.78 grams of a polylauryl methacrylate-g-polyethylene glycol stabilizer, 38.90 grams of toluene, and 12.97 grams of hexane into a flask. The mixture was then heated to 60° C. Once the mixture was heated to 60° C, 0.4 grams of isophorone diisocyanate were gradually added to the mixture. The mixture was maintained under heat at 60° C overnight. Completion of the reaction was confirmed by utilizing Infrared

Spectroscopy to check for the disappearance of the NCO peak. Once the reaction was complete, the mixture was removed from heat, yielding polyurethane

microspheres according to the present disclosure.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. An oxygen delivery dressing for delivering oxygen to a tissue of a mammal comprising:

a substrate;

a polyurethane carrier; and

an oxygen producing compound;

wherein the polyurethane carrier is configured to contain the oxygen producing compound until the oxygen delivery dressing is contacted by a catalyst.

2. The oxygen delivery dressing of claim 1 , wherein the polyurethane carrier is comprised of an isocyanate component and a hydroxy functional component.

3. The oxygen delivery dressing of claim 2, wherein the isocyanate component comprises a polyisocyanate, a diisocyanate, or a combination thereof.

4. The oxygen delivery dressing of claim 2, wherein the hydroxy functional component comprises a polyol.

5. The oxygen delivery dressing of claim 5, wherein the polyol comprises a polyethylene glycol, a polycaprolactone, or a combination thereof.

6. The oxygen delivery dressing of any one of claims 2-5, wherein the

isocyanate component, the hydroxy functional component, or both the isocyanate component and the hydroxy functional component is biodegradable.

7. The oxygen delivery dressing of any one of the preceding claims, wherein the oxygen producing compound comprises a percarbonate.

8. The oxygen delivery dressing of any one of the preceding claims, wherein the polyurethane carrier comprises a wrap or a plurality of microspheres.

9. The oxygen delivery dressing of claim 8, wherein the wrap forms all or a portion of the substrate.

10. The oxygen delivery dressing of claim 8, wherein the wrap is configured to be at least partially impermeable to oxygen produced by the oxygen producing compound.

11. The oxygen delivery dressing of claim 8, wherein the plurality of microspheres are at least partially integrated into the substrate.

12. The oxygen delivery dressing of claim 8 or 11 , wherein the plurality of microspheres are separated from the wound dressing until the wound dressing is applied to a mammal.

13. The oxygen delivery dressing of any one of the preceding claims, wherein the catalyst comprises a wound exudate, water, saline, hydrogen peroxide solution , an enzyme, a metal nanoparticle or colloid, sunlight, or a combination thereof.

14. A method of forming an oxygen delivery dressing for delivering oxygen to a tissue of a mammal comprising:

forming a polyurethane carrier;

dispersing an oxygen producing compound into the polyurethane carrier; and incorporating the polyurethane carrier containing the dispersed oxygen producing compound into a substrate;

15. The method of claim 14, further comprising forming the polyurethane carrier by reacting an isocyanate component and a hydroxy functional component.

16. The method of claim 14 or 15, wherein the reaction further comprises a solvent, wherein the solvent is removed from the polyurethane carrier after the oxygen producing compound has been dispersed into the polyurethane carrier.

17. The method of claim 15 or 16, wherein the polyurethane carrier is formed by an addition reaction comprising pre-polymerized prepolymers or by an in situ reaction of the isocyanate component and the hydroxy functional component.

18. The method of claim 17, wherein the prepolymers comprise at least one prepolymer comprising hydroxy functional functionality, and at least a second prepolymer comprising an isocyanate.

19. The method of one of claims 14-18, wherein the polyurethane carrier comprises a plurality of microspheres or a wrap, and wherein the oxygen producing compound is dispersed within the microspheres or the wrap.

20. The method of claim 19, wherein the plurality of microspheres are formed by dispersing the oxygen producing compound and the hydroxy functional component in a nonaqueous solvent, and then adding the isocyanate component.