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WO2017035280A1 - Pansements et aides à la cicatrisation de lésion cutanée - Google Patents

Pansements et aides à la cicatrisation de lésion cutanée Download PDF

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Publication number
WO2017035280A1
WO2017035280A1 PCT/US2016/048495 US2016048495W WO2017035280A1 WO 2017035280 A1 WO2017035280 A1 WO 2017035280A1 US 2016048495 W US2016048495 W US 2016048495W WO 2017035280 A1 WO2017035280 A1 WO 2017035280A1
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WIPO (PCT)
Prior art keywords
dressing
medium
bandage
weight
nanosilver
Prior art date
Application number
PCT/US2016/048495
Other languages
English (en)
Inventor
Sanjay Dhar
Mohammad Saeed KHARAZMI
Mohammad Ali KHARAZMI
Original Assignee
Nugene, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nugene, Inc. filed Critical Nugene, Inc.
Publication of WO2017035280A1 publication Critical patent/WO2017035280A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode
    • A61N1/044—Shape of the electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0448—Drug reservoir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0468—Specially adapted for promoting wound healing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0472—Structure-related aspects
    • A61N1/0476—Array electrodes (including any electrode arrangement with more than one electrode for at least one of the polarities)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0472—Structure-related aspects
    • A61N1/0492—Patch electrodes
    • A61N1/0496—Patch electrodes characterised by using specific chemical compositions, e.g. hydrogel compositions, adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Definitions

  • TITLE Skin damage healing aids and dressings
  • This invention is in the field of dermal care and treatment.
  • it concerns compositions that improve the condition of skin damage by topical application together with dressings
  • Skin damage includes burns, wounds, scars, wrinkled skin, blemished skin, acne, or other skin conditions.
  • the invention also includes methods of treating skin using such compositions and dressings.
  • the dressings may include electroactive dressings.
  • Skin may be damaged by a variety of chronic insults including aging, sun exposure, past wound healing, and cosmetic treatments.
  • circulation lessens and dermal fibroblast cells become less active; skin becomes thinner and loses elasticity.
  • Aged skin shows a decrease in volume and elasticity. There is a need to prevent and reverse these conditions to maintain healthy, youthful skin.
  • Skin may be damaged by other more acute conditions such as infections, wounds, and acne. There is a need to treat these conditions that accelerates healing while regaining the appearance and resiliency of healthy skin.
  • a stem cell is an undifferentiated or relatively undifferentiated cell that is capable of giving rise to more cells of the same type, and from which certain other kinds of cell arise by differentiation.
  • Adipose-derived stem cells are stem cells extracted from adipose tissues. Human adipose tissue is available ex vivo as a result of cosmetic procedures including liposuction. Adipose tissue, like other tissue types, is not a homogenous mixture of a single cell type. Instead adipose tissue includes a combination of fat cells, vasculature, connective tissue, and blood cel ls.
  • Stem cells may be extracted from such tissue by any of a number of methods known in the art, including treatment with su rfactants or enzymes (including proteases such as such as collagenase, or trypsin), maceration, separation by centrifugation, filtering, or settling, ultrasonic treatment, adherent culturing, or some combination of these methods.
  • su rfactants or enzymes including proteases such as such as collagenase, or trypsin
  • maceration separation by centrifugation, filtering, or settling
  • ultrasonic treatment adherent culturing, or some combination of these methods.
  • adipose-derived stem cells may be grown in tissue culture by a number of methods known in the art, including growth on three-dimensional scaffolds or supports, growth in suspension culture, or growth on the surface of plastic or glass vessels.
  • adipose-derived stem cells and their progeny produce a variety of growth-promoting and healing materials such as growth factors, cytokines, stress proteins, and nutrients including TGF-B, PDGF, and GM-CSG, interleukins, and matrix proteins (collectively, stem cell products). While many of these have been identified, the cells likely also secrete other substances due to their pluri-potency either not yet known or with beneficial functions yet to be precisely identified. Some of these materials may be effective at low concentration. Another object of this invention is to provide treatment compositions including stem cell products.
  • Autologous human adipose derived stem cells are stem cells derived from adipose tissue of an individual and subsequently used in treating that individual.
  • Tissue-derived products particularly those derived from minimally processed human tissue, may contain human infectious agents or antigens.
  • the invention includes embodiments with
  • compositions containing stem cells autologous with the treated individual are not necessarily free of infectious agents or antigens, but the treated individual has already been exposed to these autologous agents and antigens so that the risk of further infection or immune reaction should be low.
  • Another object of this invention is to provide treatment compositions including autologous stem cells to aid healing with reduced risk of infection or immune reaction.
  • Human adipose-derived stem cell conditioned (“HADSCC) medium is provided.
  • Human stem cells such as adipose-derived stem cells, produce a variety of growth- promoting and healing materials such as growth factors and cytokines. These mixtures of stem cell products may be harvested from cultured adipose-derived stem cells by collecting the culture medium to which such cells have been exposed.
  • adipose-derived stem cells includes supply of nutrients for the cells through provision of an aqueous culture medium.
  • Cells grow in culture in contact with medium and extract nutrients from it. These cells also deliver to the medium products of their growth and metabolism. Among the products are the growth factors and cytokines discussed above as well as metabolic products.
  • Conventional tissue culture requires replacement of culture medium as cells use up nutrients and deliver products that may affect future cell growth. This replacement may be either continuous, with a portion of the medium removed as new medium is added, or intermittent with periodic replacement of some or all of the culture medium in a vessel.
  • Culture medium removed after exposure to cells in culture is known as spent or conditioned medium.
  • Culture medium removed after exposure to human adipose-derived stem cells will be referred to as HADSCC medium.
  • Bandages for wounds or burns are commonly composed of sterile absorbent dressings that are fastened in place by separate fasteners such as tape, adhesives, compressive textiles, or ties.
  • Some bandages may be pretreated with antimicrobials to retard wound infection.
  • wound dressings impregnated with certain healing promoting or microbiocidal materials, such as nanosilver cause wounds to heal more quickly.
  • Nanosilver is used extensively in wound management, particularly in burn treatment.
  • Other reported applications include chronic wounds, burns injuries in children and neonates, ulcers (including diabetic ulcers, rheumatoid arthritis-associated leg ulcers, and venous ulcers), toxic epidermal necrolysis, healing of donor sites, and meshed skin grafts.
  • Other bandages may be untreated but applied with or over topically applied aids such as antimicrobials, clotting factors, desiccants.
  • dressings that may include materials such as pyrvinium or its salts or analogs, gelatin, silver, cellulose, alginate, collagen, a hydrocolloid, a hydrogel, a skin substitute, a wound filler, a growth factor, an antibody, a protease, a protease inhibitor, an antibacterial peptide, an adhesive peptide, a hemostatic agent, living cells, honey, nitric oxide, a corticosteroid, a cytotoxic drug, an antibiotic, an antimicrobial, an antifungal, an antiseptic, nicotine, an anti-platelet drug, an NSAID, colchicine, an anti-coagulant, a vasoconstricting drug or an
  • US 2011/0091568 to Lipton ef al. describes several types of stem cells and media derived from growth of those cells. Lipton also discloses "plasters, bandages, dressings, gauze pads, patches and the like, containing an appropriate amount of conditioned medium and, optionally, other ingredients. In some cases use may be made of plasters, bandages, dressings, gauze pads, patches and the like which have been impregnated with a topical formulation containing the therapeutic formulation.” Lipton ef al.
  • HADSCC medium does not describe "an appropriate amount” other than “optimal percentage of the conditioned media or extract in each composition can vary according to the composition's formulation and the therapeutic effect desired” and by reciting a range of concentrations (apparently in relation to cosmetic procedures) that span more than six orders of magnitude. Lipton ef al. also does not describe any details which would enable the skilled practitioner to produce effective plasters, bandages, dressings, gauze pads, patches and the like. There is thus a need for a bandage that contains HADSCC medium in proportions and amounts that support effective healing.
  • US 8911963 to Epstein ef al. describe a therapeutic bandage including conditioned medium and/or processed conditioned medium impregnated into a polymer.
  • the therapeutic bandage is a polymer impregnated with processed conditioned medium that is applied topically in the form of a bandage, patch, or a configured mesh.
  • An embodiment of the bandage is described as a gauze bandage impregnated with a biodegradable polymer comprising conditioned medium.
  • the bandage can be lyophilized and stored for future use, then reconstituted by added moisture or by wound moisture.
  • the polymer is said to permit sustained release of the processed cond itioned medium.
  • the polymer may be a non-biodegradable polymer that removed after use.
  • the stem cells can be isolated from adipose tissue.
  • the described therapeutic bandages rely on the polymer embedding to retain and release an effective mix of growth factors from the bandage over an effective time course.
  • HADSCC medium contains a complex mix of growth factors that may not be equally soluble in a given polymer. There is thus a need for a bandage that contains HADSCC medium where retention and release of growth factors does not rely on polymer embedding.
  • Electroactive wound dressings produce local electric fields by providing electrical half cells in proximity to healing skin. Wound exudate or exogenously administered fluid close the half cells into a full electrical cell, or battery of electrical cells that generate low-level currents between electrodes on the dressing and extending into proximal healing tissue.
  • Commercially available dressings sold by Vomaris Wound Care, Inc. of Tempe Arizona under the registered trademark Procellera ® are said to provide effective antimicrobial protection to the wound site, inhibiting the growth of harmful microorganisms that may cause infection. Without infection, wounds are said to heal faster.
  • the dressings feature a staggered matrix pattern silver or silver chloride and zinc electrodes dots applied to the dressing surface.
  • the range of penetration of the current produced by electric fields from electroactive dressings depends on the conductive path between the tissues and the dressing, upon the configuration of the tissues themselves, and upon the pattern of electrodes on the dressings.
  • a dressing that provides a pattern that alters the field distribution as compared to conventional dressings to provide some measure of targeting to the current produced.
  • a dressing and composition that provides stem cell products or even stem cells themselves at the same location as the current.
  • exogenous stem cells su pport wound healing; wound healing is to some measure dependent on natural electric fields in tissue; and exogenously applied electric fields can promote both cellular migration and wound healing.
  • Half-cell arrays on wound dressings can deliver electric fields to healing wounds and skin.
  • kits, compositions, and methods include kits, compositions, and methods.
  • the kits of the invention include a dressing having a cathode and an anode each forming an electrical half-cell and a conductive treatment gel containing HADSCC media.
  • the gel also may include a gelling agent and a viscosity of at least 3000 cP. In some embodiments, the viscosity may range between about 5000 and about 20000cP.
  • the dressing may further include a flat flexible substrate having parallel first and second su rfaces. The first surface may support the anode and the cathodes.
  • the anode may include metallic zinc deposited on a region of the first surface of the substrate and the cathode may include metallic silver deposited on a second region of the first surface of the substrate.
  • the first region does not overlap the second region.
  • the first region may include a plurality of discrete spots distributed in a regular array.
  • the second region may also include a plurality of discrete spots distributed in a regular array, with the first region spots intercalated among the second region spots.
  • the first region includes a plurality of discrete spots
  • the second region includes a plurality of circles, each circle enclosing one of the spots.
  • the treatment gel may include HADSCC medium of at least 50% by weight and gelling agent of at least 0.5% by weight of the treatment gel.
  • the gelling agent may be at least 1% by weight of the treatment gel.
  • the gelling agent may be a hydroxymethyl cellulose or a carboxymethyl cellulose.
  • the treatment gel may include ionic salts from about 50 mEq/L to about 200 mEq/L and in some embodiments about 140 mEq/L. Components of the gel from any of these ranges may be combined with other components present in any of their respective ranges.
  • the invention includes a conductive treatment gel containing human adipose-derived stem cells for topical application.
  • the treatment gel may contain a gelling agent of at least 0.5% by weight and a culture medium to support the cells.
  • the gelling agent may be a
  • the gel may have a viscosity of at least 3000 cP. In some embodiments, the viscosity may range between about 5000 and about 20000cP.
  • the composition may include ionic salts from about 50 mEq/L to about 200 mEq/L and in some
  • the treatment gel may further include a culture medium, which may include one of Dulbecco's Modified Eagle's Medium or RPMI 1640 medium.
  • the medium may contain 0.0025 - 0.5% nanosilver particu late by weight of the medium. Components of the gel from any of these ranges may be combined with other components present in any of their respective ranges.
  • the invention also includes a method of treating a skin condition in a human.
  • the method includes the steps of providing a treatment gel and a dressing having complementary electrical half-cells, applying the treatment gel to the skin or to the dressing, a nd applying the dressing to the skin.
  • the dressing includes a first region and a second region distinct from the first region, with the first region having a metallic zinc deposit and the second region having a metallic silver deposit.
  • the first region may include a first plurality of discrete spots
  • the second region may include a second plurality of discrete spots.
  • the first plurality of discrete spots may be intercalated among the second plurality of discrete spots, forming a matrix of alternating zinc and silver spots.
  • first region may include a plurality of discrete spots
  • the second region may include a plurality of circles, with each circle enclosing one of the spots.
  • the spots may be separated by about 2 mm or less.
  • the treatment gel has a viscosity of at least about 3000 cP and an ionic content of between about 50 mEq/L to about 200 mEq/L and in some embodiments about 140 mEq/L. In some embodiments, the viscosity may range between about 5000 and about 20000cP.
  • the treatment gel may contains an HADSCC medium.
  • the HADSCC medium may form at least 50% by weight of the treatment gel.
  • the gel may contain 0.0025 to 0.5% nanosilver particulate by weight of the medium.
  • the treatment gel contains human adipose-derived stem cells autologous to the human receiving the treatment.
  • the treatment gel may further include a culture medium, which may include one of Dulbecco's Modified Eagle's Medium or RPMI 1640 medium.
  • the gel may contain 0.0025 to 0.5% nanosilver particulate by weight of the medium.
  • the skin condition may include one or more of a wound, a scar, a blemish, acne, a stretch mark, or a wrinkle.
  • the invention includes a bandage that has a sterile dressing and a composition including a conditioned medium.
  • the conditioned medium may be a sterile dressing with the conditioned medium applied to the sterile dressing.
  • the conditioned medium may be contained in nanocapsules, and may be concentrated by centrifugal filtration prior to loading into the nanocapsules.
  • the nanocapsules may be applied to the sterile dressing as an aqueous suspension and air dried.
  • the nanocapsules may include nanoliposomes or polymer nanocapsules.
  • the invention includes a bandage that has a sterile dressing and a composition including a conditioned medium.
  • the conditioned medium may be dispersed in an emollient base and the emollient base applied to the sterile dressing.
  • the conditioned medium may be harvested from culture of human adipocyte-derived stem cells.
  • the conditioned medium may form about 40% by weight of the composition.
  • the stem cells may be cultured in Dulbecco's Modified Eagle's Medium or RPMI 1640 medium containing 0.0025 - 0.5% of a nanosilver particulate by weight.
  • the nanosilver particulate includes a stabilizing coating including one or more of citrate, tannic acid, polyvinylpyrrolidone, silica, polyethylene glycol, oligonucleotides, or a peptide.
  • the emollient base includes an oil and an emulsifying agent, with the oil forming about 5-20% by weight of the composition and the emulsifying agent forming about 10-20% of the composition.
  • the oil may include one or more of coconut oil, avocado oil, neem oil, rosemary oil, manuka oil, safflower oil, or geranium oil.
  • the sterile dressing includes a textile or a polymer.
  • the sterile dressing is a film, foam, semi-solid gel, pad, gauze, or fabric.
  • the bandage may also include a substance or element for the fixation of the bandage to a wound, such as a tie, an adhesive, a tape, a compression stocking, or an adherent gel.
  • the sterile dressing may have a wound- facing surface with a peripheral area and a central area. The peripheral area may include an adhesive, and the emollient base may be applied to the central area.
  • the sterile dressing includes a wound-facing surface, and the wound-facing surface includes an adhesive over substantially the entirety of the wound-facing surface.
  • the sterile dressing includes a second surface opposing the wound-facing surface, and the emollient base may applied to the second surface.
  • the invention also includes a method including the steps of applying to a wound a bandage that has a sterile dressing and a composition including a conditioned medium.
  • the conditioned medium may be dispersed in an emollient base and the emollient base applied to the sterile dressing.
  • the bandage is then secured to the wound.
  • the method also includes adding a liquid to the bandage before applying the bandage to the wound.
  • the composition is dried and the liquid rehyd rates the dried composition.
  • the emollient base su bstantially immobilizes the conditioned medium and the liquid elutes the conditioned medium from the bandage.
  • the wound may be any of a dermal wound, an epidermal wound, a burn, an infectious lesion, a surgical site, an ulcer, or a scar.
  • the invention also includes a bandage having a composition applied to a sterile dressing.
  • the composition has major components of about 5-30% by weight of an oil, about 10-30% by weight of an emulsifying agent, and about 40-60% by weight of a conditioned medium harvested from culture of human adipocyte-derived stem cells.
  • the composition may also include about 1-5% vitamin E or coconut oil.
  • the invention includes bandage that includes a sterile dressing and a conditioned medium applied to the sterile dressing.
  • the conditioned medium may be concentrated from media harvested from culture of human adipose derived stem cells.
  • the conditioned media may contain nanosilver.
  • the sterile dressing may include a flat flexible su bstrate having a first surface and a second surface parallel to the first surface.
  • the first surface may su pport a cathode and an anode.
  • the anode may include metallic zinc deposited on a first region of the first surface of the substrate and the cathode may include metallic silver deposited on a second region of the first surface of the substrate.
  • the first region does not overlap the second region.
  • the first region may include a first plurality of discrete spots, and the second region may include a second plurality of discrete spots.
  • the first plurality of discrete spots may be intercalated among the second plurality of discrete spots to form a regular array.
  • the invention includes a skin damage treatment device including a dressing and a conductive treatment gel.
  • the dressing has a cathode and an anode. Each of the cathode and the anode form an electrical half-cell,
  • the treatment gel has a human adipose-derived stem cell culture ("HADSCC") medium and a gelling agent.
  • the treatment gel has a viscosity of at least 3000 cP and ionic salts in the range of about 50 mEq/L to about 200 mEq/L.
  • the dressing further includes a flat flexible substrate having a first surface and a second su rface parallel to the first surface. The first surface supports the cathode and the anode, and the cathode and the anode include a first electrode and a second electrode. The second electrode forms a closed ring surrounding the first electrode.
  • the embodiments described may form the anode from a plurality of discrete anode spots.
  • the cathode includes a plurality of discrete cathode spots; the plurality of anode spots may be intercalated among the plurality of cathode spots.
  • the treatment gel may include at least 50% by weight of the HADSCC medium and at least about 0.5% by weight of a gelling agent. In some embodiments, the treatment gel includes at least 1.0% by weight of the gelling agent, and the gelling agent includes a hydroxymethyl cellulose or a
  • the invention includes a conductive treatment gel including a gelling agent of at least 0.5% by weight, a human adipose-derived stem cell, a culture medium, and ionic salts at a concentration of about 50 mEq/L to about 200 mEq/L.
  • the gelling agent may include a hydroxy methly I cellulose or a carboxymethyl cellulose and the gel may have a viscosity of at least 3000 cP.
  • the culture medium may include about 0.0025 to about 0.5% nanosilver particulate by weight.
  • the invention also includes a method of treating a skin condition in a human having steps of providing a treatment gel and a dressing.
  • the dressing includes complementary electrical half-cells.
  • the method has further steps of applying the treatment gel to the skin or to the dressing, and applying the dressing to the skin to be treated.
  • the gel contains one of a human adipose-derived stem cell conditioned medium or a human adipose-derived stem cell.
  • the gel may contain human adipose-derived stem cells autologous to the human, a culture medium, and about 0.0025 to about 0.5% nanosilver particulate by weight of the medium.
  • the invention also includes embodiments of a bandage having a sterile dressing; and a composition with a conditioned medium applied to the sterile dressing.
  • the conditioned medium may be contained in a plurality of nanocapsules.
  • the nanocapsules may be applied to the sterile dressing as an aqueous suspension and air dried.
  • the aqueous suspension may include a nanosilver particulate.
  • the conditioned medium may be dispersed in an emollient base with the emollient base applied to the sterile dressing.
  • the emollient base may include an oil and an emulsifying agent with the oil forming about 5-20% by weight of the composition and the emulsifying agent forming about 10-20% of the composition.
  • the conditioned medium may be harvested from culture of human adipocyte- derived stem cells and may form about 40% by weight of the composition.
  • the invention also includes a method of treating a wound including steps of applying the bandage as described above to the wound and securing the bandage to the wound.
  • the composition may be dried and the method also includes adding a liquid to the bandage to rehydrate the composition.
  • the invention includes a bandage having a sterile dressing and a composition consisting essentially of about 5-30% by weight of an oil, about 10-30% by weight of an emulsifying agent, and about 40-60% by weight of a conditioned medium harvested from culture of human ad ipocyte-de rived stem cells.
  • the invention includes a bandage having a sterile dressing and a conditioned medium applied to the sterile dressing.
  • the conditioned medium is concentrated from media harvested from culture of hu man adipose derived stem cells and includes a nanosilver particulate.
  • any of the described bandages may include a sterile dressing have a flat flexible substrate with a first surface and a second surface parallel to the first surface.
  • the first surface supports a cathode and an anode.
  • the cathode and the anode include a first electrode and a second electrode, and the second electrode forming a closed ring surrounding the first electrode.
  • Fig. 1 illustrates a prior art dressing including an array of cathodes and anodes.
  • Fig. 2 illustrates an embodiment of a dressing of the invention that includes an array of core- ring electrodes.
  • FIG. 3 illustrates steps of an embodiment of a method of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • a wound dressing typically includes a film, gel, foam, gauze, textile, polymer, or fabric.
  • Some dressings may include non-absorbable components such as silicone, polyacrylamide gels, conventional textiles, or PTFE.
  • Other dressings, particularly those used for internal wounds may include polymers that are naturally biodegradable in the body such as fibrin, PLGA, PGA, PLA, polycaprolactone or hyaluronic acid. Dressing may be designed to adhere or to remain free of the wound surface.
  • Dressings may be supplemented by creams, ointments, or included materials that promote healing or reduce infection.
  • This invention includes compositions applied to the dressings themselves that promote healing of skin damage to which the dressings are applied.
  • inflammation stage In the wound healing process, injured tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized.
  • Three major phases are an inflammation stage of zero to three days, a proliferation stage of three to twelve days, and a remodeling phase of a few days to six months or more.
  • platelet aggregation and clotting form a matrix which traps plasma proteins and blood cells and induces the in-migration of various cells from surrounding tissues.
  • cellular proliferation phase new connective or granulation tissue and blood vessels form.
  • remodeling phase granulation tissue is replaced by a network of collagen and elastin fibers producing scar tissue.
  • Each of these phases is at least partly dependent on signaling by growth factors produced by healing and adjacent tissue.
  • wound dressings include compositions that contain cell culture medium that has been conditioned by growth of human stem cells. These dressings supply exogenous growth factors derived from expansion of the stem cells in tissue culture. These exogenous growth factors can augment the response generated by the wound healing process itself.
  • growth of such adipose-derived stem cells includes supply of nutrients for the cells through provision of an aqueous culture medium.
  • Cells grown in culture deliver to the medium stem cell products including growth factors and cytokines as well as metabolic products.
  • Culture medium removed after exposure to cells includes stem cell products as well as residual components of the original medium, such as essential amino acids, salts, vitamins, minerals, trace metals, sugars, lipids, and nucleosides.
  • Cell culture medium attempts to supply the components necessary to meet the nutritional needs required to grow cells in a controlled, artificial and in vitro environment. Nutrient formulations, pH, and osmolarity may vary depending on the type of cell cultured, on cell density, and on the culture system employed.
  • Conditioned medium also contains a variety of cellular metabolites and secreted proteins, including, for example, biologically active growth factors, inflammatory mediators and other extracellular proteins.
  • suitable culture media are Dulbecco's Modified Eagle's Medium and RPMI 1640. Such media may be supplemented by other nutrients, growth supporting materials, or antibiotics as is known in the art.
  • An exemplary process of producing a human adipose derived stem cell conditioned (“HADSCC”) medium is that described in PCT US2014/034738, commonly assigned with this application, the specification of which is incorporated by reference.
  • the bandages of the invention include a HADSCC medium where the media is supplemented with nanosilver particulates before exposure to the human adipose-derived stem cell culture.
  • the stem cells are cultured in the presence of the nanosilver particulates.
  • Nanosilver can affect the healing of damaged tissue when applied during wound healing or burn healing. Nanosilver may also affect the growth of human adipose-derived stem cells in culture and their production of stem cell products including growth factors, cytokines, stress proteins, and nutrients.
  • HADSCC medium where the stem cells are cultured in the presence of the nanosilver particulates
  • HADSCC silver medium may contain a different mix of stem cell products than HADSCC minim m where the stem cells are cultured in the absence of the nanosilver particulates.
  • the media may be otherwise free of or have reduced amounts of antimicrobials such as antibiotics.
  • HADSCC silver medium (other than the presence of nanosilver and possible absence of antibiotics) may be prepared by a similar process to that of HADSCC media without nanosilver.
  • media harvested from stem cells cultured without nanosilver may be su pplemented with nanosilver after harvesting the conditioned media.
  • HADSCC medium (or HADSCC silver medium) may be further prepared by concentration or by nanoencapsulation or both. Concentration preparation steps reduce the amount of water in the medium and consequently concentrate the active components of the medium. This step may also serve to desalt the material by passing small ions. Concentration may be performed by any of a variety of methods known in the art, including centrifugal filtration, dialysis, tangential flow filtration, or exposure to water absorbing polymers.
  • HADSCC medium may be concentrated by centrifugal filtration using a Centricon ® or Microcon ® centrifugal filter devices according to the directions supplied with device by its manufacturer, EMD Millipore of Billerica, Massachusetts. Centricon ® and Microcon ® are registered trademarks of EMD Millipore. Using such a device, active components of the HADSCC medium may concentrated by from about five to about 200 times. We have found particular efficacy for subsequent processing when the active components of the HADSCC medium are concentrated about 50 times.
  • the media treated by this process (or any similar process known in the art) will be referred to as concentrated media, but unless indicated otherwise, subsequent use of the term HADSCC medium includes concentrated media as well as the HADSCC medium as harvested.
  • HADSCC media from cells cultured without nanosilver may receive nanosilver either before or after concentration.
  • HADSCC medium may be treated by nanoencapsulation to help enhance stability by protecting the HADSCC medium from exposure to environmental materials or conditions that may degrade the activity of the active materials.
  • Nanoencapsulation may also serve to control the release of active materials to a desired time (e.g. when exposed to a solvent) or at a desired rate.
  • Nanoencapsulation may be performed by any method known in the art, including those reviewed by Subhash Chandra Yadav, Avnesh Kumari, and Ramdhan Yadav in their paper entitled Development of peptide and protein nanotherapeutics by nanoencapsulation and nanobioconjugation published in Peptides 32 pp. 173-187 (2011). This review is hereby incorporated by reference for its disclosure of methods of nanoencapsulation.
  • a suitable method of nanoencapsulation includes emulsification polymerization using aqueous phase methacrylate monomer and a photoinitator such as benzoin ethyl ether emulsified with HADSCC medium with polyethylene oxide as a stabilizer and exposure to UV light after emulsification to produce poly(methacrylate) encapsulated active components of HADSCC medium.
  • the nanocapsules may range from about 50 to about 1000 nm in diameter. While the nanocapsules may be close to monodiserse (depending on the method of preparation), in some embodiments, the size of nanocapsules may be deliberately widely distributed to control the rate of release of active materials. Widely distributed populations of nanocapsules may be prepared by altering the conditions of emulsification during encapsulation or by mixing two or more batches of nanocapsules with different size.
  • nanoencapsulated HADSCC medium may be prepared as phospholipid nano-emulsions or nano-liposomes.
  • nanoencapsulated HADSCC medium may be prepared using the apparatus and method described in US patent publication 2008/0182019 entitled Hollow Microsphere Particle Generator. This publication is hereby incorporated by reference for its disclosure of methods of encapsulation of aqueous phase materials.
  • Nanoencapsules containing HADSCC medium may be washed by dialysis, by centrifugal filtration, by tangential flow filtration, or by centrifugation and decanting, or by other techniques known in the art, to produce washed nanoencapsulated HADSCC medium. Washing helps remove unreacted monomers or initiator as well as materials not incorporated in nanocapsules. Alternatively, and depending on the materials used in the encapsulation process, nanoencapsulated medium may be used without further processing. HADSCC media from cells cultured without nanosilver may receive nanosilver either before or after nanoencapsulation.
  • nanoencapsulated media may be resuspended in a buffer, in sterile saline, in water, or in a suspension containing other materials.
  • nanoencapsulated HADSCC media from cells cultured without nanosilver may be resuspended in buffer or solvent containing nanosilver.
  • nanoencapsulated HADSCC medium may be applied directly to wound dressings and dried in place, as by air drying.
  • the media encapsulated as described above (and by similar processes known in the art) will be referred to as nanoencapsulated media, but unless indicated otherwise, subsequent use of the term HADSCC medium (or media) includes nanoencapsulated media.
  • otherwise untreated HADSCC medium or concentrated HADSCC medium may be applied to wound dressings and dried in place.
  • these materials may be mixed with other materials such as nanosilver (in the case when the HADSCC media was derived from cu Iture without nanosilver), antimicrobials, antioxidants, or support materials such as thickeners that help to retain the materials in place.
  • nanosilver in the case when the HADSCC media was derived from cu Iture without nanosilver
  • antimicrobials in the case when the HADSCC media was derived from cu Iture without nanosilver
  • antioxidants or support materials such as thickeners that help to retain the materials in place.
  • compositions [0067] In other embodiments, HADSCC media (including HADSCC silver media), or
  • nanoencapsulated media may be mixed with other components prior to application to dressings or bandages.
  • These embodiments of the invention may include support ingredients such as oils, vitamins, and emulsifying agents.
  • Oils may include any of a variety of oils helpful to form an emulsion with the aqueous media components.
  • Exemplary oils include coconut oil, avocado oil, neem oil, rosemary oil, manuka oil, safflower oil, and geranium oil.
  • Emulsifying agents may include commercial cold process waxes such as Jeesperse ® CPW-CG-T (a mixture of cetyl alcohol, sodium acrylate, sodium acryloyl dimethyl taurate copolymer, glyceryl monostearate, and caprylic triglyceride). Jeesperse is a registered trademark of Jeen International Corporation of Fairfield, New Jersey. Other support ingredients may also be present.
  • the bandages may include ingredients that make them more suitable for treatment of burns as opposed to other wounds.
  • Bandages more suitable for treatment of burns include vitamin E (Tocopheryl Acetate) in amounts of from about 1-5% by weight of the composition.
  • Bandages more suitable for treatment of wounds may include coconut oil in amounts of from about 1- 5% by weight of the composition.
  • a suitable composition for inclusion in bandages includes about 40% to about 60% by weight of HADSCC media or HADSCC silver media. Oils may range 5-20% with emulsifying agents in the range of 10-20% of the mixture. The balance may be other aqueous ingredients such as aloe vera gel and other plant extracts.
  • HADSSC silver media may include especially complementary stem cell products.
  • nanosilver particulates have in some instances been associated with cytotoxic effects. These negative effects of nanosilver may be at least in part ameliorated by the growth factors contained in the HADSSC medium.
  • Dressings may take many forms, but a dressing is generally a flexible substrate, roughly planar, that conforms to the portion of the body including the wound and protects the wound from the environment. Dressings may hold the edges of wound together, absorb and remove fluids from a wound, add moisture when required, or help to contain and apply medications to the wound. Dressings are generally sterilized to avoid introducing infectious organisms. Any materials added to dressing must be capable of withstanding a sterilization procedure. Sterile dressings suitable for use in embodiments of the invention include textiles, polymers, or composites. Textiles may be woven, such as traditional gauze, or nonwoven sheet or web structures bonded together by entangling fiber or filaments.
  • the sterile dressing may be a polymer film, foam, semi-solid gel, or pad.
  • Suitable composite materials may include multi-layer assemblages of absorbent, bibulous, or hydrophilic materials covered by protective layers that may either pass or prevent passage of moisture.
  • the wound-facing surface may include a polymer gel that prevents adherence to the wound.
  • the bandage may also include a substance or element for fixing of the bandage to a wound, such as a tie, an adhesive, a tape, a compression stocking, or an adherent gel.
  • the sterile dressing may have a wound-facing surface with a peripheral area and a central area.
  • the protective layers may extend beyond the boundary of the absorbent, bibulous, or hydrophilic materials or of a nonadherent wound-facing surface in a peripheral region that includes adhesives to hold the bandage in position.
  • the emollient base containing the HADSCC medium may be applied to the central area.
  • the sterile dressing may include a wound-facing surface that includes an adhesive over substantially the entirety of the wound-facing surface.
  • the sterile dressing includes a second surface opposing the wound-facing surface, and the emollient base may applied to the second su rface. This embodiment may be used primarily to bring together edges of a wound, so adhesive may be required over the entire surface.
  • the invention also includes a method including the steps of applying to a wound a bandage that has a sterile dressing and a composition including a conditioned medium.
  • the conditioned medium is dispersed in an emollient base and the emollient base is applied to the sterile dressing.
  • the bandage is then secured to the wound.
  • the method also includes adding a liquid to the bandage before applying the bandage to the wound.
  • the composition is dried and the liquid rehyd rates the dried composition.
  • the emollient base substantially immobilizes the conditioned medium and the liquid elutes the conditioned medium from the bandage.
  • the wound may be any of a dermal wound, an epidermal wound, a burn, an infectious lesion, a surgical site, an ulcer, or a scar.
  • the invention also includes electroactive dressings treated with a conditioned medium or with cells.
  • the electroactive dressings function, when wetted by a conductive fluid such as the treatment gels of the invention, as electrical batteries that cause a flow of current between the different electrodes.
  • the current is not limited to the dressing but flows in a response to electrical fields determined by the geometry of the electrodes and of the dressing as applied to the skin.
  • the current flows are generally below the level of human perception as they are limited in magnitude to the order of microamperes. These currents, and the voltages that produce them, aid healing by, among other possible mechanisms, encouraging the migration of cells into the treated region.
  • the currents may include currents of ions, such as silver ions, that have antimicrobial or wound treatment properties.
  • HADSCC medium may be dried onto an electroactive dressing.
  • a preferred drying process includes adding the medium to the dressing while the medium is at low temperature, preferably about 4° Celsius.
  • the dressing may then be rapidly frozen and then dried so as to prevent extended oxidation and reduction of the electrodes.
  • the dressing with dried HADSCC medium may be applied to the skin with a conventional conductive gel composition.
  • the HADSCC medium may be nanoencapsulated as described for other embodiments.
  • the conditioned medium may be dispersed in an emollient base and the emollient base applied to the sterile electroactive dressing.
  • the emollient base containing the nanoencapsulated HADSCC medium may be dried onto an electroactive dressing as described above.
  • the invention includes treatment gel suspensions containing ionic conductive materials in combination with a microcurrent-providing membrane.
  • the currents are produced when electrodes from complementary half cells within a dressing are joined by the gel into a battery; electrical fields from these batteries extend into tissue under treatment.
  • the gel may include an HADSCC medium.
  • the gels may include living adipose-derived stem cells and a support medium.
  • Complementary electrical half-cells are half cells that include at least two electrodes with different electrochemical potentials under operable conditions. Operable conditions means when the half cells are co-wetted by an ionically conductive fluid such as the described treatment gels of the invention.
  • Fig. 1 illustrates a prior art electroactive dressing useful in some embodiments of the invention.
  • Dressing 10 includes a flexible sheet having front surface 14 and rear surface 19 parallel to front surface 14.
  • Dressing 10 is thin with respect to its linear extent. Its thickness may be about 0.030 inches.
  • Dressing 10 may be bibulous and porous to promote wetting by the treatment gel and to retain electrode materials.
  • Front surface 14 includes two types of electrodes formed by deposition of metal. The metal may be deposited as particulate suspensions by conventional printing processes. The particulates may be entrapped within the interstices of the porous body or may be attached to the su rface of the body through the use of binding agents within the suspensions.
  • the invention includes a dressing that may be similar to that of Fig. 1.
  • Multiple first electrodes 18 form a regular array of spots interspersed or intercalated with multiple second electrode spots 16. While the illustrated embodiment shows electrodes 18 of different size from electrodes 16, this arrangement depends on the relative surface area of the individual particulates.
  • the spots may of similar sizes or the spots may include more complex geometry such as the small void visible in the center of each first electrode 18. The spacing of the spots may be about 0.5 to about 5 mm.
  • Fig. 2 illustrates a second electroactive dressing useful in some embodiments of the invention.
  • Dressing 20 is similar to dressing 10 except that the distribution of metallic electrodes differs from that of dressing 10.
  • Dressing 20 includes a flexible sheet having front surface 28 and rear surface 29 parallel to front surface 28.
  • the flexible sheet of dressing 20 may be hydroph ilic to help retain aqueous liquids in close proximity to the metallic electrodes.
  • Suitable materials include cellulosic materials such as gauze fabric or paper, glass fiber materials, or hydrophilic polymers such as acrylics, nylons, other polymers treated to provide a hydrophilic surface, or a combination of any of these materials.
  • first electrodes 22 may be deposited in a regular array of spots.
  • first electrodes 22 may be deposited in a rectangular grid.
  • Second electrodes 24 are deposited as a rectangular grid of circles, with each second electrode 24 surrounding one of the first electrodes 22. Additional first electrodes are deposited as spots 26 in a second rectangular grid offset from the grid of first electrodes 22.
  • Dressing 22 when wetted by a conductive treatment gel, may produce a different pattern of voltages and currents that may be more appropriate for some skin conditions than dressing 10. The choice of dressing may depend in part on the desired depth of the treatment area of the affected skin. Without intent to be bound by theory, Inventors believe that the structure of dressing 20 causes a deeper penetration of electric fields into tissue underlying dressing 20 than does dressing 10.
  • the currents produced by suitably applied dressings may decrease over time as the available material of the electrodes is either oxidized or reduced.
  • the integrated current (over the application period of the dressing) may be controlled by adjusting the size of one or both of the electrodes. A smaller electrode is more rapidly depleted, so that a dressing including smaller electrodes delivers less current over the life of the dressing. On the other hand, a smaller electrode permits more precise targeting of the electric field because of the dominance of fringing field effects.
  • the individual electrodes may be between about 0.1 mm and 10 mm in diameter. In some embodiments, electrode feature size (diameters of spots and width of lines or rings) may be about 0.5 mm.
  • the intensity and duration of the current may also be adjusted to some extent by the depth of deposition of the electrode materials. This in turn depends on both the thickness of the dressing and on the distribution of electrode materials in that depth. A thicker dressing can hold more electrode materials, but some of the materials are thereby more distant from the treated site, decreasing the effective penetration depth of the electric field. Further, thick materials are generally less flexible and more difficult to apply comfortably to a treated area, though they may have greater mechanical durability for longer term use.
  • dressing thickness may be about 0.003 to about 0.050 inches. Short term dressings (generally intended for one day or less of application) may have thicknesses of about 0.003 to about 0.02 inches. Longer term dressings (intended for more than one day of treatment before changing) may have thickness of about 0.02 to about 0.05 inches.
  • compositions of the invention also include treatment gels that are applied between electroactive dressings and the skin to be treated. These compositions and dressings may need to remain in place for hours or days at a time. Accordingly, the compositions contain thickening or gelling agents that serve to reduce flow and evaporation and retain the compositions in proximity to the application site.
  • Appropriate thickening or gelling agents include methylcellulose, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, among others.
  • the weight proportions of thickening or gelling agents depends on the particular properties of the materials. Gelling agents may be used concentrations of 0.5% to 10%, depending on the agent.
  • type 7H3SXF of Aqualon ® CMC brand of sodium carboxymethylcellulose available from Hercules Incorporated of Wilmington, Delaware may be mixed at a weight concentration 1.00%. Aqualon is a registered trademark of Hercules Incorporated.
  • the compositions include a treatment gel that has a viscosity of 3000cP.
  • the viscosity may be higher, ranging between about 5000 and about 20000cP.
  • the choice of viscosity depends on the nature of the dressing, the extent of the skin treatment area, the length of time the dressing is to be applied between changes, and the environmental conditions. In dry or hot conditions where the dressing is expected to remain in place for extended periods (one day or longer), a higher viscosity is advantageous because it reduces liquid loss. For shorter durations and for small areas, a lower viscosity is preferred because it may be more easily and comfortably applied.
  • the treatment gel may contain additional ingredients such as antimicrobials, added growth factors, peptides, emollients, oils, or emulsifying agents.
  • Antimicrobials include nanosilver materials or antibiotics and serve to prevent growth of infectious agents or other bacteria. Nanosilver materials may also serve to more directly promote healing.
  • the treatment gel may contain 0.0025 to 0.5% nanosilver particulate by weight of the gel. In embodiments containing culture medium (including HASCC medium) nanosilver may be present in similar concentration by weight of the medium rather than of the treatment gel as a whole.
  • the balance of the treatment gels may include other materials such as those detailed in the Examples.
  • a composition used in combination with an electroactive dressing needs to provide a conductive electrical path between the half cells of the dressing and between the dressing and the skin.
  • the ionic concentration may be approximately that of human interstitial fluid or of human blood, ranging about 50 mEq/L to about 200 mEq/L and in some embodiments about 140 mEq/L sodium chloride equivalent.
  • the compositions may be diluted with deionized water or augmented with sodium chloride or other ionic components to adjust the final concentration to within this range.
  • the compositions of the invention contain relatively large concentrations (exceeding 50%) of HADSCC Media and other components having appreciable ionic concentration. We have found that no adjustment is required for some embodiments.
  • Silver is an effective killing agent against many types of bacteria, viruses, and fungi. It is widely used as a microbicide, as a preservative, and as a deodorant. Both preservative and deodorant properties are commonly ascribed to its microbicidal activity. Silver may also enhance the antibacterial activity of various antibiotics such as penicillin, erythromycin, and vancomycin. Reduced silver particles with size range below about 100 nm are commonly called nanosilver. Nanosilver particles frequently are capped with surface chemical groups that support their stability and dispersion in aqueous suspension.
  • Nanosilver dispersions have anti-inflammatory activity in human application; nanosilver may alter the expression of enzymes that are important in inflammatory and tissue repair processes, such as matrix metallo-proteinases.
  • nanosilver can modulate cytokines involved in wound healing such as by suppressing expression of interleukin (IL)-12, and IL-1 and of TNF-a, and it may induce apoptosis of inflammatory cells.
  • IL interleukin
  • the magnitude of the anti-inflammatory effects of nanosilver is related to the exposure of the treated tissue to reduced silver atoms and thus on a per gram basis depends on the size of the nanosilver particulates.
  • the enhanced effects from smaller particles may be greater than linear with surface area as particles approach a few hundred atoms due to quantum confinement effects. To some extent the effects also depend on the shape of the particles as different shapes expose different crystalline planes with different packing density of silver atoms. The size producing an optimum combination of properties depends on the particular microenvironment, the tissue treated, and the effect measured.
  • the invention includes a treatment gel composition that includes a conditioned medium and a nanosilver particulate.
  • the conditioned medium may be harvested from culture of human adipocyte-derived stem cells.
  • the stem cells may be cultured in the presence of the nanosilver particulate.
  • the culture medium may include one of Dulbecco's Modified Eagle's Medium or RPMI 1640 medium containing 0.0025 - 0.5% nanosilver particulate by weight of the medium.
  • the stem cells are cultured in medium that does not contain a nanosilver particulate. Instead the conditioned medium is compounded with the nanosilver particulate after the media is harvested from the stem cell culture.
  • the nanosilver particulate may form about 0.001 - 0.2% by weight of the composition.
  • the nanosilver particulate includes a stabilizing coating, such as a coating including one or more of citrate, tannic acid, polyvinylpyrrolidone, silica, polyethylene glycol, oligonucleotides, or a peptide.
  • the nanosilver particulate may include silver particles have a size range of about 1-10 nm.
  • the treatment gels of the invention include an HADSCC medium where the media is supplemented with nanosilver particulates before exposure to the human adipose- derived stem cell culture.
  • the stem cells are cultured in the presence of the nanosilver particulates.
  • nanosilver can affect the healing of damaged tissue when applied during wound healing or burn healing, so also may nanosilver affect the growth of human adipose-derived stem cells in culture and their production of stem cell products including growth factors, cytokines, stress proteins, and nutrients.
  • HADSCC medium where the stem cells are cultured in the presence of the nanosilver particulates
  • HADSCC silver medium may contain a different mix of stem cell products than HADSCC medium where the stem cells are cultured in the absence of the nanosilver particulates.
  • the media may be otherwise free of or have reduced amounts of antimicrobials such as antibiotics.
  • HADSCC silver medium (other than the presence of nanosilver and possible absence of antibiotics) may be prepared by a similar process to that of HADSCC media without nanosilver.
  • the treatment gels may include a HADSCC medium where the media is compounded with nanosilver particulates after the media is harvested.
  • Both embodiments containing HADSCC silver media and those containing HADSCC media compounded with nanosilver particulates after the media is harvested contain nanosilver particulates as well as stem cell products, but the mixture of stem cell products may differ because of the effect of the nanosilver particulates during the growth of the stem cells.
  • the treatment gels include autologous human adipose-derived stem cells supported in a culture medium.
  • the cells may be present at a concentration that ranges from about 103 to about 107 cells per mL and in some embodiments from about 5 x 105 to about 3 x 106 cells per mL.
  • the cells may be cryopreserved but are preferably freshly harvested from culture vessels immediately before use.
  • Gels containing living cells may include added culture medium (without any serum products) to support the cells and antioxidant preservatives such as ascorbic acid. Examples of suitable culture media are Dulbecco's Modified Eagle's Medium and RPMI 1640. Such media may be su pplemented by other nutrients, growth supporting materials, or antibiotics as is known in the art. However such culture media do not contain any serum products, including any bovine fetal calf serum.
  • the invention includes a method of treating a skin condition in a human.
  • the steps of the method 100 are illustrated schematically in Fig. 3.
  • a treatment gel an electroactive dressing as described above provided.
  • a user applies the treatment gel either to the surface of the skin to be treated or to the surface of the dressing containing the electrodes.
  • the user applies the dressing to the skin.
  • the dressing may be fastened by any of a number of methods known in the art such as by using an adhesive tape or by a overwrapping bandage.
  • the skin condition treated may be any of a broad variety of conditions including wounds, scars, blemishes, acne, stretch marks, or wrinkles.
  • the listed ingredients are typically combined in a cleaned and sterilized tank with moderate mixing or in smaller batches in sterile disposable labware.
  • the ingredients may be added in the order listed, one at a time, mixing well between additions.
  • the first two examples are formulations for conductive treatment gels to be applied between treated skin and electroactive dressings as disclosed above.
  • the third example describes a process of producing nanoencapsulated HADSCC medium and applying it to dressings.
  • the final two examples describe emollient treatment compositions for application to dressings as disclosed above.
  • Acetyl Hexapeptide-8 (Argireline) 5-10.0%
  • Niacinamide (Vitamin B3) 1-3.0 %
  • EGF-l(Human Oligopeptide-1) 0.001-0.01%
  • nanoencapsulated medium may be applied directly to wound dressings and dried in place, as by air or vacuum-assisted drying.
  • the application process (as well as all processing steps for the HADSCC medium and the subsequent encapsulation and any wash steps take place under sterile conditions (as in a laminar hood or sterile clean room).
  • component materials or the finished product or packaging may be subject to sterilization steps. Such steps are well known in the art and will not be further discussed.
  • Nanoencapsulated media are prepared by harvesting HADSCC medium, concentrating the harvested medium by centrifugal filtration, and nanoencapsulating the concentrated medium. The nanoencapsulated media is subsequently washed, with the nanocapsules resuspended in an application buffer.
  • the treated gauze may be packed as a sterile dressing and applied directly to a wound or may first be moistened with sterile water (about O.lmL per cm2).
  • Example 4 Composition applied to dressings
  • the listed ingredients are typically combined in a cleaned and sterilized tank with moderate mixing or in smaller batches in sterile disposable labware.
  • the ingredients may be added in the order listed, one at a time, mixing well between additions.
  • the ingredients may be subject to mechanical emulsification during processing.
  • the HADSCC media may include nanosilver as discussed above and may include the HADSCC media as a suspension of nanoencapsulated media as described in example 3.
  • Niacinamide (Vitamin B3) 5-10%
  • Example 5 Composition applied to dressings for burns
  • the listed ingredients are typically combined in a cleaned and sterilized tank with moderate mixing or in smaller batches in sterile disposable labware.
  • the ingredients may be added in the order listed, one at a time, mixing well between additions.
  • the ingredients may be subject to mechanical emulsification during processing.
  • the HADSCC media may include nanosilver as discussed above a nd may include HADSCC media as a suspension of nanoencapsulated media as described in example 3.
  • Niacinamide (Vitamin B3) 5-10%

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Abstract

Le dispositif selon l'invention comprend des pansements ayant une cathode et une anode, chacun formant une demi-cellule électrique, et un gel de traitement conducteur contenant des milieux HADSCC. Le gel de traitement peut également contenir des cellules souches dérivées de tissu adipeux humain. Le procédé comprend la fourniture d'un gel de traitement et d'un pansement, l'application du gel de traitement sur la peau ou le pansement, et l'application du pansement sur la peau. D'autres modes de réalisations concernent des pansements combinant des pansements stériles avec une composition comprenant un milieu conditionné. Le milieu conditionné peut être nano-encapsulé ou peut être dispersé dans une base émolliente et appliqué sur le pansement stérile.
PCT/US2016/048495 2015-08-24 2016-08-24 Pansements et aides à la cicatrisation de lésion cutanée WO2017035280A1 (fr)

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US201562209324P 2015-08-24 2015-08-24
US201562209319P 2015-08-24 2015-08-24
US62/209,324 2015-08-24
US62/209,319 2015-08-24

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WO2020130800A1 (fr) * 2018-12-21 2020-06-25 Cytonex Sdn. Bhd. Milieu conditionné de cellules souches

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* Cited by examiner, † Cited by third party
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US4022204A (en) * 1974-11-21 1977-05-10 Warner-Lambert Company Dimensionally stable shaped eye bandages
US4361552A (en) * 1980-09-26 1982-11-30 Board Of Regents, The University Of Texas System Wound dressing
US5705485A (en) * 1987-09-18 1998-01-06 Ethicon, Inc. Gel formulations containing growth factors
US20050192636A1 (en) * 2004-02-19 2005-09-01 Silverleaf Medical Products, Inc. Batteries and methods of manufacture and use
WO2008060374A2 (fr) * 2006-10-06 2008-05-22 University Of Virginia Patent Foundation Procédés et compositions utiles pour une cicatrisation de plaie chez les diabétiques
US20080206171A1 (en) * 2007-02-26 2008-08-28 L'oreal Conditioned medium and uses thereof
US20110091572A1 (en) * 2008-06-05 2011-04-21 Davidson Richard E Acne treatment compositions comprising nanosilver and uses
US20120195969A1 (en) * 2010-09-29 2012-08-02 Aidan Research And Consulting, Llc Treatment of acne by conditioned media
US20140348911A1 (en) * 2011-08-08 2014-11-27 Pontificia Universidad Catòlica De Chile Spray formulation of mesenchymal stem cells for the treatment of chronic wounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020130800A1 (fr) * 2018-12-21 2020-06-25 Cytonex Sdn. Bhd. Milieu conditionné de cellules souches

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