Medical products and methods configured for controlled release of nitric oxide

Abstract

The disclosure concerns various medical devices implemented to provide a nitric oxide rich environment for anti-microbial or anti-thrombogenic benefits. The medical device generally includes a nitric oxide donor material that is contained within a sealed cavity, and a transport medium that defines and captivates the entirety of the cavity, wherein the transport medium is permeable to both water and nitric oxide. As the nitric oxide donor material becomes saturated with water from the surrounding tissue or fluids, nitric oxide is chemically released, and the resulting nitric oxide is communicated through the transport medium to a treatment site for anti-microbial and anti-thrombogenic benefits.

Claims

1. A medical device, comprising: a transport medium; and a cavity being contained within the transport medium; and a woven material disposed within the cavity and surrounded by the transport medium; characterized in that: the transport medium is permeable to water and nitric oxide, the transport medium comprises a water permeability coefficient between 40 and 55000 Barrers, and the woven material comprises a nitric oxide donor material embedded therein.

2. The medical device of claim 1, wherein the transport medium comprises a biocompatible polymer material.

3. The medical device of claim 2, wherein the biocompatible polymer material comprises: cellulose, collagen, citrulline, arginine, tetrahydrobiopterin, ornithine, Nitric Oxide Synthase Trafficking Inducer (NOSTRIN), arigininosuccinate, L-citrulline malate, polyglucose, polyacrylonitrile, polykeratin, siloxane, carboxymethyl cellulose, polyester, polyurethane, polyfibrin, poly(lactic-co-glycolic acid), neoprene, sorbothane, polychloroprene, polyamide, polyimide, polyethylene glycol, polypropylene oxide, polymethlyacrylate, polyvinyl, polydextrin, alginate, polyisobutylene tackifiers, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

4. The medical device of claim 1, wherein the nitric oxide donor material comprises: diazeniumdiolated diamine, S-nitroso-albumin, S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitrosoglutathione (GSNO), diazeniumdiolated dibutylhexyldiamine (DBHD N202), S-nistrosocystine, Diethylenetriamine/nitric oxide adduct (DETA/NO), Diethylamine NONOate (DEA/NO), Dipropylenetriamine NONOate (DPTA/NO), 6-(2-Hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine (MAHMA/NO), 1,2,4-triazole analogues of diclofenac, NCX 4040, ketoprofen-NO hybrids, nitrosoproline (PROLI/NO), spermine (SPER/NO), S-nitroso-N-acetylcysteine, nitroglycerin (GTN), isorbide dinitrate (ISDN) or a combination thereof.

5. The medical device of claim 1, wherein the holding woven material comprises: collagen, cellulose, fabric, polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, polyester, polyurethane, polyfibrin, poly-para-phenylene terephthalamide, polyamide, polysaccharide, poly(lactic-co-glycolic acid), siloxane, nylon, aliphatic, or semi-aromatic polyamides, or a combination thereof.

6. The medical device of claim 1, wherein the nitric oxide donor material is embedded within the woven material.

7. The medical device of claim 1, wherein the transport medium comprises a nitric oxide permeability of 0.1 to 8.0 Flux Units.

8. The medical device of claim 1, further comprising an excipient.

9. The medical device of claim 8, wherein the excipient comprises a monosaccharide, a disaccharide, a polysaccharide, a polyhydric alcohol, a polypeptide, or a combination thereof.

10. The method of claim 8, wherein the excipient comprises: collagen, cellulose, glucose, corn starch, crosspovidone, carboxymethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), sorbitol, xylitol, lactose hydrous or anhydrous or monohydrate or spray dried, povidone (PVP), poly(lactic-co-glycolic acid), Talc, silicone, pure arcylic, modified arcylic, natural rubber, synthetic rubber, epoxy, polyurethane, isocyanate, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

11. The medical device of claim 2, wherein the biocompatible polymer material comprises an -acetal moiety, a -acetal moiety, a hydroxyl moiety, a nitrile moiety, a nitrate ester moiety, a pro-alpha2(I) moiety, a carboxyl moiety, or a combination thereof.

12. The medical device of claim 1, wherein the medical device comprises: a transdermal patch, catheter, implantable device, implantable pouch, implantable patch, anastomosis ring, woven material, diabetic foot ulcer wound dressing, chronic wound dressing, burn wound dressing, trauma wound dressing, mouth ulcer pad, negative pressure wound dressing accessory, wipe, swab stick, gauze accessory, condom, acne pad, acne wipe, facial mask, or a sock.

13. The medical device of claim 1, wherein the transport medium is configured to communicate light from a light source to the nitric oxide donor material, wherein the light comprises a wavelength between 240 nm and 650 nm.

14. The medical device of claim 1, said device comprising a first layer and a second layer, wherein the first layer includes the transport medium, cavity and nitric oxide donor material, and wherein the second layer comprises: arginine, EDTA, citrulline, NOSTRIN, arigininosuccinate, L-citrulline malate, tetrahydrobiopterin, ornithine, or a combination thereof.

15. The medical device of claim 14, further comprising a third layer, wherein the third layer comprises: cellulose, collagen, citrulline, arginine, tetrahydrobiopterin, ornithine, Nitric Oxide Synthase Trafficking Inducer (NOSTRIN), arigininosuccinate, L-citrulline malate, polyglucose, polyacrylonitrile, polykeratin, siloxane, polyester, polyurethane, polyfibrin, poly(lactic-co-glycolic acid), neoprene, sorbothane, polychloroprene, polyamide, polyimide, polyethylene glycol, polypropylene oxide, polymethlyacrylate, polyvinyl, polydextrin, alginate, polyisobutylene tackifiers, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

16. The medical device of claim 15, wherein the first layer is configured to deploy nitric oxide in a first phase; the second layer is configured to deploy EDTA in a second phase subsequent to the first phase; and the third layer is configured to deploy collagen in a third phase subsequent to the second phase.

17. A method, comprising: contacting a body of a patient with the medical device of claim 1.

18. A medical device, comprising: a transport medium; a cavity being defined and substantially surrounded by the transport medium; the transport medium being permeable to water and nitric oxide; and a nitric oxide donor material disposed within the cavity, characterized in that: the nitric oxide donor material is embedded within a woven material.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows a portion of a medical device having multiple lumens.

(2) FIG. 2 shows the portion of the medical device of FIG. 1 having one lumen thereof filled with a nitric oxide donor material.

(3) FIG. 3 shows a side view of the medical device of FIGS. 1-2, wherein the lumen filled with a nitric oxide donor material comprises plugs on either end to seal a cavity within the device.

(4) FIG. 4 shows a portion of a medical device wherein a holding material is captured within a lumen, the holding material including a nitric oxide donor material embedded therein.

(5) FIG. 5 shows a medical device pad having a cavity portion.

(6) FIG. 6 shows the pad of FIG. 5 wherein the cavity portion contains a powdered nitric oxide donor material.

(7) FIG. 7 shows a pad of FIG. 5 wherein the cavity portion contains a holding material and the holding material contains a nitric oxide donor material embedded therein.

(8) FIG. 8 illustrates a medical device pad having a coating on an outer layer.

(9) FIG. 9 shows various layered pads each configured with a combination of a nitric oxide donor material, EDTA, arginine, and/or collagen.

(10) FIG. 10 shows a medical device pad with a first layer and a second layer.

(11) FIG. 11 shows a medical device pad with a first layer, a second layer and a third layer.

(12) FIG. 12 shows a sock that is knitted with a filament, the filament comprising a transport medium coating the filament and a nitric oxide donor material embedded within the filament.

(13) FIG. 13 shows a plot showing UV modulated nitric oxide release from a SNAP catheter.

(14) FIG. 14 shows average nitric oxide flux peak vs. UV LED intensity.

DESCRIPTION OF EMBODIMENTS

(15) In the following description, for purposes of explanation and not limitation, details and descriptions are set forth in order to provide a thorough understanding of various embodiments of the invention. However, it will be apparent to one skilled in the art that the invention may be practiced in other embodiments, including certain variations or alternative combinations that depart from these details and descriptions. As such, this disclosure is not intended to be limiting with respect to the spirit and scope of the invention as-claimed.

Example 1Catheter

(16) Turning now to the drawings, and in accordance with a first embodiment, an improved catheter being configured for anti-microbial and anti-thrombogenic treatment is disclosed.

(17) FIG. 1 shows a cross-section of a water-permeable tubular medical device 100, such as, for example, a tubular portion of a Foley urinary catheter, with at least a first lumen 11, a second lumen 12, and a third lumen 13. Each of the first thru third lumens are disposed within a water-permeable transport medium 14. The first lumen is sealed at the terminal ends (See FIG. 3) to define an enclosed reservoir or cavity. Accordingly, as it relates to this illustrated embodiment, the first lumen 11 may also be referred to as a cavity 11.

(18) FIG. 2 shows the medical device 100 of FIG. 1 with the addition of a nitric oxide donor material 15 contained within the cavity 11. Here, the cavity 11 is a lumen-type cavity (first lumen) extending along a length of the catheter; however, one with skill in the art will appreciate that any number, shape or design of the cavity may be implemented to yield one or more cavities which perform the same function in substantially the same manner. For example, in some other embodiments, multiple reservoirs or cavities may extend along a length of the catheter. However, in this example, surrounding the lumen-type cavity 11 is a transport medium 14. The transport medium substantially surrounds the cavity 11 and the nitric oxide donor material 15 therein.

(19) Moisture from an adjacent environment or treatment site is permitted to permeate through the transport medium and into the cavity, wherein upon encountering the nitric oxide donor material a chemical reaction occurs thereby releasing nitric oxide from the nitric oxide donor material. The nitric oxide within the cavity is then capable of permeating through the transport medium into the adjacent environment where it functions as an anti-microbial and anti-thrombogenic agent at the treatment site.

(20) In addition to the cavity 11, nitric oxide donor material 15, and transport medium 14, the medical device 100 (a catheter in this example) comprises a second lumen 12. The second lumen 12 may provide an additional cavity for housing a nitric oxide donor material, or may have some ancillary function, such as a port for balloon inflation.

(21) Moreover, the medical device 100 may comprise a third lumen 13. The third lumen may provide an additional cavity for housing a nitric oxide donor material, or may have some ancillary function, such as to guide the flow and transport of body fluids, for example urine.

(22) Accordingly, the medical device may comprise one or more lumens, and each of the lumens may be independently configured to comprise a nitric oxide donor material therein.

(23) Where the cavity forms a lumen, the openings at either end of the lumen may be sealed as shown in FIG. 3. This can be accomplished by inserting plugs 16a; 16b at either exposed end, or by any conventional means that would be appreciated by one having skill in the art. The result would be a contained cavity 11 with the nitric oxide donor material 15 therein. Here, the catheter comprises a first lumen that is sealed to form the cavity 11 therein, a second lumen 12 and third lumen 13. The first lumen is filled with a nitric oxide donor material 13 and sealed at the openings.

(24) Third lumen 15 is typically larger than 2 mm.sup.2, but depends on the size of medical device 100, which is typically measured in French (Fr). The first thru third lumens may comprise any functionally appropriate shape, including annular, such as a circular or oval shape. Although not depicted, in certain approaches the device contains only one or two lumens, with at least a first lumen containing a nitric oxide donor material 15. Additionally, or alternatively, the device may comprise more than three lumens, with at least a first lumen forming a cavity containing a nitric oxide donor material 13.

(25) In one embodiment, the nitric oxide donor material may comprise a mixture of nitric oxide donor materials. In certain aspects, the mixture comprises a powdered form of the nitric oxide donor material 13. Additionally, or alternatively, the mixture may comprise excipients that modify or modulate the properties of the nitric oxide donor material 13 and the performance of the medical device 100. These properties may include, but are not limited to: shelf life, stability, release rate, and potency.

(26) In another embodiment, is illustrated FIG. 4, the nitric oxide donor material can be embedded in a holding material 17. For example, holding material 17 may comprise a woven material that serves as a matrix loosely holding the nitric oxide donor material 15. In certain embodiments, the holding material 17 may also include excipients to modify the properties of the nitric oxide donor material 15. The woven material or matrix can be a filament, or series of wound filaments. The nitric oxide donor material may be dissolved in a solvent, and saturated into the holding material prior to evaporation of the solvent. In this regard, the nitric oxide donor material can be embedded within the woven material along with any additional agents, excipients and the like.

(27) FIG. 4 shows a medical device 200, wherein the nitric oxide donor material 15 is embedded in the holding material 17, and the holding material is further contained in the cavity 11 and surrounded by a transport medium 14. The medical device 200 also comprises a second lumen 12 and a third lumen 13.

(28) In certain aspects, transport medium 14 comprises a material that is water permeable or semipermeable, thereby giving medical device 100; 200 water permeable properties such that water may permeate into one or more of the first thru third lumens, or the cavity containing nitric oxide donor material 15. In practice, transport medium 14 has a permeability coefficient of moisture that ranges from between approximately 40 to approximately 55000 Barrers, although any appropriate coefficient may be used to give appropriate device characteristics for the release of nitric oxide or other therapeutic molecules as described herein. In certain embodiments, transport medium 14 has a first permeability to water molecules in the gas phase and second permeability to water molecules in the liquid phase.

(29) Additionally, or alternatively, transport medium 14 may comprise a material permeable or semipermeable to nitric oxide. For example, nitric oxide donor material 15 releases nitric oxide when the nitric oxide containing cavity (e.g., first lumen 11) is moist and the released nitric oxide permeates through transport medium 14. In certain embodiments, the released nitric oxide permeates through an inner surface of the first lumen through transport medium 14 and through an outer surface of the transport medium at a rate that is equivalent to or greater than that of localized endothelial cells, or 0.4-1.6 NO Flux Units, wherein a NO Flux Unit is defined as 1.010.sup.10 mol cm.sup.2 min.sup.1. In certain approaches, nitric oxide donor material 15 releases nitric oxide under physiological conditions in predictable quantities in the range of 0.4 to 4.0 NO Flux units for the duration of use.

(30) In general, transport medium 14 may comprise a biocompatible material. In certain embodiments, the transport medium may be formed from a hydrophilic material. The transport medium may be formed from a polymer from the group consisting of: an -acetal moiety, a -acetal moiety, a hydroxyl moiety, a nitrile moiety, a nitrate ester moiety, and a carboxyl moiety. In certain approaches, the transport medium is formed from the group consisting of: cellulose (cotton, flax, hemp), polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, silicone, polyester, polyurethane, polyfibrin (silk), and mixtures thereof.

(31) The medical device described in FIGS. 1-4 generally comprises a transport medium made of water-permeable materials such as cellulose (cotton, flax, hemp), fabric, polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, polyester, polyurethane, polyfibrin (silk), poly-para-phenylene terephthalamide (Kevlar), and mixtures thereof. These materials may form part of a medical device construct such as: catheters, implants, feeding tubes, arteriovenous catheters, balloon catheters, sutures, anastomosis rings, resuscitators, drainage tubes, nasal catheters, gastrostomy catheters, and oxygenators. This medical device construct form factor and design allows the release of nitric oxide after patient catheterization to provide antibacterial, anti-thrombosis, anti-stenosis, and antifungal properties to improve healing and prevent catheter dysfunction.

Example 2Pad

(32) In another embodiment, as illustrated in FIGS. 5-7, a medical device may take the form of a pad 300. The pad generally includes a transport medium 314 forming an enclosure around an inner cavity 311, wherein the inner cavity is filled with or otherwise comprises a nitric oxide donor material 315. Properties such as composition and thickness of the transport medium are selectively implemented to allow for permeability of water (moisture) into the cavity and nitric oxide out of the cavity.

(33) The pad may comprise a flat contour 318 at the delivery side, or other contour for engaging an anatomical feature of a patient. The pad may be implemented as a medical dressing, wound healing pad, bandage, or other pad device as conventionally provided in the art.

(34) Additionally, a thickness of the transport medium at the delivery side of the pad can have a second thickness 314b that is less than a first thickness 314a associated with the rest of the pad.

(35) As shown in FIG. 8, a coating 319 or additional layer can be applied to all sides of the pad except the delivery side such that the pad will have a higher permeability at the delivery side, thereby allowing a bulk of the nitric oxide to permeate through the delivery side of the pad.

(36) In another embodiment, as illustrated in FIG. 6, the pad may comprise a first shell portion, and a second delivery portion, wherein the transport medium forms the delivery portion and wherein the shell portion is less permeable or non-permeable to water and/or nitric oxide. In this regard, the shell and transport medium combine to surround and encapsulate a cavity, wherein a nitric oxide donor material is contained within the cavity.

(37) The pad 300 may be practiced with the nitric oxide donor material in a powdered form or mixture (FIG. 6). Again, as above, the powdered form may comprise a nitric oxide donor material, a mixture of nitric oxide donor materials, or a mixture of one or more nitric oxide donor materials, excipients and/or other active wound healing agents.

(38) Alternatively, the pad 300 may be practiced with the nitric oxide donor material being embedded in a holding material.

(39) The transport medium made of water-permeable materials such as cellulose (cotton, flax, hemp), fabric, polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, polyester, polyurethane, polyfibrin (silk), poly-para-phenylene terephthalamide (Kevlar), and mixtures thereof, is used in the creation of a biocompatible medical dressing.

(40) The pad 300 can be used to cover and protect wounds sites as a bactericidal transdermal patch with breathability properties and enhance wound healing such as wound covers, catheter bandages, bandages, acne sites, and surgery wounds. The embodiments that are used in the creation of these biocompatible medical constructs may include ulcer pads, foot pads, sanitary pads, socks, condoms, diapers, tampons, socks, and wound covers.

Example 3Multi-Phase Pad

(41) In another embodiment, a multi-phase pad is disclosed. The multi-phase pad is configured to support wound healing by providing different agents and factors over time.

(42) In an experiment, different dressing formulations containing a variety of ratios of SNAP, silicone, and optionally collagen (Type IV) were evaluated for NO flux over a 5-7 day interval. NO released from sample bandages was assessed via chemiluminescence at body temperatures (37.5 C.) in 10 mM PBS (pH 7.4, containing 100 M EDTA) using the Nitric Oxide Analyzer (NOA) 280i (Boulder, Colo., USA) that measures NO release by placing the samples in a clear glass sample vessel elevated above a shallow reservoir of PBS buffered solution purged with a nitrogen gas bubble solution. In the cell vacuum, water vapor should contact the bandage solution without need. This setup was employed to simulate water vapor emanating from the dermal or wound surface. Samples reach a plateau nitric oxide release value within the sample vessel (in PPB or PPM), which is recorded converted into a NO flux value with the surface area of dressings. NO release from surfaces and devices, such as the catheters allow them to mimic the functions of endothelial cells lining the inner walls of all blood vessels, which endogenously release NO at localized fluxes of (0.5-4.0)10.sup.10 mol cm.sup.2 min.sup.1. The NO Flux profiles from the sample bandages measured over a 5-7 day period are shown in FIG. 9. Nearly every SNAP/Silicone formulation dressing is characterized by an initially high burst of NO release on Day 1, which plateaus to 1.25 to 0.5010.sup.10 mol cm.sup.2 min.sup.1 (NO flux units) at the end of the study. Initially elevated NO flux values are important for rapid or accelerated initiation of the inflammation of the wound healing cascade and differentiation of macrophages from M1 to M2 phenotype. As wound healing progresses, localized nitric oxide concentrations should subside, and this behavior is displayed by the NO flux profiles of the sample bandages.

(43) Zucker Diabetic Fatty (ZDF) rats (n=3) were used at 70 days age. Based on a 24-month lab-rat and 80-year human lifespans, these ZDF rats were roughly equivalent to 23-40-year-old human clinical research subjects. These animals have an inbred genetic lineage with a diabetic marker of predisposition for consistent development of Type 2 diabetes. ZDF rats can express a non-diabetic phenotype if kept on a normal diet or can be induced with Type 2 diabetes when fed a specific nutritional composition, namely Purina 5008 pellets after acclimation. The animals were initially non-diabetic and had an average weight of 31215 g were housed in Biocrede animal facilities according to IACUC-approved husbandry protocols for feeding, cage cleaning, and enrichment. With increased age, ZDF rats are expected to have slightly slower progression of wound healing compared to younger animals, due to a combination of normal slowing metabolic processes in addition to the advanced progression of diabetes within the subject. The rats were subjected to a 2-week acclimatization period necessary to induce Type 2 diabetes through the Purina 5008 food, such that the diet-induced diabetic state was achieved in n=3 rats at the time of the surgical procedure. The control ZDF rat was given a normal rat chow (info on chow). On the day of surgery, the diabetic rats weighed an average of 37923 g while the control rat weighted 314 g Rats were initially anesthetized in a vented anesthesia chamber using 4-5% isoflurane, and kept at 1-3% for the remainder of the procedure. Their hair was removed from the back using clippers and Veet, and the skin cleaned using iodine and 70% alcohol. Three 6 mm round skin lacerations, including the panniculosus camosus, were made on each side of the midline using surgical biopsy punches. Silicone splints 10 mm in inner diameter and 15 mm in outer diameter were then adhered using Superglue to surround all 6 wounds. To ensure that splints were secured in place, they were also sutured onto the skin for reinforcement. Round patches 8 mm in diameter with test compounds were placed in the center of the splints to cover the lacerations. Patches of the same size were cut from waterproof transparent dressing to be used as control. The entirety of the shaved skin was then covered using waterproof transparent dressing to maintain sterility of the surgical areas. Finally, adhesive sports tape was wrapped around rats' torso to protect the surgical area. Rats were then placed into clean cages and remained single house for the rest of the study. Sports tape and 3M were removed to evaluate and photograph wounds on days 7 and 14 after surgery. New 3M and sports tape were used to replace dressing. Diabetic ZDF rats remained on the Purina 5008 diet, while control ZDF rats remained on normal rat chow for the rest of the study.

(44) The layers composing each dressing assembly are detailed in FIG. 9. Wound dressings denoted CS1-CS3 contained a collagen base, a silicone layer containing one of three SNAP amounts: 0.2 mg (CS1), 0.8 mg (CS2), and 1.6 mg (CS3), and a polyurethane cover layer. Dressings with CASP labeling contained a collagen base layer, a silicone layer containing 0.8 mg SNAP, a layer of arginine powder, and a polyurethane cover layer. SAP1-3 dressings contained a base layer of silicone with one of three SNAP amounts: 0.2 mg (SAP1), 0.8 mg (SAP2), and 1.6 mg (SAP3), with a layer of arginine powder above, and a polyurethane cover layer. Dressings labeled 3MS1-3MS3 are composed of a base layer of 3M Tegaderm polyurethane, with a layer of silicone on top with one of three SNAP amounts: 0.2 mg (3MS1), 0.8 mg (3MS2), and 1.6 mg (3MS3). CA labeled dressings contained a collagen base layer and with a secondary collagen layer containing a heavy concentration of arginine above, followed by a polyurethane cover layer on top. CAS dressings contained a collagen base layer, followed by a secondary collagen layer containing a heavy concentration of arginine, followed by a silicone layer containing 0.8 mg SNAP, and a polyurethane cover layer. Dressings labeled C with Cover were composed of collagen base layers with a polyurethane membrane cover layer on top. PCS dressings were composed of cellulose base layers containing 0.8 mg SNAP with special polyurethane membranes on top. B dressings were composed of commercial grade hydroxypropyl methylcellulose (HCMP) base layers with a polyurethane top coat. Dressings with the CSAP layer were composed of collagen base layers followed by silicone layers containing 0.8 mg SNAP, followed by arginine powder, and finally a polyurethane cover layer on top. Dressing labeled TST4-TST6 are composed of a base layer of polyurethane, with a layer of cellulose layer containing one of three SNAP amounts: 2 mg (TST4), 2.4 mg (TST5), and 3 mg (TST6), followed by a polyurethane cover layer on top.

(45) Results: The wound size was measured and details about inflammation, scar tissue, or pus formation was noted. Each wound size was calculated by D=D.sub.1D.sub.26416D.sub.022 D1+D.sub.2643D.sub.04, where D.sub.1 and D.sub.2 are the longest and shortest diameters of the wound and

(46) $D_0=\frac{D_1-D_2}{D_1+D_2}.$
The reduction of wound coverage area after treatment with commercial collagen dressings served as the wound size baseline, with a normalized numerical value of 1. Dressings or treatments with faster progression of wound healing than the commercial collagen dressing have normalized wound size numerical values of <1 and dressings or treatments with slower wound healing have normalized wound size values of >1. Compared with the normalized collagen data, the silicone-based SNAP dressing displayed accelerated wound-healing with an average normalized wound size of 0.728 (SD=0.204, SE=0.156) and the silicone-based with SNAP & arginine displayed a normalized wound size of 0.928 (SD=0.346, SE=0.200), indicating an increased rate of healing of diabetic wounds compared to top of the line and more expensive collagen based dressings currently used in the market. Six laceration wounds were created on the back of ZDF rats following IACUC approved protocol on anesthesia, and silicone, bandages, and SNAP & Silicone wound dressing were applied and secured. 7 days of recovery time was given before and bandages were removed around day 5, and photographs and measurements of the wound size were taken again. n=6 measurements of all different wound dressing types in ZDF diabetic rats are shown in FIG. 4. The silicone-based dressings with added SNAP displayed a normalized wound size of 0.799 (SD=0.204, SE=0.083). The p-value for silicone and SNAP based, nitric oxide (NO) releasing, wound-healing dressings over a standard collagen bandage from both studies were applied to n=6 Type 2 diabetic (ZDF) rats treated with silicone based and added SNAP over the standard collagen dressing is 0.037, which is statistically significant.

(47) In accordance with yet another embodiment, as illustrated in FIG. 10, a multi-phase pad 400 is provided for treating a wound in accordance with various phases. The multi-phase pad can comprise a first layer, wherein the first layer comprises a transport medium 414 forming a cavity 411, and a nitric oxide donor material 415 disposed within the cavity. The nitric oxide donor material may comprise a powdered material, a mixture, or may be embedded in a holding material as described herein. In addition to the first layer, the multi-phase pad (medical device) comprises a second layer 420, wherein the second layer comprises arginine, EDTA, citrulline, NOSTRIN, arigininosuccinate, L-citrulline malate, tetrahydrobiopterin, ornithine, or a combination thereof. These materials being hosted in the second layer provide the second phase of treatment with benefits to reduce the activity of proteases to promote preferential differentiation of M1 macrophages to M2 macrophages or act as a NO enhancer.

(48) Optionally, the multi-phase pad may comprise re-epithelialization benefits to promote cellular proliferation and migration for the formation of grandulation tissue. In order to achieve this, the device may include as the second layer (420, FIG. 10) in addition to the nitric oxide donor material layer, or as a third layer (430, FIG. 11) in addition to the NO donor material and the EDTA layer described above, a layer which comprises: cellulose, collagen, citrulline, arginine, tetrahydrobiopterin, ornithine, Nitric Oxide Synthase Trafficking Inducer (NOSTRIN), arigininosuccinate, L-citrulline malate, polyglucose, polyacrylonitrile, polykeratin, siloxane, polyester, polyurethane, polyfibrin, poly(lactic-co-glycolic acid), neoprene, sorbothane, polychloroprene, polyamide, polyimide, polyethylene glycol, polypropylene oxide, polymethlyacrylate, polyvinyl, polydextrin, alginate, polyisobutylene tackifiers, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

(49) Accordingly, a multi-phase pad can comprise a first layer that is configured to deploy nitric oxide in a first phase; a second layer that is configured to deploy EDTA or other activity modulating agent or differentiation agent in a second phase subsequent to the first phase; and optionally a third layer that is configured to deploy collagen or other re-epithelialization agent in a third phase subsequent to the second phase.

(50) Alternatively, a multi-phase pad can comprise a first layer that is configured to deploy nitric oxide in a first phase; a second layer that is configured to deploy collagen or other re-epithelialization agent in a third phase subsequent to the second phase.

Example 4Medical Tubing

(51) The embodiments described herein, such as a transport medium made of water-permeable materials such as cellulose (cotton, flax, hemp), fabric, polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, polyester, polyurethane, polyfibrin (silk), poly-para-phenylene terephthalamide (Kevlar), and mixtures thereof, that is used in the creation of a biocompatible medical construct may include tubing devices, such as: catheters, implants, feeding tubes, arteriovenous catheters, balloon catheters, sutures, anastomosis rings, resuscitators, drainage tubes, nasal catheters, gastrostomy catheters, and oxygenators. These medical device constructs release NO after catheterization to provide antibacterial, anti-thrombosis, anti-stenosis, and antifungal properties to improve healing and prevent catheter dysfunction.

Example 5Sock

(52) A filament 501, such as acrylic, cotton, linen, nylon, polyester, polypropylene, rayon, silk, elastane, wool, or other fiber filament, is used to knit a sock 500 for wearing about a foot of a user. Prior to knitting, the filament is saturated in a solution comprising a nitric oxide donor material and a solvent, and subsequently dried by allowing the solvent to evaporate. The resulting filament forms a holding material which holds the nitric oxide donor material therein. The filament is further coated with a polymer or other material as described herein, or otherwise as appreciated by one with skill in the art, that coats the filament to act as a transport medium. The transport medium is permeable by both water and nitric oxide, such that moisture from the user's foot may permeate into the filament of the sock to cause a chemical reaction of the nitric oxide donor material, thereby releasing nitric oxide which ultimately permeates the transport medium and engages the dermal site for anti-microbial therapy.

(53) The sock would be useful as a disposable sock, or one with limited duration, since the nitric oxide would be substantially spent after one wash.

(54) All or a portion of the sock may comprise the filament described above. For example, the filament can be used to knit a ball portion, heel portion, or other portion of a sock, and sewn in with other sock portions to form a completed sock.

ExampleLight Modulated NO Release

(55) S-nitroso-N-acetylpenicillamine (SNAP) is mixed with excipients such as cellulose, in a 2.5:1 weight ratio, filled into a silicone urinary Foley catheter center lumen, sealed on both ends with silicone in sections of 2 cm incubated at 37 C. in PBS (pH 7.4, 100 mM EDTA), and NO release measured using a Sievers Nitric Oxide Analyzer (NOA; GE Water and Process Technologies, CO) while purging the solution with N2 (Airgas, Mich.) gas. As an example, while measuring NO release, a UV LED light source (277 nm at 2,500 mW/cm.sup.2) was focused at a distance of 2.0 cm from the sample forming a 4 cm.sup.2 area of incidence through a square aperture onto the sample, corresponding to an intensity of 2,500 mW/cm.sup.2. The light source was also placed at distances of 9.0 cm and 16.0 cm, corresponding to intensities of 625.00 and 277.78 mW/cm.sup.2, respectively. The source current to the excitatory LED was controlled by a mechanical switch, and the 360 nm wavelength was chosen since it aligns with peak excitation wavelengths described in various literature sources.

(56) FIGS. 13-14 demonstrate NO can be predictably modulated following light activation at 360 nm with 2-minute duration pulses at different irradiance levels 277.78 mW/cm.sup.2, 625.00 mW/cm.sup.2, and 2,500.00 mW/cm.sup.2 at different, and measured NO fluxes were 11.89, 21.31, and 33.23, (all10.sup.10 mol cm.sup.2 min.sup.1) respectively. Measurements were made at 37 C. using the Sievers Nitric Oxide Analyzer. During the first 30 seconds of the UV LED irradiance, NO release would fall to a minimal baseline, but would surpass the resting NO release plateau of the sample at 37 C. by the end of the 2.0 min pulse. Catheter samples containing only SNAP without excipients were prepared at the same time, and evaluated by the same 260 nm UV modulation protocol to demonstrate that the increased NO release from the sample resulted from the interaction between UV light and SNAP rather than an interaction between UV light and the solid excipients.

CONCLUSION

(57) In accordance with the above details and descriptions, and as supported by the illustrated examples, we hereby disclose:

(58) A medical device, comprising: a transport medium; a cavity being defined and substantially surrounded by the transport medium; the transport medium being permeable to water and nitric oxide; and a nitric oxide donor material disposed within the cavity.

(59) The transport medium may comprise a biocompatible polymer material. The biocompatible polymer material may comprise a water permeability coefficient between 40 and 55000 Barrers. The biocompatible polymer material may further comprise: cellulose, collagen, citrulline, arginine, tetrahydrobiopterin, ornithine, Nitric Oxide Synthase Trafficking Inducer (NOSTRIN), arigininosuccinate, L-citrulline malate, polyglucose, polyacrylonitrile, polykeratin, siloxane, carboxymethyl cellulose, polyester, polyurethane, polyfibrin, poly(lactic-co-glycolic acid), neoprene, sorbothane, polychloroprene, polyamide, polyimide, polyethylene glycol, polypropylene oxide, polymethlyacrylate, polyvinyl, polydextrin, alginate, polyisobutylene tackifiers, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

(60) The nitric oxide donor material may comprise: diazeniumdiolated diamine, S-nitroso-albumin, S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitrosoglutathione (GSNO), diazeniumdiolated dibutylhexyldiamine (DBHD N2O2), S-nistrosocystine, Diethylenetriamine/nitric oxide adduct (DETA/NO), Diethylamine NONOate (DEA/NO), Dipropylenetriamine NONOate (DPTA/NO), 6-(2-Hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine (MAHMA/NO), 1,2,4-triazole analogues of diclofenac, NCX 4040, ketoprofen-NO hybrids, nitrosoproline (PROLI/NO), spermine (SPER/NO), S-nitroso-N-acetylcysteine, nitroglycerin (GTN), isorbide dinitrate (ISDN) or a combination thereof.

(61) The medical device may further comprise a holding material, wherein the holding material is disposed within the cavity. The holding material may comprise: collagen, cellulose, fabric, polyglucose, polyacrylonitrile, polykeratin, polydimethylsiloxane, polyester, polyurethane, polyfibrin, poly-para-phenylene terephthalamide, polyamide, polysaccharide, poly(lactic-co-glycolic acid), siloxane, nylon, aliphatic, or semi-aromatic polyamides, or a combination thereof. In some embodiments, the nitric oxide donor material can be embedded within the holding material.

(62) The transport medium may comprise a nitric oxide permeability of 0.1 to 8.0 NO Flux Units. For purposes herein, a NO Flux Unit is defined as 4.110.sup.10 mol cm.sup.2 min.sup.1.

(63) The medical device may further comprise an excipient, such as a filler material, bulking agent, inert material, or other material that is combined with the nitric oxide donor material for purposes of dispersing the nitric oxide donor material within the cavity or other useful purpose as would be recognized by one with skill in the art. The excipient may comprise a monosaccharide, a disaccharide, a polysaccharide, a polyhydric alcohol, a polypeptide, or a combination thereof. The excipient may comprise: collagen, cellulose, glucose, corn starch, crosspovidone, carboxymethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), sorbitol, xylitol, lactose hydrous or anhydrous or monohydrate or spray dried, povidone (PVP), poly(lactic-co-glycolic acid), Talc, silicone, pure acrylic, modified acrylic, natural rubber, synthetic rubber, epoxy, polyurethane, isocyanate, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof.

(64) In some embodiments, the biocompatible polymer material may comprise an -acetal moiety, a -acetal moiety, a hydroxyl moiety, a nitrile moiety, a nitrate ester moiety, a pro-alpha2(I) moiety, a carboxyl moiety, or a combination thereof.

(65) While a myriad of possible implementations will be appreciated by one with skill in the art, specific examples may include: a transdermal patch, catheter, implantable device, implantable pouch, implantable patch, anastomosis ring, woven material, diabetic foot ulcer wound dressing, chronic wound dressing, burn wound dressing, trauma wound dressing, mouth ulcer pad, negative pressure wound dressing accessory, wipe, swab stick, gauze accessory, condom, acne pad, acne wipe, facial mask, or a sock.

(66) The transport medium may be configured to communicate light from a light source to the nitric oxide donor material, wherein the light comprises a wavelength between 240 nm and 650 nm.

(67) In another embodiment, the medical device includes a first layer and a second layer, wherein the first layer includes the transport medium, cavity and nitric oxide donor material, and wherein the second layer comprises: arginine, EDTA, citrulline, NOSTRIN, arigininosuccinate, L-citrulline malate, tetrahydrobiopterin, ornithine, or a combination thereof. The medical device may further comprise a third layer, wherein the third layer comprises: cellulose, collagen, citrulline, arginine, tetrahydrobiopterin, ornithine, Nitric Oxide Synthase Trafficking Inducer (NOSTRIN), arigininosuccinate, L-citrulline malate, polyglucose, polyacrylonitrile, polykeratin, siloxane, polyester, polyurethane, polyfibrin, poly(lactic-co-glycolic acid), neoprene, sorbothane, polychloroprene, polyamide, polyimide, polyethylene glycol, polypropylene oxide, polymethlyacrylate, polyvinyl, polydextrin, alginate, polyisobutylene tackifiers, carboxymethyl cellulose, alginate, gelatin, agarose, or a combination thereof. In this regard, the first layer is configured to deploy nitric oxide in a first phase; the second layer is configured to deploy EDTA in a second phase subsequent to the first phase; and the third layer is configured to deploy collagen in a third phase subsequent to the second phase.

(68) In another aspect, a method for practicing the invention comprises the step of (i) contacting a body of a patient with a medical device as described herein.

(69) In another embodiment, the method comprises: (i) selecting a nitric oxide donor material, (ii) selecting an excipient to modulate nitric oxide release rates from the nitric oxide donor material, (iii) combining the nitric oxide donor material and the excipient to form a mixture, (iv) spreading the mixture within a cavity resident within at least a portion of a device, and (v) sealing the cavity with a material that is semipermeable to both water and nitric oxide.

(70) In yet another embodiment, the method comprises: (i) selecting a nitric oxide donor, (ii) dissolving the nitric oxide donor in a solvent to form a solution, (iii) placing a holding material within the solution to absorb a portion or the entirety of the solution, (iv) evaporating the solution such that at least a portion of the nitric oxide donor is suspended by the holding material, and (v) placing the holding material within the reservoir.

INDUSTRIAL APPLICABILITY

(71) The invention may be practiced in various embodiments to provide a medical device that is configured to provide a nitric oxide rich environment to surrounding tissue for achieving anti-microbial and anti-thrombogenic therapeutic benefits.

(72) Additionally, methods for providing anti-microbial and anti-thrombogenic benefits to a medical patient are disclosed.

(73) As such, the invention is applicable to medical products and procedures.

REFERENCE SIGNS LIST

(74) (11) first lumen/lumen cavity (12) second lumen (13) third lumen (14) transport medium (15) nitric oxide donor material (16a; 16b) plugs (17; 317) holding material (100; 200; 300; 400; 500) medical device (311; 411) cavity (315; 415) nitric oxide donor material (314a; 314b; 414) transport medium (318) flat contour (319) coating (420) second layer (430) third layer (501) filament with embedded nitric oxide donor material