WO2006100155A1 - Dispositif pour le soin des plaies, et procede de fabrication associe, impliquant l'utilisation de monoxyde d'azote - Google Patents

Dispositif pour le soin des plaies, et procede de fabrication associe, impliquant l'utilisation de monoxyde d'azote Download PDF

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Publication number
WO2006100155A1
WO2006100155A1 PCT/EP2006/050895 EP2006050895W WO2006100155A1 WO 2006100155 A1 WO2006100155 A1 WO 2006100155A1 EP 2006050895 W EP2006050895 W EP 2006050895W WO 2006100155 A1 WO2006100155 A1 WO 2006100155A1
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Prior art keywords
nitric oxide
eluting
eluting polymer
polymer
wound
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PCT/EP2006/050895
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English (en)
Inventor
Tor Peters
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Nolabs Ab
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Publication date
Priority claimed from EP05006495A external-priority patent/EP1704877A1/fr
Priority claimed from EP05018269A external-priority patent/EP1757278A1/fr
Application filed by Nolabs Ab filed Critical Nolabs Ab
Publication of WO2006100155A1 publication Critical patent/WO2006100155A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments

Definitions

  • This invention pertains in general to the field of a device for wound care, involving the use of nitric oxide (NO) . More particularly the invention relates to a device for performing said wound care, and a process for manufacturing of said device, involving the use of nitric oxide (NO) .
  • Wounds are a common occurrence in the daily life. These wounds may vary widely, depending on how they are obtained. Irrespectively, these wounds need to be taken care of in one way or another.
  • the normal way to take care of such wounds is to provide the wound with a wound care, such as plaster, bandage, dressing, wound dressing, pressure bandage etc., depending on the severity and size of the obtained wound.
  • a wound care such as plaster, bandage, dressing, wound dressing, pressure bandage etc., depending on the severity and size of the obtained wound.
  • Nitric oxide is a highly reactive molecule that is involved in many cell functions.
  • nitric oxide plays a crucial role in the immune system and is utilized as an effector molecule by macrophages to protect itself against a number of pathogens, such as fungi, viruses, bacteria etc., and general microbial invasion.
  • This improvement of healing is partly caused by NO inhibiting the activation or aggregation of blood platelets, and also by NO causing a reduction of inflammatory processes at the site of an implant.
  • NO is also known to have an anti-pathogenic, especially an anti-viral, effect, and furthermore NO has an anti-cancerous effect, as it is cytotoxic and cytostatic in therapeutic concentrations, i.e. it has among other effects tumoricidal and bacteriocidal effects .
  • NO has for instance cytotoxic effects on human haematological malignant cells from patients with leukaemia or lymphoma, whereby NO may be used as a chemotherapeutic agent for treating such haematological disorders, even when the cells have become resistant to conventional anti-cancer drugs.
  • This anti- pathogenic and anti-tumour effect of NO is taken advantage of by the present invention, without having adverse effects .
  • NO is actually toxic in high concentrations and has negative effects when applied in too large amounts to the body. NO is actually also a vasodilator, and too large amounts of NO introduced into the body will cause a complete collapse of the circulatory system.
  • NO has a very short half-life of fractions of a second up to a few seconds, once it is released. Hence, administration limitations due to short half-life and toxicity of NO have been limiting factors in the use of NO in the field of anti-pathogenic and anti-cancerous treatment so far.
  • polymers with the capability of releasing nitrogen oxide when getting in contact with water are for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible with natural products, after the release of nitrogen oxide.
  • polyalkyleneimines such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine)
  • NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NO x group per 1200 atomic mass unit of the polymer are disclosed, X being one or two.
  • S- nitrosylated polymer is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups .
  • a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate .
  • Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner to tissues and organs to aid the healing process and to prevent injury to tissues at risk of injury.
  • Electrospun nano-fibers of linear poly (ethylenimine) diazeniumdiolate deliver therapeutic levels of NO to the tissues surrounding a medical device while minimizing the alteration of the properties of the device.
  • a nanofiber coating because of the small size and large surface area per unit mass of the nanofibers, provides a much larger surface area per unit mass while minimizing changes in other properties of the device.
  • US 6,737,447 discloses a coating for medical devices, which coating provides NO delivery by using nanofibers of L-PEI .
  • the fibers according to US 2004/0131753 may be used for wound healing.
  • WO 96/13164 describes water insoluble polymeric NONOate complexes, which are capable of accelerating wound repair through the controlled release of NO.
  • the polymeric NONOate according to WO 96/13164 is PEI-C.
  • the elution of nitric oxide from the polymer according to US 2004/0131753 is not regulated in any way.
  • US 2004/0259840 discloses nitric oxide releasing lipid molecules. Thus, US 2004/0259840 does not disclose a nitric oxide eluting polymer. The elution of nitric oxide from the lipid according to US 2004/0259840 is not regulated in any way.
  • US 6,261,594 discloses a chitosan based nitric oxide donor composition, comprising a modified chitosan polymer, for wound dressings.
  • the elution of nitric oxide from the composition according to US 6,261,594 is not regulated in any way.
  • US 5,405,919 discloses a polymeric composition capable of releasing nitric oxide.
  • US 5,405,919 discloses compositions comprising nitric oxide/nucleophile adducts which are bound to a polymer and which release nitric oxide in a physiological environment.
  • the elution of nitric oxide from the composition according to US 5,405,919 is not regulated in any way.
  • the disclosure is both silent concerning an improvement of present technology in respect of treatment of wounds by the use of NO and a carrier material that regulates and/or controls the elution of nitric oxide.
  • an improved, or more advantageous, device for the treatment of wounds is needed. It is desired that the device presents an improved wound healing and anti- microbial, anti-inflammatory, and anti-viral effect, would be advantageous, and in particular a device allowing for target treatment of wounds would be advantageous .
  • the present invention preferably seeks to mitigate, alleviate or eliminate one or more of the above-identified deficiencies in the art and disadvantages singly or in any combination and solves, among others, at least some of the problems mentioned above, by providing a device for said treatment of wounds, a manufacturing method for the latter and a use of nitric oxide according to the appended patent claims .
  • a device that allows for target treatment of wounds .
  • the device comprises a nitric oxide (NO) eluting polymer arranged to contact the area to be treated, such that a therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer to said area.
  • NO nitric oxide
  • a manufacturing process for such a device is provided, wherein the process is a process for forming a device that allows for target treatment of wounds.
  • the process comprises selecting a plurality of nitric oxide eluting polymeric particles, such as nano fibres, fibres, nano particles, or microspheres, and deploying said nitric oxide eluting particles in a condom/sheath, tape/coating, fibres, nano-particles, or micro-spheres to be comprised in said device.
  • the NO eluting particles are admixed to an ointment, gel, hydrogel, foam, cream, gel, or foam.
  • the present invention has at least the advantage over the prior art that it provides target exposure of a wound to NO, whereby blood perfusion and vasodilatation are increased, simultaneously as an anti-viral, an antiinflammatory, and an anti-microbial, therapy is achievable.
  • Fig. 1 is a schematic illustration of a patch/pad 10 according to an embodiment of the invention.
  • Fig. 2 is a schematic illustration of a tape or coating 20 according to an embodiment of the invention.
  • Fig. 3 is a schematic illustration of a condom/sheath 30 according to an embodiment of the invention.
  • Fig. 4 is a schematic illustration of a sock 40 according to an embodiment of the invention
  • Fig. 5 is an illustration of two different elution profiles for two different mixtures of nitric oxide eluting polymer and carrier material .
  • NO nitrogen monoxide
  • NOS nitric oxide synthase
  • cNOS constitutive enzyme
  • iNOS inducible enzyme
  • NO reacts with active oxygen to attack exogenous microorganisms and cancer cells, but also to cause inflammation and tissue injury.
  • cGMP cyclic GMP
  • vasodilator action improvement of the blood circulation, anti-platelet- aggregating action, anti-bacterial action, anti-viral action, anti-inflammatory action, anticancer action, acceleration of the absorption at the digestive tract, renal function regulation, neurotransmitting action, erection (reproduction), learning, appetite, and the like.
  • inhibitors of the enzymatic activity of NOS have been examined for the purpose of preventing inflammation and tissue injury, which are considered to be attributable to NO generated in a large amount in a living body.
  • the promotion of the enzymatic activity (or expressed amount) of NOS has not been examined for the purpose of exhibiting various protective actions for a living body by promoting the enzymatic activity of NOS and producing NO appropriately.
  • polymers with the capability of releasing nitrogen oxide when getting in contact with water.
  • polymers are for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible. Another advantage is that NO is released without any secondary products that could lead to undesired side effects .
  • the polymers according to the present invention may be manufactured by electro spinning, gas spinning, air spinning, wet spinning, dry spinning, melt spinning, and gel spinning.
  • Electro spinning is a process by which a suspended polymer is charged. At a characteristic voltage a fine jet of polymer releases from the surface in response to the tensile forces generated by interaction by an applied electric field with the electrical charge carried by the jet. This process produces a bundle of polymer fibres, such as nano-fibres. This jet of polymer fibres may be directed to a surface to be treated.
  • US 6,382,526, US 6,520,425, and US 6,695,992 disclose processes and apparatuses for the production of such polymeric fibres. These techniques are generally based on gas stream spinning, also known within the fiber forming industry as air spinning, of liquids and/or solutions capable of forming fibers .
  • NO eluting polymers are given in US-5, 770, 645, wherein polymers derivatized with at least one -NOX group per 1200 atomic mass unit of the polymer are disclosed, X being one or two.
  • One example is an S- nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups .
  • Akron University has developed NO-eluting L-PEI molecule that can be nano-spun onto the surface of permanently implanted medical devices, such as implanted grafts, showing significant improvement of the healing process and reduced inflammation when implanting such devices.
  • a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly (ethylenimine) -diazeniumdiolate .
  • Linear poly (ethylenimine) diazeniumdiolate releases nitric oxide (NO) in a controlled manner.
  • a polymer comprising an O-nitrosylated group is also a possible nitric oxide eluting polymer.
  • the nitric oxide eluting polymer comprises diazeniumdiolate groups, S- nitrosylated and O-nitrosylated groups, or any combinations thereof.
  • said nitric oxide eluting polymer is a poly (alkyleneimine) diazeniumdiolate, such as L-PEI-NO (linear poly (ethyleneimine) diazeniumdiolate) , where said nitric oxide eluting polymer is loaded with nitric oxide through the diazeniumdiolate groups and arranged to release nitric oxide at a treatment site.
  • poly (alkyleneimine) diazeniumdiolate such as L-PEI-NO (linear poly (ethyleneimine) diazeniumdiolate)
  • nitric oxide eluting polymer examples are selected from the group comprising amino cellulose, amino dextrans, chitosan, aminated chitosan, polyethyleneimine, PEI-cellulose, polypropyleneimine, polybutyleneimine, polyurethane, poly (buthanediol spermate) , poly (iminocarbonate) , polypeptide, Carboxy Methyl Cellulose (CMC) , polystyrene, poly (vinyl chloride), and polydimethylsiloxane, or any combinations of these, and these mentioned polymers grafted to an inert backbone, such as a polysaccharide backbone or cellulosic backbone.
  • the nitric oxide eluting polymer may be a O-derivatized NONOate . This kind of polymer often needs an enzymatic reaction to release nitric oxide.
  • said device is in form of a patch/pad, according to Fig. 1, which patch/pad is suitable to be applied on the face, arm, hand, thigh, back, stomach, neck, on which body part the wound to be treated is located.
  • this patch/pad is attached by any suitable adhering means, such as materials that adhere to the skin.
  • said device may be manufactured in the form of a polyurethanes, or polyethylene, tape or coating, according to Fig. 2.
  • This polyurethane tape or coating may easily be wrapped around, or applied on, the wounded area to be treated.
  • At least the side facing the body may be covered with NO-eluting nano- particles, or micro-spheres, or nano-filament of NO-eluting L-PEI . When these particles or filaments get in contact with the moisture, in form of sweat, on the inside of the tape or coating, the elution of NO starts .
  • the patch/pad or tape/coating may be manufactured by any other suitable material, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of thesebiodegrad.
  • the NO-eluting polymer may be integrated in, spun together with, or spun on top of, any of these materials in all of the embodiments of the present invention .
  • the device according to the present invention is applied on the area to be treated, such as any part of the body in need of treatment of at least one wound, such as the face, neck, shoulders, hands, arms, back, chest, stomach, bottom, thigh, genitals, lower leg, and/or foot.
  • an elution of NO is initiated by adding water in any possible way. This may for example be accomplished by applying a water soaked patch on said patch/pad, or spraying or bathing said patch/pad with water. Often, the moisture/water obtained from the sweat secreted underneath the device according to the present invention, is enough to obtain a satisfactory elution of NO from said NO eluting polymer.
  • the healing effect of the wound is obtained, as the NO eluting polymer elutes NO on the area to be treated, by an increased blood perfusion and vasodilatation, whereby an increased healing effect of the tissue of interest is achieved.
  • the increased blood perfusion and vasodilatation may, in another embodiment of the present invention, result in an improved effect when combined with other wound care products, comprising active components.
  • the synergistic effect from NO and other wound healing, or anti-microbial, anti-inflammatory, or anti-viral, components is within the scope of the present invention.
  • the device is in form of fibres, nano-particles, or micro- spheres of a NO eluting polymer, which fibres, nano- particles, or micro-spheres are integrated in a gel, cream, or foam, that may either be in a smearing or compressed structure.
  • the nitric oxide eluting polymer such as powder, nano-particles or micro- spheres, can be incorporated in foam.
  • the foam may have an open cell structure, which facilitates the transport of the proton donor to the nitric oxide eluting polymer.
  • the foam can be of any suitable polymer such as polyurethane, polystyrene, polyester, polyvinylchloride, polyolefins, or latex.
  • the device is in form of a cream, a gel or a combination of the two. Since the nitric oxide eluting polymer is activated by proton donors the nitric oxide eluting polymer has to be separate from the proton donor until one wants to initiate the elution of nitric oxide, i.e. use the device. One way to accomplish this is to have a syringe with two separate containers .
  • a proton donor-based gel In one container you have a proton donor-based gel and in the other a non proton donor-based gel, comprising the nitric oxide eluting polymer. Upon using the device the two gels are squeezed from the syringe and mixed together, the proton donor in the first gel comes in contact with the nitric oxide eluting polymer in the second gel and the elution of nitric oxide starts .
  • These fibres, nano-particles, or micro-spheres may be formed from the NO-eluting polymers comprised in the present invention, for example polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible, after the release of nitrogen oxide.
  • polyalkyleneimines such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible, after the release of nitrogen oxide.
  • They may also be encapsulated in any suitable material, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC), protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • any suitable material such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Car
  • the term "encapsulating” is intended to be interpreted as fixating the nitric oxide eluting polymer in a three dimensional matrix such as a foam, a film, a nonwoven mat of nano- fibers or fibers, or other materials with the capability to fixate the NO eluting polymer, or enclosing the nitric oxide eluting polymer in any suitable material.
  • the fibres, nano-particles, or micro-spheres may also be integrated in a hydrogel, which is mixed directly before use .
  • This embodiment has the advantage of being able to penetrate pockets and corners in the skin, and/or wound, for closer elution of NO on the area to be treated.
  • the device is in form of a latex or rubber condom/sheath, said condom/sheath being covered with nano- filament of any of the NO-eluting polymers according to above, such as polyalkyleneimines, such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine) , which polymers have the advantage of being biocompatible, after the release of nitrogen oxide.
  • polyalkyleneimines such as L-PEI (Linear PolyEthylenelmine) and B-PEI (Branched PolyEthylenelmine)
  • the condom/sheath is covered on the inside with nano-filament of L-PEI.
  • This condom/sheath may be in any suitable size, such as a suitable size for rolling said condom/sheath over the thigh, arm, neck, head, foot etc., to be treated. These sizes may for example vary from small, medium, and large sized condoms/sheaths in accordance with the different sizes, in respect of the different body parts, of persons in the population.
  • the condom/sheath according to the invention may even have a size suitable for covering a foot, such as a sock, according to Fig. 4, or a foot- condom/sheath, or other specific part of the body, to be able to obtain treatment of a wound.
  • the condoms/sheaths are coated with NO eluting nano fibres .
  • the condoms/sheaths are made of, or comprise nanofilaments, e.g. made by electro or gas jet spinning.
  • the condoms/sheaths comprises microspheres eluting NO in use.
  • the three aforementioned embodiments employ L-PEI material loaded with NO. Activation on NO release may be done by e.g. foot sweat, proton donor, such as water, sprayed onto the condoms/sheaths immediately prior to use, or a proton donor bag configured for releasing proton donor upon activation, e.g. by pushing onto the bag thus bursting (see below) .
  • the NO-eluting condom/sheath When the NO-eluting condom/sheath according to certain embodiments of the present invention is treated with or gets in contact with the moisture, in form of secreted sweat, the NO-eluting condom/sheath starts to elute NO to the area to be treated.
  • the device is moistured or wettened immediately prior to application or use for controlling or activating the elution of NO.
  • the condom/sheath, sock, patch/pad, or tape/coating is covered on the inside with NO-eluting nano-particles, or microspheres, according to above.
  • the condom/sheath, sock, patch/pad, or tape/coating contains a small proton donor bag or sealed proton donor sponge. This proton donor bag or sealed proton donor sponge is used to activate the elution of NO from the NO-eluting nano-particles, or micro-spheres. Persons that not easily sweat may be helped by the use of this embodiment.
  • a nitric oxide eluting polymer is provided, and/or combined, with microencapsulated proton donor.
  • This may for example be done by first manufacture micro capsules, containing a proton donor, such as water or water containing liquid, in a state of the art manner. These micro capsules are then applied on the NO eluting polymer.
  • the application of the micro capsules on the NO eluting polymer may for example be done by gluing, such as pattern gluing, or instead spinning the NO eluting polymer onto said micro capsules. In this way a device or a system, comprising NO eluting polymer and micro encapsulated proton donor is manufactured.
  • the device or system When the device or system is applied on the target area the device or system is compressed or squeezed. Said compression or squeezing results in breakage of the micro capsules.
  • the NO eluting polymer is thus exposed to proton donor, and the elution of NO from the NO eluting polymer is initiated on the target area.
  • the proton donor inside the micro capsules is released by heating or shearing the micro capsules until the micro capsules are ruptured.
  • the micro capsules are formed into a film, tape, or sheath. Thereafter, a film, tape, or sheath of an NO eluting polymer is glued onto the film, tape, or sheath of micro capsules.
  • a film, tape, or sheath of an NO eluting polymer is glued onto the film, tape, or sheath of micro capsules.
  • the film, tape, or sheath of the NO eluting polymer is glued onto the film, tape, or sheath of the micro capsules in patterned way.
  • the obtained pattern includes spaces where there is no glue, in which spaces the proton donor will be transported to the NO eluting polymer once the micro capsules are broken from compression or squeezing. When the proton donor gets in contact with the NO eluting polymer the elution of NO starts.
  • the combination of film, tape, or sheath of micro capsules and NO eluting polymer may be applied on a target area. Thereafter the combination is compressed or squeezed, which results in that the target area is exposed to NO.
  • the NO eluting polymer is spun directly onto the film, tape, or sheath of micro capsules, containing proton donor.
  • the combination of film, tape, or sheath of micro capsules and spun NO eluting polymer may be applied on a target area. Thereafter the combination is compressed or squeezed, which results in that the target area is exposed to NO.
  • the device or system is provided with an activation indicator.
  • This activation indicator indicates when the micro capsules are satisfyingly broken, hence when the NO eluting polymer is subjected to enough proton donor to elute an efficient amount of NO.
  • This activation indicator may for example be obtained by colouring the proton donor that is trapped inside the micro capsules. When the micro capsules are broken the coloured proton donor escapes the microcapsules and the colour gets visualised while efficiently wetting the NO eluting polymer.
  • Another way of obtaining an activation indicator is to choose to manufacture the micro capsules in a material, or choose a wall thickness of said micro particles, that creates a sound when the micro capsules break. It is also possible to admix a scent in the proton donor, contained in the micro capsules. This results in that the user of the device or system may smell the scent when the proton donor escapes from the micro capsules after breakage thereof.
  • a substance that changes color when it comes in contact with water can be incorporated in the device.
  • the device or system only allows NO-elution in one direction.
  • one side of the device according to the invention has low permeability, or substantially no permeability, to nitric oxide. This may be accomplished by applying a material on one side of the device according to the invention that is not permeable to NO.
  • Such materials may be chosen from the group comprising common plastics, such as fluoropolymers, polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • This embodiment is also easy to manufacture as the NO eluting polymer, e.g.
  • L-PEI (or nitric oxide eluting polymer and carrier material, which will be explained in more detail below) may be electro or gas-jet spun onto the surface of the device according to the invention of e.g. the mentioned plastics, latex, or cotton.
  • the device is provided with one membrane, which is permeable to nitric oxide, on a first side of the device, and another membrane, which has low permeability or substantially no permeability to nitric oxide, on a second side of said device.
  • This embodiment provides the possibility to direct the elution to said first of the device, while the elution of nitric oxide is substantially prevented from said second side. Thereby, a greater amount of nitric oxide will reach the intended area to be treated.
  • the activation of the nitric oxide eluting polymer may be accomplished by contacting said polymer with a suitable proton donor.
  • the proton donor may be selected from the group comprising water, body fluids (blood, lymph, bile, etc.), alcohols (methanol, ethanol, propanols, buthanols, pentanols, hexanols, phenols, naphtols, polyols, etc.), aqueous acidic buffers (phosphates, succinates, carbonates, acetates, formats, propionates, butyrates, fatty acids, amino acids, etc.), or any combinations of these.
  • the fibres, nano-particles, or micro-spheres may be integrated in a soluble film that disintegrates on the inside of the condom/sheath, sock, patch/pad, or tape/coating, according to the present invention, in order to elute NO at the area of interest when the soluble film gets in contact with the moisture, in form of sweat or from the water bag or sealed water sponge, on the area to be treated.
  • the device When placed on an area to be treated the device provides prevention and treatment of wounds .
  • the device only allows NO-elution in one direction.
  • one side of the device such as condom/sheath, sock, patch/pad, or tape/coating, is non- permeable to NO. This may be accomplished by applying a material on one side of the device that is not permeable to NO.
  • Such materials may be chosen from the group comprising common plasties, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • This embodiment is also easy to manufacture as the NO eluting polymer, e.g.
  • L-PEI nano fibres may be electro or gas-jet spun onto the surface of the device of e.g. the mentioned plastics, latex, or cotton.
  • a condom it may be rolled up, or a sheath may be turned outside in after manufacturing to protect the NO eluting polymer during packaging, transport and prior to use from external influences, being e.g. mechanical (abrasion of the polymer) , chemical (moisture deactivating the device prior to use) etc.
  • the NO-eluting device is acting as a booster for drug eluting patches, e.g. pharmaceuticals, vitamins, nicotin, nitroglycerin, Non-Steroidal Anti-Inflammatory Drugs (NSAID) , such as diclofenac, ibuprofen, aspirin, naproxen, COX-2 inhibitors, choline magnesium trisalicylate, diflunisal, salsalate, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, indomethacin, sulindac, tolmetin, meloxicam, piroxicam, meclofenamate, mefenamic acid, nabumetone, etodalac, ketorolac, celecoxib, valdecoxib, and rofecoxib; steroids, such as cortisone, prednisone, methylprednisolone, predni
  • steroids such as cort
  • such devices may achieve a synergetic effect, when NO is eluted from the devices.
  • NO has a vasodilatory effect on the region where the device having the combination compound actuates.
  • Vasodilated tissue is more susceptible to certain medications and thus more easily treated by the medical preparations and still NO has in addition to that the anti-inflammatory, anti-bacterial etc. effect.
  • an unexpected surprisingly effective treatment is provided.
  • NO eluting poymer is applied on devices for ostomy care, such as a ostomy bag, gaskets for said ostomy bag etc.
  • This embodiment provides the advantage of providing anti-inflammatory, anti-bacterial, and anti-viral effect, which advantage is especially important in the early stages of ostomy.
  • NO eluting poymer is applied on a intravenous dressing.
  • the area surrounding an intravenous catheter is provided with anti-microbial, anti-inflammatory, antithrombotic and anti-viral effect.
  • This embodiment has the advantage of protecting an area which otherwise is exposed to a high possibility of getting in contact with infectious material .
  • the device elutes nitric oxide (NO) from said eluting polymer in a therapeutic dose, such as between 0.001 to 5000 ppm, such as 0.01 to 3000 ppm, such as 0.1 to 1000 ppm, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 91, 92, 93, 94, 95, 96,
  • the concentration may vary widely depending on where the concentration is measured. If the concentration is measured close to the actual NO eluting polymer the concentration may be as high as thousands of ppm, while the concentration inside the tissue in this case often is considerably lower, such as between 1 to 1000 ppm.
  • polymers or materials may be chosen from any suitable material or polymer, such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly (acrylic acid), Carboxy Methyl Cellulose (CMC) , protein based polymers, gelatine, biodegradable polymers, cotton, and latex, or any combinations of these.
  • suitable material or polymer such as polyethylene, polypropylene, polyacrylonitrile, polyurethane, polyvinylacetates, polylacticacids, starch, cellulose, polyhydroxyalkanoates, polyesters, polycaprolactone, polyvinylalcohol, polystyrene, polyethers, polycarbonates, polyamides, polyolefins, poly
  • nitric oxide releasing polymer such as a diazoliumdiolate group
  • acidity of the environment surrounding the nitric oxide eluting polymer the acidity of the environment surrounding the nitric oxide eluting polymer
  • temperature of the environment surrounding the nitric oxide releasing polymer higher temperature promotes elution of nitric oxide
  • a nitric oxide eluting polymer such as L-PEI-NO
  • a carrier polymer such as L-PEI-NO
  • the nitric oxide eluting polymer may be mixed with more than one carrier polymer, whereby be elution or release may be tailor made to fit specific needs.
  • Such a need may for example be a low elution during a first period of time, when the environment of the nitric oxide eluting polymer is hydrophobic, and a faster elution during a second period of time, when the environment of the nitric oxide eluting polymer has been altered to be more hydrophilic.
  • hydrophilic polymer acts the opposite way.
  • an hydrophilic polymer is polyethylene oxide
  • one example of an hydrophobic polymer is polystyrene.
  • Fig. 5 illustrates two elution profiles (NO concentration vs. time) for two different polymer mixtures; a nitric oxide eluting polymer mixed with a hydrophilic carrier polymer in an acidic environment (A) , and a nitric oxide eluting polymer mixed with a hydrophobic carrier polymer in a neutral environment (B) .
  • this carrier polymer is substituted by another material with hydrophobic or hydrophilic properties. Therefore, the term "carrier material" in the present context should be interpreted to include carrier polymers and other materials with hydrophilic or hydrophobic properties .
  • the elution of nitric oxide from a nitric oxide eluting polymer, such as L-PEI-NO is influenced by the presence of protons. This means that a more acidic environment provides a quicker elution of nitric oxide.
  • nitric oxide eluting polymer or mixture of nitric oxide eluting polymer and carrier material
  • an acidic fluid such as an ascorbic acid solution
  • the carrier polymers and carrier materials mentioned above may affect other characteristics than the regulation of nitric oxide elution.
  • An examples of such characteristic is mechanical strength.
  • the NO-eluting polymer may be integrated in, spun together with, or spun on top of, any of these materials in all of the embodiments of the present invention.
  • This spinning includes electro spinning, air spinning, dry spinning, wet spinning, melt spinning, and gel spinning.
  • fibers of a polymer mixture comprising a nitric oxide eluting polymer and a carrier polymer, or a carrier material, with predefined nitric oxide eluting characteristics. These characteristics may be tailor made for different elution profiles in different applications.
  • the nitric oxide eluting polymer may comprise a secondary amine, either in the backbone or as a pendant, as described previously.
  • the secondary amine should have a strong negative charge to be easy to load with nitric oxide. If there is a ligand close to the secondary amine, such as on a neighbour atom, such as a carbon atom, to the nitrogen atom, with higher electronegativity than nitrogen (N) , it is very difficult to load the polymer with nitric oxide. On the other hand, if there is a electropositive ligand close to the secondary amine, such as on a neighbour atom, such as a carbon atom, to the nitrogen atom, the electronegativity of the amine will increase and thereby increase the possibility to load the nitric oxide elution polymer with nitric oxide.
  • the nitric oxide polymer may be stabilized with a salt.
  • a positive counter ion such as a cation
  • This cation may for example be selected from the group comprising any cation from group 1 or group 2 in the periodic table, such as Na + , K + , Li + , Be 2+ , Ca 2+ , Mg 2+ , Ba 2+ , and/or Sr 2+ .
  • Different salts of the same nitric oxide eluting polymer have different properties.
  • a suitable salt may be selected for different purposes.
  • cationic stabilized polymers are L- PEI-NO-Na, i.e. L-PEI diazeniumdiolate stabilized with sodium, and L-PEI-NO-Ca, i.e. L-PEI diazeniumdiolate stabilized with calcium.
  • Another embodiment of the present invention comprises mixing the nitric oxide eluting polymer, or a mixture of the nitric oxide eluting polymer and a carrier material, with an absorbent agent.
  • This embodiment provides the advantage of an accelerated elution of nitric oxide since the polymer, or polymer mixture, via the absorbent agent, may take up the activating fluid, such as water or body fluid, much faster.
  • 80 % (w/w) absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material
  • 10 to 50 % (w/w) absorbent agent is mixed with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material .
  • the elution of nitric oxide is activated by a proton donor, such as water, it may be an advantage to keep the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material, in contact with said proton donor. If an indication requires an elution of nitric oxide during a prolonged period of time, a system is advantageous, which presents the possibility to keep the proton donor in contact with the nitric oxide eluting polymer, or mixture of nitric oxide eluting polymer and carrier material. Therefore, in still another embodiment of the present invention, the elution of nitric oxide may be regulated by adding an absorbent agent.
  • the absorbent agent absorbs the proton donor, such as water, and keeps the proton donor in close contact with the nitric oxide eluting polymer during prolonged periods of time.
  • Said absorbent agent may be selected from the group comprising polyacrylates, polyethylene oxide, carboxymethylcellulose, and microcrystalline cellulose, cotton, and starch.
  • This absorbent agent may also be used as a filling agent. In this case said filling agent may give the nitric oxide eluting polymer, or mixture of said nitric oxide eluting polymer and a carrier material, a desired texture.
  • the NO-eluting polymers in the devices may be combined with silver, such as hydroactivated silver.
  • silver such as hydroactivated silver.
  • the integration of silver in the devices gives the healing process an extra boost.
  • the silver is releasable from the devices in the form of silver ions.
  • the integration of silver in the device may present several advantages.
  • One example of such an advantage is that the silver may keep the device in itself free from bacteria or viruses, while the nitric oxide eluting polymer elutes the therapeutic dosage of nitric oxide to the target site.
  • the device may be manufactured by, for example electro spinning, gas spinning, air spinning, wet spinning, dry spinning, melt spinning, and gel spinning, of L-PEI or other polymers comprising L-PEI or being arranged in combination with L-PEI.
  • L-PEI is the charged at a characteristic voltage, and a fine jet of L-PEI releases as a bundle of L-PEI polymer fibres.
  • This jet of polymer fibres may be directed to a surface to be treated.
  • the surface to be treated may for example be any suitable material in respect of a device according to the present invention.
  • the electro spun fibres of L-PEI then attach on said material and form a coating/layer of L-PEI on the device according to the invention.
  • NO-eluting polymers it is of course possible to electro spin the other NO-eluting polymers, according to above, on the device while still being inside the scope of the present invention.
  • the NO-eluting polymers are electro spun in such way that pure NO-eluting polymer fibres may be obtained.
  • the manufacturing process of devices according to embodiments of the present invention presents the advantages of large contact surface of the NO-eluting polymer fibres with the area to be treated, effective use of NO-eluting polymer, and a cost effective way of producing the device.
  • the device according to the invention comprises the NO eluting polymer and/or said carrier in non-fibrous form.
  • a method of treating at least one wound comprising applying a device, that comprises a nitric oxide (NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, and thereby exposing said treatment site of said at least one wound on a body to said nitric oxide when said polymer in use elutes nitrogen oxide (NO) by eluting a therapeutic dose of nitric oxide from said nitric oxide eluting polymer to said treatment site.
  • a device that comprises a nitric oxide (NO) eluting polymer configured for eluting a therapeutic dosage of nitrogen oxide (NO) when used for said treatment, and thereby exposing said treatment site of said at least one wound on a body to said nitric oxide when said polymer in use elutes nitrogen oxide (NO) by eluting a therapeutic dose of nitric oxide from said nitric oxide eluting polymer to said treatment site.
  • NO nitric oxide
  • said site of said at least one wound is a head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body
  • said method comprises applying a condom/sheath, sock, patch/pad, cream, ointment, foam, hydrogel, and tape/coating to said head, face, neck, shoulder, back, arm, hand, stomach, genital, thigh, leg, or foot, of a body, for said exposure.
  • nitric oxide in a therapeutic dose for therapeutically treating and/or preventing at least one wound on a body.
  • the invention may be implemented in any suitable form.
  • the elements and components of the embodiments according to the invention may be physically, functionally, and logically implemented in any suitable way. Indeed, the functionality may be implemented in a single unit, in a plurality of units, or as part of other functional units.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

L'invention concerne un dispositif et un procédé de fabrication de ce dispositif destinés au traitement des plaies. Le dispositif (5) comprend un polymère d'élution du monoxyde d'azote (NO) agencé pour être en contact avec la zone de la plaie à traiter, de telle façon qu'une dose thérapeutique de monoxyde d'azote soit éluée par ledit polymère d'élution du monoxyde d'azote sur ladite zone de la plaie, accélérant ainsi la guérison d'une plaie sur ladite zone. Le polymère d'élution du monoxyde d'azote (10) (NO) est intégré à un matériau support, de façon que celui-ci régule et contrôle l'élution dudit dosage thérapeutique de monoxyde d'azote (NO). L'invention concerne en outre un procédé de fabrication dudit dispositif.
PCT/EP2006/050895 2005-03-24 2006-02-13 Dispositif pour le soin des plaies, et procede de fabrication associe, impliquant l'utilisation de monoxyde d'azote WO2006100155A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
EP05006495A EP1704877A1 (fr) 2005-03-24 2005-03-24 Dispositif de traitement des plaies comprenant un polymère à élution de monoxyde d'azote
EP05006495.5 2005-03-24
US66650305P 2005-03-30 2005-03-30
US60/666,503 2005-03-30
EP05018269A EP1757278A1 (fr) 2005-08-23 2005-08-23 Dispositif, système ou méthode contenant un liquide microencapsulé pour la libération d'oxyde nitrique à partir d'un polymère
EP05018269.0 2005-08-23
US71100605P 2005-08-24 2005-08-24
US60/711,006 2005-08-24

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WO2008104032A1 (fr) * 2007-03-01 2008-09-04 D-Swell Pty Ltd Bandage pour le corps comprenant un emballage de forme posologique à base de carbonate de sodium
WO2008116925A1 (fr) * 2007-03-27 2008-10-02 Nolabs Ab Dispositif de distribution dermique topique destiné à la distribution d'oxyde nitrique
WO2009049208A1 (fr) * 2007-10-12 2009-04-16 The University Of North Carolina At Chapel Hill Utilisation d'oxyde nitrique pour amplifier l'efficacité de l'argent et d'autres agents cicatrisants topiques
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US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
WO2012113060A1 (fr) * 2011-02-25 2012-08-30 University Of Windsor Appareil pour la libération contrôlée d'oxyde nitrique topique
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
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US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
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US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
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CN110606956A (zh) * 2019-08-05 2019-12-24 北京化工大学常州先进材料研究院 一种壳聚糖-纤维素复合材料及其敷料
US10821203B2 (en) 2008-11-21 2020-11-03 Pq Silicas Uk Limited Composition and dressing with nitric oxide
CN112646240A (zh) * 2020-12-10 2021-04-13 中国地质大学（武汉） 一种纳米甲壳素复合气凝胶及其制备方法和应用
WO2021071434A1 (fr) * 2019-10-11 2021-04-15 Agency For Science, Technology And Research Dispositif de détection de pression et procédés associés

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US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US11691995B2 (en) 2005-05-27 2023-07-04 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
WO2008104032A1 (fr) * 2007-03-01 2008-09-04 D-Swell Pty Ltd Bandage pour le corps comprenant un emballage de forme posologique à base de carbonate de sodium
WO2008116925A1 (fr) * 2007-03-27 2008-10-02 Nolabs Ab Dispositif de distribution dermique topique destiné à la distribution d'oxyde nitrique
WO2008116497A1 (fr) * 2007-03-27 2008-10-02 Nolabs Ab Dispositif d'administration dermique topique pour une administration d'oxyde nitrique
US8399005B2 (en) 2007-10-12 2013-03-19 University Of North Carolina At Chapel Hill Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents
WO2009049208A1 (fr) * 2007-10-12 2009-04-16 The University Of North Carolina At Chapel Hill Utilisation d'oxyde nitrique pour amplifier l'efficacité de l'argent et d'autres agents cicatrisants topiques
US7862598B2 (en) 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8349262B2 (en) 2007-10-30 2013-01-08 The Invention Science Fund I, Llc Nitric oxide permeable housings
US8642093B2 (en) 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US8877508B2 (en) 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US8980332B2 (en) 2007-10-30 2015-03-17 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
US10080823B2 (en) 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices
US7846400B2 (en) 2007-10-30 2010-12-07 The Invention Science Fund I, Llc Substrates for nitric oxide releasing devices
US10835636B2 (en) 2008-11-21 2020-11-17 Pq Silicas Uk Limited Composition and dressing with nitric oxide
US10821203B2 (en) 2008-11-21 2020-11-03 Pq Silicas Uk Limited Composition and dressing with nitric oxide
US10376538B2 (en) 2009-08-21 2019-08-13 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US9919072B2 (en) 2009-08-21 2018-03-20 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US11583608B2 (en) 2009-08-21 2023-02-21 Novan, Inc. Wound dressings, methods of using the same and methods of forming the same
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US9522260B2 (en) 2011-02-25 2016-12-20 University Of Windsor Apparatus for the controlled release of topical nitric oxide
WO2012113060A1 (fr) * 2011-02-25 2012-08-30 University Of Windsor Appareil pour la libération contrôlée d'oxyde nitrique topique
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
CN110606956B (zh) * 2019-08-05 2021-07-27 北京化工大学常州先进材料研究院 一种壳聚糖-纤维素复合材料及其敷料
CN110606956A (zh) * 2019-08-05 2019-12-24 北京化工大学常州先进材料研究院 一种壳聚糖-纤维素复合材料及其敷料
WO2021071434A1 (fr) * 2019-10-11 2021-04-15 Agency For Science, Technology And Research Dispositif de détection de pression et procédés associés
CN112646240A (zh) * 2020-12-10 2021-04-13 中国地质大学（武汉） 一种纳米甲壳素复合气凝胶及其制备方法和应用

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