WO2016192571A1 - 作为再生性皮肤替代物的多功能皮肤或创面复合敷料 - Google Patents

作为再生性皮肤替代物的多功能皮肤或创面复合敷料 Download PDF

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WO2016192571A1
WO2016192571A1 PCT/CN2016/083460 CN2016083460W WO2016192571A1 WO 2016192571 A1 WO2016192571 A1 WO 2016192571A1 CN 2016083460 W CN2016083460 W CN 2016083460W WO 2016192571 A1 WO2016192571 A1 WO 2016192571A1
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Prior art keywords
wound
dressing
skin
dressing material
composite dressing
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PCT/CN2016/083460
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English (en)
French (fr)
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陈晓英
熊光明
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陈晓英
熊光明
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Priority to EP16802494.1A priority Critical patent/EP3305335A4/en
Publication of WO2016192571A1 publication Critical patent/WO2016192571A1/zh
Priority to US15/822,020 priority patent/US20180085486A1/en

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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
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/225—Mixtures of macromolecular compounds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • 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
    • A61L15/18—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing inorganic materials
    • 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
    • A61L15/425—Porous materials, e.g. foams or sponges
    • 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
    • A61L15/52—Water-repellants
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds

Definitions

  • the present invention relates to a skin or wound protection and healing material, and a preparation method and method thereof, in particular to a multifunctional skin or wound dressing as a regenerative skin substitute and its use in regenerative medicine, wound care, wound care, medical beauty Applications in other fields.
  • Wound healing is a very orderly and complex process.
  • Acute wound healing usually follows a well-defined procedure, which is described as follows: coagulation; inflammation; cell proliferation and matrix repair; epithelialization and reconstruction of scar tissue. These responses are regulated by cytokines, chemokines, and growth factors, as well as the effects of these factors on cellular receptors. The shape and location of the wound determines whether the wound will heal well. Interference with wound healing can also lead to complications. These factors may include malnutrition, reduced blood supply, tissue trauma, denervation, and infection. Complications that may be caused include hypertrophic scars and keloids, contractures, splits, granulation and adhesions.
  • Chronic wounds are the result of a process that does not restore inadequate repair of anatomical and functional integrity over a suitable length of time. Chronic wounds are rare in otherwise healthy individuals. In fact, patients with chronic wounds often have chronic diseases such as diabetes, obesity, cardiovascular disease, kidney disease and cancer. Chronic wounds are often disguised as comorbidities. In fact, it is a silent epidemic that affects a significant portion of the world's population and poses a significant and growing threat to global public health and the economy.
  • Diabetic foot ulcers have long-term unhealed, especially in patients with neuropathy/peripheral vascular disease. The serious consequence is amputation. It is estimated that there are more than one million diabetic patients requiring amputation each year worldwide, which means that one amputation occurs in the world every 30 seconds. The five-year survival rate after amputation at one end is only 50%.
  • chronic wound care such as hemorrhoids and extremity ulcers, which are closely related to the elderly, has become an increasingly serious health problem in the West. It is said that the United States is governing every year. Chronic wounds cost up to $25 billion (Brem H et al., Molecular Medicine 2007; 13:30-9). In addition to developed countries such as the United States, the incidence of diabetes and obesity has risen sharply around the world. Due to increased health care costs and an aging population, the burden of treating chronic wounds is growing rapidly.
  • Chronic venous insufficiency accounts for 80%-90% of lower extremity ulcers and affects 2%-5% of the population (Kane DP, chronic wound healing and chronic wound management, from: Chronic Wound Care: Clinical Originality of Healthcare Professionals Information Book, Fourth Edition, Malvern, PA: HMP Communications; 2007: 11-23).
  • Other types of unhealed wounds are surgery, diabetes, arteries, burns, dermatitis, vasculitis, and radiation.
  • chronic wounds are characterized by long-term inflammation, bacterial bioburden, and ischemia.
  • there are multiple components that are not conducive to healing such as high levels of inflammatory cytokines, proteases, and low levels of growth factors. These changes terminate the healing process and increase the likelihood of septic infections. Therefore, solving the problem that may cause physiological wound changes can restart the healing process.
  • wound care products there are a variety of wound care products on the market, including basic wound care products (bandages, dry dressings, cleansing); advanced wound care products (films, foam dressings, collagen, alginates, hydrocolloids, hydrogels) , superabsorbent); bioactive wound care products (artificial skin and skin substitutes); and therapeutic equipment (negative pressure wound therapy, decompression, electrostimulator, ultraviolet therapy, oxygen and hyperbaric chamber equipment) , vortex therapy device, electromagnetic therapy device and ultrasound therapy device, etc.).
  • basic wound care products bandages, dry dressings, cleansing
  • advanced wound care products films, foam dressings, collagen, alginates, hydrocolloids, hydrogels
  • bioactive wound care products artificial skin and skin substitutes
  • therapeutic equipment negative pressure wound therapy, decompression, electrostimulator, ultraviolet therapy, oxygen and hyperbaric chamber equipment
  • vortex therapy device electromagnetic therapy device and ultrasound therapy device, etc.
  • topical treatment of wound beds is the most important aspect of wound care.
  • a wide variety of topical wound care products have been developed to address the different components of complex wound healing processes, including antibacterial/anti-infective wound dressings, wet wound dressings, bioactive substances such as growth factor-containing creams, Acellular matrix of preserved extracellular biologically active factors, amnion and living cell-based skin substitutes.
  • dressings that promote a moist wound environment include films, foams, alginates, hydrocolloids, hydrophilic fibers, and hydrogels. The hydrocolloid achieves a moist wound environment by fluid gelation of the wound surface on the wound bed.
  • Foam has better absorption capacity than film and hydrocolloid; however, there is less exudate in the wound or has been treated by treatment In rare cases, some foams other than those believed to be "non-invasive" have the disadvantage of adhering to a wound bed.
  • the undissolved dissolved hydrocolloid matrix looks like pus or infection; and it typically produces a characteristic odor.
  • Hydrocolloid dressings, pastes, and powders are difficult to remove from the body cavity and the wound that has formed the sinus. When in contact with the wound fluid, the alginate transitions from the fiber to a gel that provides non-adhesive wound contact and a moist environment for healing.
  • Hydrogels contain high moisture in the gel lattice, so they are not only non-adherent, but also provide sufficient moisture for the wound. However, hydrogels require a secondary dressing. If used improperly or if the dressing is not changed in time, the alginate is at risk of being supersaturated, which may impregnate the surrounding skin or may dry out and adhere to the wound tissue.
  • Live cell-based skin substitutes eg, APLIGRAF, DERMAGRAFT, etc.
  • APLIGRAF eg., APLIGRAF, DERMAGRAFT, etc.
  • a well-prepared wound bed no infection and healthy granulation tissue.
  • wounds usually have concurrent long-term inflammation, ischemia, irritability/unviable tissue/fibrous tissue, carrion, large exudates, and antibiotic-resistant bacterial organisms. membrane.
  • transplanting expensive skin substitutes even when combined with other advanced forms of wound care
  • the proper handling and operation of many bioactive wound care products and medical devices requires extensive technical training for health care workers, sometimes surgeons, and most often nurses and/or home caregivers.
  • the existing market still has great demand for high-end advanced, high-performance, cost-effective skin regeneration, wound healing innovative materials and innovative products, in order to simplify and smooth out the whole wound care treatment process, simplifying and simplifying, speeding up healing and preventing Amputation, reduce scarring, improve healing quality, thereby reducing patient suffering and financial burden on the medical system.
  • the present invention provides innovative dressing materials that can be used to protect the skin and heal various acute and chronic wounds.
  • the dressing is a novel composite material with bionic skin for effective protection of the skin and body surface wound beds.
  • the properties and properties of the substitute are soft and flexible to conform to the rugged contour of the wound bed. They do not adhere to the wound bed during the replacement without damaging the new tissue, do not disturb the healing dynamics, and protect the basal nerve of the wound.
  • the tip reduces pain.
  • it acts as a semi-closed, breathable bionic skin barrier to create an ideal moist-balanced local microenvironment that facilitates healing of the wound.
  • the dressing material of the present invention also has a plurality of functions: enabling non-invasive/non-surgical self-dissolution to debride inactivated or necrotic tissue to control microbial infection and reduce the biological burden of the wound while allowing healthy living tissue in the body. Minimizes damage, provides antioxidant soothing and stimulates microcirculation and tissue regeneration, including capillary and nerve regeneration.
  • the dressing materials of the present invention have been clinically proven to accelerate the healing of acute and chronic wounds, and achieve superior healing quality and minimize scar formation.
  • a skin or wound composite dressing material comprises at least one active layer, the substrate of the active layer is a porous polymer, and the porous polymer substrate is impregnated with a semi-solid hydrophobic composition; wherein the semi-solid hydrophobic composition comprises a fatty acid and Solid inorganic particles embedded in a porous polymer substrate.
  • the semi-solid hydrophobic composition is mechanically processed so that the fatty acid is substantially uniformly impregnated into the porous polymer substrate, and the solid inorganic particles are substantially uniformly embedded in the porous polymer substrate.
  • the semi-solid hydrophobic composition is substantially uniformly impregnated into the polymeric substrate to collectively form a substantially uniform layer having a thickness of from 0.1 to 10 mm.
  • the porous polymer has a network structure, and the material constituting the network structure itself includes fibers having a bundle structure, and the fibers of each bundle structure are composed of a plurality of microfibrils.
  • microfibrils have a gap between each other.
  • the microfibril cross section has a maximum diameter of 0.01-20 microns.
  • the porous polymer may be selected from the group consisting of cotton, silk, linen, polyester, nylon, polyamide, polypropylene, polyurethane, polytetrafluoroethylene, viscose, bamboo fibrils, bamboo pulp fibers, corn.
  • the semi-solid hydrophobic composition contains less than 5% by weight of the total weight of the composite wound dressing.
  • the semi-solid hydrophobic composition further comprises one or more of a curing agent, a bioabsorbable composition, and a hydrocolloid.
  • the concentration of the fatty acid is from 20 to 80% by weight based on the total weight of the composite wound dressing.
  • the solid inorganic particles may be selected from the group consisting of talc, silica, alumina, magnesia, zinc oxide, iron oxide, zinc carbonate, calcium carbonate, calcium chloride, calcium phosphate, calcium sulfate, and One or more of titanium dioxide.
  • the solid inorganic particles have an average size of from 0.01 to 50 microns, or at least 80% of the solid inorganic particle size is less than 50 microns or 30 microns.
  • the concentration of the solid inorganic particles is 20-80% of the total weight of the composite wound dressing.
  • the composite wound dressing can accelerate the softening or liquefaction of necrotic tissue or eschar on the wound surface, thereby causing the wound to be self-dissolving and debriding within 1-4 days.
  • the composite dressing material comprises at least two separate layers, wherein the first layer comprises a porous polymeric substrate impregnated with a semi-solid hydrophobic composition and the second layer comprises a hydrophilic composition Polymer substrate.
  • the hydrophilic composition preferably comprises a hydrocolloid such as a modified cellulose such as carboxymethylcellulose and hydroxyethylcellulose or alginate, chitin, chitosan and hyaluronic acid. combination.
  • a hydrocolloid such as a modified cellulose such as carboxymethylcellulose and hydroxyethylcellulose or alginate, chitin, chitosan and hyaluronic acid. combination.
  • the composite dressing material comprises at least two separate layers, wherein the first layer comprises a porous polymeric substrate impregnated with a semi-solid hydrophobic composition and the second layer comprises a porous foamed polymeric substrate.
  • a skin or wound composite dressing kit comprising the composite dressing described above; and an outer package housing encasing the dressing material.
  • kit further includes a first protective sheet covering the wound-facing side of the active layer of the composite wound dressing, and/or an adhesive material for securing the dressing material to the skin of the mammal.
  • a method of preparing a skin or wound composite dressing impregnating a porous polymeric substrate with a semi-solid hydrophobic composition comprising a fatty acid and solid inorganic particles such that the solid inorganic particles are substantially uniformly Embedded in a polymer substrate.
  • the preparation method comprises: processing and grinding solid inorganic particles, and then adding to a fatty acid, heating and stirring to form a hydrophobic composition which is semi-solid at room temperature; semi-solid After the hydrophobic composition is melted by heating, it is uniformly injected into one or several layers of the porous polymer substrate by a machine, and cooled to room temperature to prepare a composite dressing material.
  • a method of treating a wound of a mammal using a skin or wound composite dressing comprising: positioning the composite dressing material described above to contact the wound site, and applying the dressing material Immobilized on the skin of a mammal.
  • Types of wounds include, but are not limited to, acute surgery and traumatic wounds, burns (such as heat, electrical burns, radiation, chemistry, frost and chills, and sunburn), diabetic ulcers, venous ulcers, arterial ulcers, pressure ulcers (or Skin ulcers known as acne ulcers or acne, mixed causes, for example, consisting of diabetes, cardiovascular disease, peripheral vascular disease, vasculitis, central or peripheral nerve injury, kidney disease, autoimmune disease, and cancer Ulcers, fistulas, skin fissures caused by two or more diseases in a group (caused by eczema, contact dermatitis, psoriasis/psoriasis, folliculitis, acne, lupus, herpes zoster, etc.) As well as other chronic or necrotic wounds and inflammatory lesions and conditions.
  • burns such as heat, electrical burns, radiation, chemistry, frost and chills, and sunburn
  • diabetic ulcers such as heat, electrical
  • the materials according to the invention are primarily intended to treat both infectious and non-infectious wounds (i.e., wounds that do not show clinical signs of infection).
  • Wounds are not limited to open skin rupture wounds, but also include skin intact but damaged skin and/or subcutaneous tissue, such as radioactive radiation (such as cancer radiotherapy) or other energy exposure, caused by internal or surface surgery. Inflammation of the skin, tissue fibrosis, rash, redness or edema. It can also be used for the prophylactic treatment of skin lesions.
  • the invention dressing can be applied to the affected skin site in advance, and then energy therapy can be applied to prevent or reduce tissue inflammation, fibrosis, or other forms of damage caused by energy irradiation. .
  • the dressing material can be used as a primary dressing in direct contact with the wound bed or in combination with other wound treatments throughout the treatment, such as with bioactive cell-based wound dressings, autologous or allogeneic skin grafts (including auto/allogene skin grafts) ), combined with removal of cell matrix, amniotic membrane, negative pressure wound therapy and hyperbaric oxygen therapy.
  • the innovative dressing material of the invention is quick and easy to use, and can be replaced by a non-stick wound, without cumbersome machine-assisted treatment and technical training. It can be widely used in hospitalization, outpatient treatment, rehabilitation nursing homes, nursing homes, home care, and extreme situations such as field and battlefield ambulance. Due to its excellent curative effect and healing effect, the invention's products are especially suitable for high-end specialist wound healing centers, diabetes management centers, professional burn centers, plastic surgery, dermatology, medical beauty hospitals, etc.
  • Figure 1 is a schematic view showing the structure of a sheet type embodiment of the dressing material of the present invention.
  • A Schematic diagram of the main view structure.
  • B Schematic diagram of longitudinal section structure;
  • C Schematic diagram of the structure of the fiber 21 in FIG. 1A and FIG. 1B.
  • Figure 2 shows the microstructure of an embodiment of the dressing material of the present invention presented under a scanning electron microscope.
  • A a network structure of a porous polymer substrate under a 50 ⁇ m scale
  • B a bundle structure of microfibrils in a porous polymer substrate under a 10 ⁇ m scale.
  • Figure 3 illustrates the treatment of a patient with a burn wound using an embodiment of the dressing material of the present invention.
  • Figure 4 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 5 illustrates the treatment of a patient who has been burned by boiling water using an embodiment of the dressing material of the present invention.
  • Figure 6 illustrates the treatment of a patient who has been burned by boiling water using an embodiment of the dressing material of the present invention.
  • Figure 7 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 8 is a view showing the microstructure of a solid inorganic particle in an embodiment of the dressing material of the present invention under a scanning electron microscope.
  • A microstructure of solid inorganic particles on a 20 ⁇ m scale
  • B microstructure of solid inorganic particles on a 3 ⁇ m scale.
  • Figure 9 shows the microstructure of another solid inorganic particle in one embodiment of the composite dressing material of the present invention under a scanning electron microscope.
  • A microstructure of solid inorganic particles on a 20 ⁇ m scale
  • B microstructure of solid inorganic particles on a 2 ⁇ m scale.
  • Figure 10 illustrates the treatment of a patient with chronic refractory wounds using an embodiment of the dressing material of the present invention.
  • Figure 11 illustrates the treatment of a patient with a burn wound using an embodiment of the dressing material of the present invention.
  • Figure 12 shows wound healing after treatment of a child who has been burned by boiling water with a burn ointment on the market.
  • Figure 13 illustrates the treatment of a patient with a mechanical wound with an embodiment of the dressing material of the present invention.
  • Figure 14 shows wound healing conditions after treatment of a patient with a mechanical wound similar to that shown in Figure 13 by another treatment.
  • Figure 15 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 16 illustrates the treatment of a patient with a burn wound using an embodiment of the dressing material of the present invention.
  • Figure 17 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 18 illustrates the treatment of a patient having a chemical burn wound with an embodiment of the dressing material of the present invention.
  • Figure 19 illustrates the treatment of a patient with a carbon burn wound with an embodiment of the dressing material of the present invention.
  • Figure 20 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 21 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 22 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention.
  • Figure 23 illustrates the treatment of a patient having an electrical burn wound with an embodiment of the dressing material of the present invention.
  • Figure 24 illustrates the treatment of a patient having an electrical burn wound with an embodiment of the dressing material of the present invention.
  • Figure 25 illustrates the treatment of a patient having an electrical burn wound with an embodiment of the dressing material of the present invention.
  • Figure 26 illustrates the treatment of a patient with a leg venous ulcer using an embodiment of the dressing material of the present invention.
  • Figure 27 illustrates the treatment of a patient with a leg venous ulcer using an embodiment of the dressing material of the present invention.
  • Figure 28 illustrates the treatment of a patient with a non-healing surgical wound with an embodiment of the dressing material of the present invention.
  • Figure 29 illustrates the treatment of a patient with a non-healing surgical wound with an embodiment of the dressing material of the present invention.
  • Figure 30 illustrates the treatment of a patient with a non-healing surgical wound with an embodiment of the dressing material of the present invention.
  • Figure 31 illustrates the treatment of a patient with foot gangrene using an embodiment of the dressing material of the present invention.
  • the present invention provides innovative dressing materials and methods of use thereof, and kits or devices containing the same.
  • wound care products or medical devices have been developed to address the specific problems of multi-stage wound healing processes.
  • the healing process can be more complex, involving many cell-level participants and environmental factors.
  • Commonly used wound dressings in the clinic have some advantages as well as some disadvantages, such as 1) failure to prevent microbial invasion (eg, cell-based skin substitutes, skin grafts or acellular matrix); 2) due to adhesion of the dressing to the wound surface, Removal may result in re-injury of the patient (eg, normal gauze or some silver-containing dressing that is dried at high body temperatures in burn patients); 3) the amount of exudate absorbed by the dressing on the wound surface is too low, resulting in wound surface The exudate accumulates and subsequently becomes the site of microbial attack; 4) fails to provide suitable gas permeability; 5) can only be used for general wounds and cannot be used for chronic wounds; and 6) too dry or too wet - that is, can not maintain physiology
  • a moist, balanced healing environment e.g
  • the dressing material provided by the invention is a novel material with unique and innovative multi-functionality and high efficiency, and can be used as a "one-Stop Primary Wound Dressing throughout the Wound Healing Process" without pain and damage. Repair a variety of wounds.
  • the unique nano-scale pore particles in the material are combined with the ultra-microfiber mesh to mimic the skin barrier function, and have antifouling, hygroscopicity, moisturizing, breathability, flexibility and adhesion, which can absorb the wound exudate.
  • the rapid and painless autolysis and debridement, the two-way adjustment ensures sufficient drainage, and the exudate part can be retained in the dressing in a targeted and compartmental manner, maintaining a semi-closed, which is beneficial to the repairing metabolism and physiological healing of the wound.
  • the local physiological moist environment facilitates the response inside and outside the cell, promotes the migration of the body's own fibroblasts and epidermal cells, the regeneration of wound granulation tissue and epithelial cells, accelerates the physiological healing of wounds, avoids or minimizes the use of traumatic skin grafts, and reduces the suffering of patients. Scars are produced.
  • the dressing material provided by the invention can be flexibly applied to various stages of open wound or non-opening acute wound healing and chronic wound healing: coagulation, inflammation, cell proliferation, matrix repair, epithelialization and reconstruction of scar tissue.
  • the composite dressing material is preferably in the form of a sheet and can be packaged in a disposable form, which is undesirable for preparation of the material (eg, thawing, cleaning, and maintaining the frozen cell-based skin substitute)
  • a busy clinical clinician who is troubled by a narrow temperature range suitable for cell survival or pretreatment eg, wetting of a dry therapeutic powder-containing dressing
  • a narrow temperature range suitable for cell survival or pretreatment is a highly desirable clinical advantage feature.
  • the invention is also cost effective at all levels. Since the dressing can be stored at room temperature and is in a convenient form of sheet packaging, clinicians, caregivers and/or patients themselves do not need to undergo complex technical training or operating instruments to manage and care for wounds with minimal pain and optimal healing time. .
  • the dressing is cost effective for institutional health care providers (eg, hospitals, clinics, wound care centers, burn centers, professional care facilities, rehabilitation facilities, long-term care facilities, aged care or assisted living centers), they may only
  • the dressing of the present invention is needed as a primary dressing to manage many different types of wound and skin lesions or injuries, including acute or chronic.
  • the dressing material of the present invention is a composite material having the properties and attributes of an effective skin substitute for protecting the skin or wound bed: as a thin, suitable oily semi-solid sheet, naturally and tightly covered
  • the surface of the body surface forms a semi-enclosed, physical barrier that mimics the skin, effectively blocks the pathogen contaminated wounds in the environment, and at the same time forms a heat preservation and moisturizing buffer environment, effectively covering and protecting the wound surface, and reducing the dryness and scarring of the wound due to rapid evaporation of moisture. .
  • the dressing material of the present invention is soft and pliable to conform to the undulating contour of the wound bed and has the ability of the inventors to be critical for effective control of microbial infections and inflammation.
  • the dressing materials of the present invention can be lightly compressed to form a "fine wheel" that conforms to the surface of the wound bed. Profiles, thereby minimizing the gaps and gaps in which bacteria can thrive, thereby reducing the risk of bacterial infection and the formation of antibiotic-resistant biofilms.
  • the dressing material of the present invention is soft, oily and elastic, it can be naturally adhered closely to various wounds with uneven physiological structure, and is highly flexible and flexible due to adhesion to the wound surface.
  • the patient is not easy to fall off when the body is active, and has greater limb compliance and comfort. It can be extended by the dressing to protect the wound surface, thus reducing the frequency of dressing replacement, which is very popular among medical staff and patients.
  • the dressing material of the present invention does not adhere to the wound bed at the time of replacement without damaging the new tissue, does not disturb the healing dynamics, and protects the nerve endings of the base of the wound to reduce pain. At the same time, it acts as a semi-closed, breathable bionic skin barrier to create an ideal moist-balanced microenvironment that facilitates healing of the regenerated wounds - not too wet to cause impregnation, nor too dry to cause dryness of the newly regenerated healthy tissue.
  • the dressing material can be stored at room temperature for at least 12 months and the dressing can be applied directly to the wound without any pretreatment.
  • the dressing material is also versatile - capable of automating the dissolution of debrided (autolysis debrided) inactivated or necrotic tissue to control microbial infection (eg, without resorting to Painful surgical debridement of necrotic tissue provides antioxidant soothing to promote cell proliferation and stimulate microcirculation to promote tissue regeneration, including capillary and nerve regeneration.
  • the dressing materials of the present invention have been clinically proven to accelerate healing of acute and chronic wounds, as well as achieving superior healing quality and minimizing scar formation.
  • a skin/wound composite dressing material comprising an active layer of a porous polymeric substrate impregnated with a semi-solid hydrophobic composition, wherein the composition comprises a fatty acid and an embedded polymer matrix Solid inorganic particles in the matrix of the material.
  • FIG. 1A is a top plan view of a sheet-type composite dressing material placed on a horizontal surface.
  • the composite dressing material includes an active layer 10 in which the network structure of the porous polymer substrate 2 is visible.
  • the network structure of the porous polymer substrate 2 may be regular or irregular.
  • the material of the porous polymer substrate 2 of the present embodiment constituting the network structure itself includes the fiber 21 having a bundle structure.
  • Solid inorganic particles 3 embedded in the porous polymer substrate 2 are also visible in the active layer 10, and the solid inorganic particles 3 are substantially uniformly distributed in the porous polymer substrate 2. Since FIG. 1A is only a schematic diagram, only the position distribution of the solid inorganic particles 3 is reflected, and the size of the solid inorganic particles 3 cannot be truly reflected.
  • the porous polymer substrate 2 is impregnated with the fatty acid 1.
  • Fig. 1B is a schematic longitudinal sectional view of the sheet type embodiment of Fig. 1A. Since the thickness of the sheet-shaped dressing material is very thin, only 0.1-10 mm, FIG. 1B is enlarged for the purpose of showing the structure, and the structure in FIG. 1B only reflects the basic structure of the auxiliary material, and the size and size ratio thereof. It cannot be truly reflected.
  • the fatty acid 1 is substantially uniformly impregnated in the polymer substrate 2 to form a substantially uniform layer.
  • the fatty acid 1 may extend beyond the upper and lower surfaces of the porous polymer substrate 2.
  • the thickness of the fatty acid 1 may be greater than the thickness of the fatty acid 1 on the opposite surface.
  • FIG. 1C is a schematic view showing the structure of the fiber 21 of Figures 1A and 1B.
  • each of the fibers 21 having a bundle structure is composed of a plurality of microfibrils 211.
  • the microfibrils 211 have a gap 212 between each other.
  • the solid inorganic particles 3 are distributed substantially uniformly on the surface of the microfibrils 211.
  • the microfibril cross section has a maximum diameter of from 0.01 to 20 microns, preferably from 0.01 to 10 microns or from 0.01 to 6 microns.
  • the voids between the microfibrils are preferably from 0.01 to 10 microns or from 0.01 to 3 microns.
  • 2A and 2B are microstructures of an embodiment of the composite dressing material of the present invention under a scanning electron microscope.
  • 2A shows a network structure of a porous polymer substrate on a 50 ⁇ m scale, and also shows a polymer substrate impregnated with a fatty acid, and solid inorganic particles embedded in a matrix of the polymer substrate.
  • Figure 2B shows the bundle structure of microfibrils in a bamboo fiber of a porous polymer substrate under a 10 ⁇ m scale, and also shows solid inorganic particles attached to the microfibril bundle. It can also be seen that there are large and small gaps between the microfibrils, just like a capillary tube can effectively absorb and evaporate water.
  • the different orientations of the microfibrils result in various nano- to micro-scale voids, and their unique structure makes them excellent in respirability, moisture retention and gas permeability.
  • the composite dressing material of the invention absorbs moisture from the middle gap of the microfibril bundle and the fine groove on the surface through the capillary effect of the polymer microfibril with ultra-fine gap, and slowly releases "breathing" to prevent excessive exudation of the wound surface. Impregnation hinders skin regeneration. This two-way regulation of moisturizing and moisture permeability maintains the physiological moist balance of the wound and creates the best healing local environment.
  • Such dressing covers the wound surface, creating a semi-closed physiological moist local ecological environment, utilizing the body's own defense mechanism to effectively promote the selection of necrotic tissue and eschar, and the self-dissolving debridement of the surrounding skin without damage.
  • the exudate also contains phagocytic cells and neutrophils, and its own produced lysin can effectively dissolve necrotic tissue. Dissolved necrotic tissue debris is removed from the wound each time the dressing is changed, avoiding or reducing the use of surgical debridement with low selectivity and high pain.
  • the composite dressing material of the present invention can rapidly soften, liquefy necrotic tissue, eschar, and self-dissolve debridement within 1-3 days, and remove dissolved necrotic tissue debris when the dressing is changed.
  • the wound surface is non-invasive, cleans the wound surface, and damages the surrounding healthy skin, thereby reducing the inflammatory reaction and promoting the rapid regeneration of granulation tissue.
  • the self-dissolving debridement dressings commonly used in the prior art such as hydrogels, hydrocolloids, etc., require at least 6-7 days.
  • the collagen hydrolase used for enzymatic debridement is greatly limited in clinical application due to poor selectivity to wound necrotic tissue and healthy tissues around the wound; in addition to biochemical enzyme preparations, its expensive price is also given to patients and medical systems. A big burden.
  • Figure 3 shows a patient treated with a burn wound using an embodiment of the dressing material of the present invention: male, 10 years old; left foot ankle is caused by boiling water to cause deep 2 degree burn; treated with a burn ointment for 4 days but the condition deteriorates followed by the present invention
  • An embodiment of the dressing material is treated and the dressing is changed every 1-2 days.
  • Figure 3A shows the presence of a large amount of necrotic tissue, eschar, and redness and inflammation of the wound and surrounding tissues before treatment.
  • the wound eschar was substantially liquefied by autolysis and debridement (Fig. 3B), and after washing with physiological saline, the wound surface became clean, leaving only a thin layer of suede (Fig. 3C). ), the inflammation of the wound and surrounding tissues subsided significantly.
  • the wound was completely healed without obvious scars (Fig. 3D, E, F, G).
  • Figure 4 illustrates the treatment of a patient with burn wounds using an embodiment of the dressing material of the present invention: male, 1 year and 5 months; right forearm and hand caused by boiling water to cause deep 2 to 3 degree burns; treatment with a burn ointment for 16 days
  • the condition deteriorated (due to the increased necrosis of the tissue exposed to the open air in the winter) and the fever was high for several days; then the treatment was carried out with the embodiment of the dressing material of the present invention, and the dressing was changed every 1-2 days.
  • Figure 4A shows that the wound surface is covered with a large amount of necrotic tissue, hard eschar, and severe redness and inflammation of the wound and surrounding tissues, accompanied by systemic inflammatory response.
  • the hard eschar of the wound is basically liquefied by autolysis and debridment, and after washing with physiological saline, the wound tends to be clean (Fig. 4B).
  • the wound showed fresh granulation tissue (Fig. 4C), wound and surrounding The inflammation of the tissue has subsided significantly.
  • Fig. 4D, E, F the skin was completely healed without skin grafting
  • Figures 5 and 6 show the use of an embodiment of the dressing material of the present invention to treat two mothers and sons who were simultaneously burnt by boiling water: mother, 32 years old; deep burns caused by boiling water in the right foot and ankles; treatment with two burn ointments After 18 days, the condition deteriorated and the injury level became a 3 degree wound. The treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 5A shows the presence of a large amount of necrotic tissue, eschar, axillary ulceration, and redness and inflammation of the wound and surrounding tissues.
  • the wound eschar is basically softened and liquefied after being treated for one day.
  • the embodiment of the dressing material of the present invention is subjected to a healing process similar to that of the mother, and the wound eschar is substantially liquefied by autolysis and debridement within 1 day, and the wound is cleaned after washing with physiological saline (Fig. 6B), after 23 days of treatment. The wound was completely healed without obvious scars (Fig. 6C, D, E, F).
  • the composite dressing material of the invention also has high adsorption property, can effectively adsorb the exudate, pus and necrotic tissue residue after autolysis and debridement, and is taken away together when dressing, effectively and fully draining to prevent wound infection and inflammation. Reduce oozing.
  • FIG. 7A shows the presence of a large amount of necrotic tissue, black eschar, and redness and inflammation of the wound and surrounding tissues on the wound before treatment.
  • the wound eschar was partially liquefied by autolysis, and the unliquefied black suede was also attached to the dressing and removed at the time of replacement (Fig. 7C), the wound was very Cleansing (Fig. 7B), the inflammation of the wound and surrounding tissues subsided significantly.
  • the wound has healed by approximately 70% (Fig. 7D, E, F).
  • FIGS. 8A and 8B are microstructures of a solid inorganic particle exhibited by a scanning electron microscope in one embodiment of the composite dressing material of the present invention.
  • Figure 8A shows the microstructure of solid inorganic particles on a 20 [mu]m scale, which appears as particles of approximately 1-10 [mu]m in length.
  • Figure 8B shows solids without a 3 ⁇ m scale
  • the particle microstructure of the machine shows that the surface of the long columnar particles has a fine groove similar to the microfibril bundle of Fig. 2B, and the groove size distribution is about 10-500 nm.
  • Figures 9A and 9B show the microstructure of another solid inorganic particle in one embodiment of the composite dressing material of the present invention under a scanning electron microscope.
  • Figure 9A shows the microstructure of solid inorganic particles on a 20 [mu]m scale, which appears as particles of approximately 1-10 [mu]m in length.
  • Fig. 9B shows the microstructure of the solid inorganic particles on a 2 ⁇ m scale. It can be seen that the particles are in the form of a lamellar agglomerate, and the surface is characterized by the accumulation of the thin-walled pores, and the pore size distribution is about 10-300 nm.
  • the solid inorganic particles in the composite dressing material of the present invention have an average size of from 0.01 to 50 microns. More preferably, at least 80% of the solid inorganic particles in the dressing material are less than 50 microns, 30 microns, 20 microns, or 10 microns.
  • Nanomaterials generally refer to materials with at least one dimension in the three-dimensional space of the basic structure in the nanometer scale (1 to 100 nm), with extremely large specific surface area and high porosity. It is generally believed that nanomaterials have the properties of quantum size effect, small size effect, surface and interface effect and synergistic effect, and have the advantages of large specific surface area, many surface active centers, high surface reactivity, strong adsorption capacity and high catalytic ability.
  • the use of the solid inorganic fine particles contained in the above examples in the composite dressing material of the present invention can exert the unique advantages of the nanomaterial and enhance the effective adsorption area of the surface of the fine particles. These are combined with the porous microfiber mesh with large specific surface area to further strengthen the adhesion, increase the biological characteristics of obvious inhibition, and effectively absorb the exudate and pus after autolysis and debridement. The necrotic tissue residue is taken away when the dressing is changed, and the drainage is effectively and effectively prevented to prevent inflammation of the wound surface and reduce exudation.
  • the composite dressing material of the present invention also has a targeted compartment for creative creation.
  • the dressing has the protective effect of targeting and compartmentality on different parts of the same wound surface.
  • the dressing can be directed to absorb and lock excess exudate, preventing it from spreading to the surrounding areas with less damage and less secretion, thus protecting the shallower wound from excessive impregnation and inhibiting healing. .
  • the patient with chronic refractory wounds was treated with the embodiment of the dressing material of the present invention: male, 61 years old; the left lower leg suffered from varicose veins for 10 years, and the infection was gradually scratched 2 years ago by pruritus, and the ulceration gradually deepened and deepened. , the formation of chronic ulcers.
  • the wounds worsened after the collision, the wounds were further enlarged and deepened, and the pain was lame; the treatment with other wound healing therapies was still unhealed; then the treatment of the dressing material of the present invention was followed, and the dressing was changed every 2-3 days.
  • Figure 10A shows the presence of necrotic tissue, pus, fiber on the wound before treatment.
  • FIG. 10C shows that the dressing locks the pus and the liquefied necrotic tissue, preventing it from spreading to the area around the wound where the damage is less and the secretion is less.
  • Figure 10D shows that after 12 days of treatment, the wound granulation tissue is fresh and the exudate is absorbed longitudinally through the dressing (Fig. 10E).
  • Figure 10F shows that the replaced dressing locks the exudate intermittently and prevents it from spreading around the wound. . After 32 days of treatment, the wound has basically healed (Fig. 10G, H)
  • the composite dressing material of the present invention effectively mimics the skin barrier effect, and the semi-closed physiological moist environment created on the wound surface greatly contributes to reducing the scar healing of the deep wound skin.
  • a physiologically humid environment hyaluronic acid grows faster and maintains a high concentration for a longer period of time
  • fibroblasts have strong migration and migration speed, and fibroblast proliferation is synchronized with collagen synthesis, thereby avoiding collagen disorder. Arranged, over-deposited. This wound healing mode is close to the early embryonic skin without scar healing mode.
  • the inorganic micro-fiber microfilament of the composite dressing material of the invention can effectively adsorb the exudate, pus and necrotic tissue residue of the wound after autolysis and debridement, and reduce the inflammatory reaction caused by cytotoxins and metabolites, thereby avoiding The excessive proliferation of type I collagen due to excessive proliferation of fibroblasts and the deep and thick fibrotic scar healing caused by disordered deposition.
  • the contracture scar is a type of scar that is divided by the function of the limb or organ. Not only does it have significant dysfunction, but it also has significant appearance changes. Deeper trauma across the joints, even after the wound has healed, is likely to cause contracture scars due to constant tension. Limited joint movement, organ deformation and displacement deformity due to its own contraction and hyperplasia. For example, especially in the joints of the hands and feet, a scar is formed, and the joint is stretched.
  • the composite dressing material of the present invention can not only rapidly heal deep wounds of joint parts (such as deep second to third degree burn wounds), but also effectively prevent the formation of contracture scars. Greatly reduce dysfunction and restore the physiological function and appearance of the wound site. This advantageous feature is of great significance in the field of orthopedics and medical aesthetics because it avoids the pain and medical cost burden of multiple scar repair and reconstruction operations.
  • Figures 4, 19, 20, 23, 24 and 25 illustrate the treatment of patients with hand deep burn wounds using an embodiment of the dressing material of the present invention.
  • Figures 3, 5, 6, 7, 13 and 14 illustrate the treatment of patients with deep burn wounds of the ankle joint using an embodiment of the dressing material of the present invention.
  • Figures 16, 18, 30 and 31 show the use of the invention An example of a dressing material treats patients with deep burn wounds in the foot.
  • Figures 11, 21 and 22 illustrate the treatment of patients with deep burn wounds of the knee joint using an embodiment of the dressing material of the present invention. It can be seen that their deep wounds did not form a contracture scar after healing, and the new tissue, including the skin, was soft and flat with almost no scar hyperplasia.
  • the inorganic microparticles containing calcium and zinc in one embodiment of the composite dressing material of the present invention can regulate collagen synthesis and decomposition by matrix metalloproteinases (MMPs) to reduce scarring.
  • MMPs matrix metalloproteinases
  • Matrix metalloproteinases MMPs are endogenous polypeptide enzymes containing calcium and zinc. The presence of calcium and zinc is closely related to the activity of MMPs to break down collagen. Compared with its normal skin, keloids and hypertrophic scars have reduced levels of trace elements such as calcium, zinc, copper, iron, manganese and selenium. The activity of MMPs is decreased, and collagen synthesis protein is larger than its decomposition, resulting in scar hyperplasia. Calcium and zinc in the dressing can effectively regulate the decomposition of excess type I collagen by MMP-1, and inhibit the cell activity through the calcium channel on the surface of fibroblasts, and reduce the excessive proliferation of type I collagen.
  • the composite dressing material preferably takes the form of a sheet and comprises an active layer of a dressing material according to the invention.
  • the active layer will typically be a wound contact layer in use, but in some embodiments it may be separated from the wound by a layer of wound treatment that directly contacts the wound, such as a bioactive cell based wound dressing, autologous or allogeneic skin. Grafts (including auto/allogene skin grafting), removal of cell stroma, amniotic membrane, etc.
  • each of the dressing sheets can be cut into any size or shape, preferably having a surface area of from 2 to 1600 cm 2 , more preferably from 2 to 400 cm 2 and most preferably from 4 to 100 cm 2 .
  • the thickness of the dressing sheet is preferably from 0.1 to 10 mm, from 0.2 to 5 mm, or from 0.4 to 2 mm.
  • the dressing sheet can be sterilized by ionizing radiation such as (cobalt-60, strontium-137, etc.) or by chemical sterilization such as ethylene oxide (EtO) and nitrogen dioxide (NO 2 ) gases.
  • ionizing radiation such as (cobalt-60, strontium-137, etc.) or by chemical sterilization such as ethylene oxide (EtO) and nitrogen dioxide (NO 2 ) gases.
  • the polymeric substrate is preferably a liquid absorbent, but non-bioabsorbable polymer that is not sufficiently degraded and absorbed in the mammal.
  • Such polymers include natural fibers or synthetic polymers. Natural fibers include, but are not limited to, cotton, silk, and linen.
  • Synthetic polymers include, but are not limited to, fibers made from chemically synthesized polymers such as polyester, nylon, polyamide, polypropylene, polyurethane, polytetrafluoroethylene, and polymers that are naturally available, such as for making sticky Gum / rayon / lyocell / TENCEL / modal (also known as "rayon” or "regenerated cellulose fiber and fabric”) derived from wood pulp (such as viscose fiber, etc.) or bamboo ( Fibers such as bamboo fibrils, bamboo pulp fibers, etc., derived from plant proteins (such as corn, large Beans, alginate and peanuts) or regenerated fibers, alginate, chitin, chitosan, hyaluronic acid, etc., derived from protein sources of animal proteins (such as casein derived from milk).
  • the fibers can be woven or non-woven.
  • the polymeric substrate is preferably a fiber having microfibrils, the microfibril cross section being of any shape, preferably cylindrical or elliptical, more preferably having irregular surface fibrils.
  • the microfibrils preferably have a cross-sectional maximum diameter of from 0.01 to 50 ⁇ m, more preferably from 0.1 to 20 ⁇ m, and most preferably from 1 to 10 ⁇ m.
  • the microfibrils may be aggregated into microfibrils with each other, and micropores may be formed between the filaments, and the pore width is preferably from 0.01 to 10 ⁇ m, more preferably from 0.1 to 10 ⁇ m, and most preferably from 0.1 to 5 ⁇ m.
  • the semi-solid hydrophobic composition is preferably substantially homogeneous such that it is substantially uniformly impregnated onto the substrate of the polymeric substrate to achieve a thickness of from about 0.1 mm to about 10 mm, alternatively from 0.2 to 5 mm, from 0.5 to 2 mm or 1 - 4 mm of this substantially homogeneous layer of impregnated polymer matrix. This effect can be achieved by a precisely controlled mechanical manufacturing process.
  • the melting temperature such as above 60 ° C, or above 70 ° C -90 ° C, or at 70 ° C -110 ° C, 80 ° C -100 ° C
  • the pressure or the like of the composition applied to the polymer matrix is adjusted.
  • the composition is hydrophobic and contains less than 5%, preferably less than 1%, most preferably less than 0.2% by weight of water (based on the total weight of the dressing material) before it is placed on the wound bed; and it contains The fatty acid is 20-80%, alternatively 30-70% or 40-60% by weight based on the total weight of the dressing material.
  • the fatty acid may be based on a vegetable or animal oil, preferably selected from the group consisting of soybean oil, rapeseed oil, olive oil, coconut oil, tea tree oil, sesame oil, pumpkin seed oil, corn oil, canola oil, castor oil, peanut oil, sunflower oil, Cottonseed oil, Chia seed oil, linseed oil, safflower oil, broccoli seed oil, almond oil, tomato seed oil, pine nut oil, macadamia nut oil, camellia seed oil, jojoba oil, grape seed oil, rose hip A group of vegetable oils consisting of oil, pomegranate seed oil, shea butter, evening primrose oil, lavender oil, and rosemary oil.
  • This oil can be a plasticizer that helps provide a flexible and soft texture of the dressing.
  • the plasticizer may also be mineral oil, petrolatum/fossil oil, silicone oil, stearate, hydrogenated ethers and esters, and natural plant based substitutes for petrolatum, such as shea butter, cocoa butter, unrefined coconut oil, Tallow, lanolin and jojoba oil.
  • the composition preferably contains a curing agent to solidify the oil and render the composition semi-solid and flexible at room temperature.
  • the curing agent is preferably beeswax (yellow or white) or an emulsifying wax which is cetearyl alcohol, polysorbate (for example, polysorbate 60), polyethylene glycol (for example, PEG-150) stearic acid.
  • the composition may further comprise a suitable bioabsorbable polymer, including a cellulose derivative selected from the group consisting of collagen, elastin, bioabsorbable, such as oxidized cellulose, galactomannan such as guar/borate, A group of polymers of glycosaminoglycans such as crosslinked hyaluronic acid, polylactide/polyglycolide, polyhydroxybutyrate, and mixtures thereof.
  • oxidized cellulose for practical use is oxidized regenerated cellulose (ORC) prepared by oxidation of regenerated cellulose, such as rayon, by utilizing hemostatic properties of ORCs that are beneficial for reducing post-operative adhesion.
  • ORC oxidized regenerated cellulose
  • Oxidized regenerated cellulose is available by the process described in U.S. Patent No. 3,122,479, the disclosure of which is incorporated herein in its entirety.
  • This material offers a number of advantages including biocompatibility, biodegradability, non-immunogenicity, and readily available commercially available properties.
  • the available ORCs have different degrees of oxidation and therefore have different rates of degradation.
  • the ORC can be used in the form of insoluble fibers, including woven, nonwoven, and knitted fabrics, or in the form of water soluble low molecular weight fragments obtained by alkaline hydrolysis of ORC.
  • the composition may further comprise a hydrocolloid to help adjust the water absorption and water permeability of the dressing material of the present invention.
  • Suitable hydrocolloids include alginate, pectin, gums such as guar or xanthan gum, modified celluloses such as carboxymethylcellulose and hydroxyethylcellulose, modified starches such as sodium starch glycolate, and mixtures thereof.
  • the hydrocolloid may be impregnated onto the matrix of the polymeric substrate of the dressing material of the present invention prior to impregnation of the semi-solid hydrophobic composition, or alternatively pre-mixed with the semi-solid hydrophobic composition and subsequently impregnated into the polymer. On the substrate of the substrate.
  • the composite dressing material comprises at least two separate layers, wherein the first layer comprises a porous polymeric substrate impregnated with a semi-solid hydrophobic composition and the second layer comprises a polymer comprising a hydrophilic composition Substrate.
  • the hydrophilic composition preferably comprises a hydrocolloid such as a modified cellulose such as carboxymethylcellulose and hydroxyethylcellulose or alginate, chitin, chitosan and hyaluronic acid. combination.
  • a hydrocolloid such as a modified cellulose such as carboxymethylcellulose and hydroxyethylcellulose or alginate, chitin, chitosan and hyaluronic acid. combination.
  • the composite dressing material comprises at least two separate layers, wherein the first layer comprises a porous polymeric substrate impregnated with a semi-solid hydrophobic composition and the second layer comprises a porous foamed polymeric substrate.
  • the foamed polymeric substrate can be a foamed dressing comprising a foamed polymer such as a polymer made from polyurethane, alginate, hydrocolloid or polyacrylate.
  • the two-layer configuration is very versatile in the manufacture of different embodiments of the composite dressing material according to the invention.
  • a dressing wherein the second layer comprises a hydrocolloid composition or a foamed polymer substrate can be used to apply a dressing to those wounds having excess exudate to absorb fluid to the maximum capacity of the dressing, thereby preventing leakage of the peripheral area of the wound. Or etched.
  • the composite dressing material further comprises a backing sheet extending over the active layer of the porous polymeric substrate impregnated with the semi-solid hydrophobic composition, the backing sheet being located on the opposite side of the active layer facing the wound.
  • the backing sheet area is larger than the active layer so that an edge region having a width of 0.2-10 cm, optionally 0.5-5 cm, extends around the active layer to form a so-called island dressing.
  • the backing sheet is preferably coated with a pressure sensitive medical grade adhesive at least in its edge region.
  • the backing sheet is substantially liquid impermeable, more preferably semipermeable, such that water vapor is permeable but does not allow liquid water or wound exudate to pass through so as not to impregnate the skin around the wound.
  • the wound under the dressing is allowed to heal under wet conditions.
  • the backing sheet is also impermeable to microorganisms. Examples of suitable continuous consistent backing sheets include polyurethanes, polyalkoxyalkyl acrylates, and methacrylates.
  • the solid particles embedded in the dressing material according to the present invention are preferably inorganic mineral particles such as talc (magnesium silicate), silica, magnesia (MgO), alumina, zinc oxide (ZnO), iron oxide (FeO, Fe). 2 O 3 , Fe 3 O 4 , Fe 4 O 5 , Fe 4 O 3 , etc.), calcium chloride, calcium carbonate (CaCO 3 ), zinc carbonate (ZnCO 3 ), calcium phosphate (Ca 3 (PO 4 ) 2 ) , calcium sulfate (CaSO 4 ) and titanium dioxide (TiO 2 ).
  • talc magnesium silicate
  • silica magnesia
  • MgO magnesia
  • alumina zinc oxide
  • ZnO iron oxide
  • FeO, Fe iron oxide
  • calcium chloride calcium carbonate
  • CaCO 3 zinc carbonate
  • ZnCO 3 calcium
  • the solid particles are preferably micronized or ground and crushed into small fine particles.
  • the average size of the particles is preferably from 0.01 to 50 microns, more preferably from 0.05 to 20 microns, and most preferably from 0.1 to 10 microns.
  • the concentration of solid particles in the dressing material is preferably from 20 to 80%, alternatively from 30 to 70% or from 40 to 60% by weight, based on the total weight of the dressing material.
  • the fine particles are of sufficiently small size to not cause pain in the wound after contact or rubbing.
  • This configuration prevents dry particles from rubbing the fragile wound bed again because it is contained in the semi-solid hydrophobic composition and embedded in the matrix of the polymeric substrate.
  • the semi-solid hydrophobic composition also prevents overgrowth of the granulation tissue into the dressing as this can cause pain, damage to the newly regenerated tissue and hinder the wound healing process after removal of the dressing. Since the particles are dispersed in the matrix of the polymer substrate, they create a network of breathable substrates that allow gas and water vapor to pass through but not allow microorganisms to pass through, thereby effectively protecting the wound bed from environmentally-derived bacteria. And other harmful microorganisms, as well as other environmental factors such as the intrusion of dust.
  • the diameter of human cells is generally 10-20 microns, and the diameter of organelles ranges from a few nanometers to hundreds of nanometers. Therefore, nanoparticles can easily communicate with biomolecules inside and outside the cell in a non-invasive manner.
  • solid particles especially when less than 0.1 micron (100 nanometers) may provide a biocompatible scaffold for tissue regeneration, More similar to the formation of natural cell supporting tissues, such as as a building block for capillary endothelial cells to regenerate blood vessels, and for neurons to regenerate nerve endings in the skin.
  • laminin, collagen, and fibronectin which are major components of the extracellular matrix (ECM)
  • ECM extracellular matrix
  • the microstructure of an embodiment of the composite dressing material of the present invention under a scanning electron microscope exhibits a void and a surface of the microfibril bundle in the microscopic three-dimensional space.
  • the groove, the wedge-shaped pores of the inorganic particles and the surface fine grooves have at least one dimension in the nanometer scale range ( ⁇ 100 nm), and have a large specific surface area and a high porosity, which are highly similar to the extracellular matrix, and are favorable for cell adhesion, differentiation and proliferation.
  • the microfibers and inorganic microparticles in this material can be used as a substrate for tissue scaffolds to provide a suitable environment for adhesion, reproduction and differentiation of cells, which is beneficial to tissue regeneration.
  • This material has a large specific surface area and can be easily immobilized on enzymes and other biocatalysts.
  • its high porosity and intra-hole connectivity are beneficial to immobilize enzymes and biocatalysts on the wound surface, maintaining a high survival rate.
  • the dressing material can conform to the contour of the wound bed (when mechanically deformed) after being applied to the wound surface, and the dressing material can generate an instantaneous potential, so-called Piezoelectric effect. Since electrical stimulation as low as 10 mV/mm has been shown to promote neuronal growth, it is believed that this piezoelectric material is effective in stimulating cellular activity on the wound bed, thereby enhancing wound tissue regeneration without any external electrical stimulation. These microparticles also adsorb bacteria on the wound bed, changing the adhesion morphology and density between the cells, thereby disrupting the formation of bacterial colonies or their biofilms, thereby reducing the bioburden of the wound.
  • the dressings of the present invention appear to have the characteristics and attributes of an effective skin substitute that is soft, flexible, and flexible to conform to the contour of the wound bed to protect the wound bed, and can act as a half Closed and breathable skin barrier to create an ideal moist balance for healing wound healing
  • the microenvironment is conducive to intracellular and extracellular response, promotes the migration of the body's own fibroblasts and epidermal cells, wound granulation tissue and epithelial cell regeneration, accelerates the physiological healing of wounds, and avoids or minimizes the use of traumatic skin grafting to prevent or reduce scarring.
  • Figure 11 shows a patient treated with a burn wound using an embodiment of the dressing material of the present invention: female, 3 years old; the lower back, buttocks and lower extremities are caused by boiling water to cause deep 2 degree burns; treated with an burn cream for 1 day but condition deterioration.
  • the treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 11A shows the presence of a large amount of vesicles and necrotic tissue on the wound before treatment, and the wound and surrounding tissues are red, swollen and inflamed.
  • Figure 18 illustrates the treatment of a patient with severe chemical burn wounds using an embodiment of the dressing material of the present invention: male, 58 years old; paper mill worker, with the right leg immersed in a storage tank containing a high temperature (130 ° C / 266 ° F) alkaline liquid After a few minutes, I was rescued and admitted to the hospital within 3 hours. He suffered a deep 2-3 degree burn (13% TBSA). Perform standard body burn management. A topical wound treatment was performed with an embodiment of the dressing material of the present invention and the dressing was changed every 1-2 days.
  • Figures 18A, 18B show the presence of a large amount of vesicles and necrotic tissue on the wound prior to treatment.
  • the foam and necrotic tissue were removed by autolysis and debridement (Fig. 18C), and a large amount of fresh granulation tissue was spread to cover the wound surface (Fig. 18D), without skin grafting, and the body was rapidly regenerated. Out of the dermis and epithelium, the wound is basically healed.
  • Figure 18E shows that the healing skin is close to physiological healing without significant scarring.
  • Figure 13 illustrates the treatment of a patient with a mechanical wound with an embodiment of the dressing material of the present invention: female, 6 years old; a motorcycle wheel wire wound to scratch the right heel, the wound deeper into the muscle layer. Treated with a wound cream for 20 days but the condition deteriorated. The treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 13A shows the presence of a large amount of hard fibrotic necrotic tissue on the wound before treatment, and the wound and week The surrounding tissue is red and swollen.
  • An embodiment of the dressing material of the present invention is applied to the wound surface (Fig. 13B) and then applied to a conventional gauze bandage (Fig. 13C).
  • the wound hard palate After applying the dressing material of the present invention for 2 days, the wound hard palate is softened and liquefied by autolysis, debriding, and adhered to the dressing, and is removed at the time of replacement, and the wound surface is very clean (Fig. 13D), the wound surface and the surrounding tissue. The inflammation subsided significantly. After 40 days of treatment, no skin grafting was required, the body regenerated the subcutaneous tissue, dermis and epithelium, and the wound completely healed (Fig. 13E, F). Fig. 13F shows that the healing skin was close to physiological healing without obvious scarring.
  • Fig. 14A and B a child patient (male, 6 years old; motorcycle wheel wire scraping wound on the right heel and the lateral side, wound deep muscle layer) treated in a hospital before January was hospitalized for 28 days. Debridement and transfer flap skin grafting 2 times. Because the wound defect of the skin graft failed to expand and deepen, the hospital arranged for skin grafting. However, the family members have seen three operations, not only skin necrosis, but also damage to the donor site, refused to accept further surgery, skin graft surgery.
  • the wound hard palate is softened and liquefied by autolysis in 2-3 days, and adhered to the dressing to be removed at the time of replacement, without skin grafting, and the body regenerates the skin. Tissue, dermis and epithelium, the wound was completely healed (Fig. 14C), and the skin condition of the donor site was also improved.
  • the inventors believe that the fatty acids embedded in the composite dressing material are applied to the living mammal to be warmed by the skin in a semi-closed moist environment, the oil can penetrate the wound surface and necrosis through the saponification process.
  • the tissue is broken down into granules to liquefy or soften the necrotic tissue as quickly as possible within 1 week, sometimes 1-3 days, 1-4 days, or 3-5 days by the autolysis debridement mechanism.
  • the liquefied or softened necrotic tissue can be easily removed by removing the dressing of the present invention, which absorbs the liquefied wound residue, leaving the fresh regenerative wound bed clean and least disrupted.
  • This model of autolysis debridement is non-invasive and retains the activity of the cells in the wound bed, including those in the surgical debridement, which may indiscriminately remove inactivated and healthy cells. Cells that are in a stagnant stage after injury but are inactivated if not resuscitated in time. Therefore, the depth of the wound can be controlled as shallow as possible to achieve faster healing.
  • the wound healing wound can be reactivated and strongly activated to create new granulation tissue and ultimately wound healing.
  • the dressing material of the present invention may also include an antioxidant.
  • an antioxidant may hinder wound healing and tissue regeneration because it produces chronic inflammation that redirects the available energy supply to antioxidant defenses in the event of damage to tissue remodeling.
  • Granulation tissue Solve the level of matrix metalloproteinase. In chronic wounds, long-term escalation of active oxides can lead to hydrogen peroxide-induced senescence or apoptosis or tissue necrosis, leading to delayed wound regeneration.
  • antioxidants or active oxygen scavengers may be naturally occurring chemicals or extracts of natural materials, such as plant and animal ingredients, preferably vitamin A, vitamin C, vitamin E, retinoids, panthenol, gluten Glycosides, carotenoids, polyphenols (eg, catechins, epicatechins, catechins, gallocatechin gallate, gallocatechin, and epigallocatechin gallate (EGCG) Green tea extract, chlorophyll, chlorophyllin, and water of a sweet tea (common name: sweet tea) leaf containing at least 50% polyphenol in the final extract powder: ethanol extract.
  • natural materials can also exert certain anti-inflammatory and/or anti-allergic effects on the wound surface, which is particularly advantageous for healing chronic wounds.
  • the antioxidant or active oxygen scavenger may also be a synthetic antioxidant including, but not limited to, anthraquinone, aniline dye, acridine dye, thiopurine dye such as gentian violet, aniline blue, methylene blue, crystal violet, acridine yellow, indigo Bright green, trypan blue, taipan red, malachite green, zaklin, methyl violet, methyl orange, methyl yellow, ethyl violet, acid orange, acid yellow, acid blue and acid red.
  • anthraquinone aniline dye
  • acridine dye thiopurine dye
  • gentian violet aniline blue
  • methylene blue crystal violet
  • acridine yellow indigo Bright green
  • trypan blue taipan red
  • malachite green zaklin
  • methyl violet methyl orange
  • methyl yellow ethyl violet
  • acid orange acid yellow
  • acid blue and acid red acid red
  • the antioxidant may be present in the dressing material of the present invention at a level of from about 0.01% to about 10% by weight, based on the dry weight of the dressing material, preferably from 0.1 to about 5%.
  • the dressing materials of the present invention may also include an antibacterial or preservative to prevent or treat wound infection.
  • Antimicrobial agents may be naturally occurring or synthetic ingredients such as colloidal silver, silver salts, silver sulfadiazine, sucralfate, quaternary ammonium salts, antibiotics (eg, tetracycline, penicillin, oxytetracycline, erythromycin, bacitracin, new) , polymyxin B, mupirocin, clindamycin and mixtures thereof), peptide antibacterial agents (such as defensins, maganin, its synthetic derivatives), chlorhexidine, povidone iodine And triclosan.
  • the naturally occurring antibacterial agent may also be an extract of a plant, such as peony bark, berberine root, comfrey root, rehmannia root, cork or sassafras root, which is preferably an oil extract; or an extract of the whole plant of Houttuynia cordata, An extract of Lonicera japonica (Japanese honeysuckle) flower extract or indigo (Dalaya leaf) root or leaf, which is preferably an ethanol:water extract.
  • a plant such as peony bark, berberine root, comfrey root, rehmannia root, cork or sassafras root
  • an extract of the whole plant of Houttuynia cordata An extract of Lonicera japonica (Japanese honeysuckle) flower extract or indigo (Dalaya leaf) root or leaf, which is preferably an ethanol:water extract.
  • the antibacterial agent may be present in the dressing material of the present invention at a level of from about 0.01% to about 10% by weight, based on the total weight of the dressing material, preferably from 0.1 to about 5%.
  • the dressing material of the present invention may further comprise an analgesic to reduce pain in the wound.
  • analgesics may be naturally occurring or synthetic ingredients such as non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, acetaminophen), anti-inflammatory steroids such as prostaglandins, codeine, dihydrocodeine Ketone, morphine, fentanyl, meperidine, methadone, oxycodone and naloxone.
  • Naturally occurring painkillers can also be plant extracts such as Yanhu Stem extract of cordenten (corydalis), dry capsule of borneol (extracted or synthesized from plants such as camphor) or poppy (poppy), which is preferably an oil extract.
  • An analgesic may be present in the dressing material of the present invention at a level of from about 0.001% to about 20% by weight, based on the total weight of the dressing material, preferably from 0.01 to about 5%.
  • a method for treating a wound in a mammal comprising: positioning the composite dressing material in contact with the wound site and securing the dressing material to the skin of the mammal on.
  • the mammal may be a human or a mammal selected from the group consisting of a dog, a cat, a pig, a cow, a horse, a sheep, a goat, a tiger, a lion, a wolf, an elephant, a rabbit, a guinea pig, a hamster, a rat, and a mouse. .
  • Types of wounds include, but are not limited to, acute surgery and traumatic wounds, burns (such as heat, electrical burns, radiation, chemistry, frost and chills, and sunburn), diabetic ulcers, venous ulcers, arterial ulcers, pressure ulcers (or Skin ulcers known as acne ulcers or acne, mixed causes, for example, consisting of diabetes, cardiovascular disease, peripheral vascular disease, vasculitis, central or peripheral nerve injury, kidney disease, autoimmune disease, and cancer Ulcers, fistulas, skin fissures caused by two or more diseases in a group (caused by eczema, contact dermatitis, psoriasis/psoriasis, folliculitis, acne, lupus, herpes zoster, etc.) As well as other chronic or necrotic wounds and inflammatory lesions and conditions.
  • burns such as heat, electrical burns, radiation, chemistry, frost and chills, and sunburn
  • diabetic ulcers such as heat, electrical
  • the materials according to the invention are primarily intended to treat both infectious and non-infectious wounds (i.e., wounds that do not show clinical signs of infection).
  • Wounds are not limited to open skin rupture wounds, but also include skin intact but damaged skin and/or subcutaneous tissue, such as radioactive radiation (such as cancer radiotherapy) or other energy exposure, caused by internal or surface surgery. Inflammation of the skin, tissue fibrosis, rash, redness or edema. It can also be used for the prophylactic treatment of skin lesions.
  • the invention dressing can be applied to the affected skin site in advance, and then energy therapy can be applied to prevent or reduce tissue inflammation, fibrosis, or other forms of damage caused by energy irradiation. .
  • a method for treating a chronic wound in a human comprising: positioning a composite dressing material of the present invention to contact a wound site of a person, and securing the dressing material thereto On a person's skin, wherein the person has an unhealed wound for at least 2 months, optionally at least 3-6 months or at least one year.
  • the person has previously used a skin substitute selected from living cells-based, skin grafting, cell removal, silver-containing dressings, enzyme debriding agents, growth factors, amnion, negative pressure wound therapy, ultrasound therapy, electrical stimulation Treatment of a group of wound care forms consisting of therapy and hyperbaric oxygen therapy.
  • a method for treating a chronic wound in a human comprising: positioning a composite dressing material of the present invention to contact a wound site of a person, and securing the dressing material to On the person's skin, the area of the wound was reduced by at least 50% during the 4 weeks of treatment.
  • the dressing material can be used as the primary dressing in direct contact with the wound bed throughout the treatment.
  • the user can conveniently apply the dressing material to the wound bed and secure it to the wound bed by using a tape bandage.
  • the dressing materials of the present invention can be used in conjunction with other wound treatment methods, such as biological cell based wound dressings, autologous or allogeneic skin grafts (including auto/allogene skin grafting), removal of cell matrices, negative pressure wound therapy (NPWT) and hyperbaric oxygen therapy.
  • the dressing material of the present invention can act as a secondary dressing over a primary dressing such as a skin graft, a biological cell-based wound dressing, a cell-free matrix, a collagen-based dressing, and the like.
  • a primary dressing such as a skin graft, a biological cell-based wound dressing, a cell-free matrix, a collagen-based dressing, and the like.
  • Such a framework is advantageous because the dressing material of the present invention provides a clean and physiologically moisturizing balanced healing environment to protect the biological dressing from degradation due to microbial infection/contamination or due to inactivation due to drying of the wound bed.
  • the dressing material of the present invention may be breathable, it may also be used under a foam dressing used in Negative Pressure Wound Therapy (NPWT) to protect the newborn regenerative wound bed from mechanical damage and to prevent the wound bed from drying out.
  • NGWT Negative Pressure Wound Therapy
  • the dressing material of the present invention can be used in combination with tissue growth promoting growth factors.
  • Growth factors may be selected from the group consisting of epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-beta), vascular endothelial growth factor (VEGF), and insulin-like A group of growth factors (IGF) and mixtures thereof.
  • EGF epidermal growth factor
  • FGF fibroblast growth factor
  • PDGF platelet-derived growth factor
  • TGF-beta transforming growth factor beta
  • VEGF vascular endothelial growth factor
  • IGF insulin-like A group of growth factors
  • the growth factor can be applied topically to the wound bed or systemically to a patient with a wound.
  • a growth factor in liquid form can be sprayed directly onto the wound bed, followed by application of the dressing material of the present invention to the wound bed.
  • Such a combination can be synergistic to further accelerate wound healing and enhance
  • the dressing materials of the present invention can be used in conjunction with silver-containing dressings.
  • the dressing material of the present invention can be applied directly to the wound surface and then applied with a silver-containing dressing (such as a nanosilver wound dressing, a silver-containing foam dressing, etc.) to further protect the wound from infection and/or absorb excessive permeation from the wound surface.
  • a silver-containing dressing such as a nanosilver wound dressing, a silver-containing foam dressing, etc.
  • the dressing material of the present invention can be widely applied to orthopedics and medical cosmetic.
  • deep second degree burns, surgery and other wounds are often treated with scars.
  • the dressing material of the present invention can directly cover the surface of the scar skin to promote the renewal metabolism of the skin, remove the scar tissue, and replace it with a newer and more normal skin tissue. It can also be combined with surgery and other medical devices, such as laser, infrared, sonic, ultrasonic, electromagnetic waves, mechanical microdermabrasion and other instruments to achieve optimal therapeutic results.
  • the dressing material of the present invention can be directly covered on the skin surface after chemical peeling (if acid peeling, etc.) to quickly inhibit skin inflammation, providing an ideal physiological moist healing local environment and reducing heat source.
  • injury and pigmentation caused by inflammation promote scar repair, skin rejuvenation after skin rejuvenation.
  • a skin or wound composite dressing kit comprising the composite dressing of the invention described above; and an outer package shell encasing the dressing material.
  • kit further includes a first protective sheet covering the wound-facing side of the active layer of the composite wound dressing, and/or an adhesive material for securing the dressing material to the skin of the mammal.
  • the kit further includes a first protective sheet overlying the wound-facing side of the active layer of composite dressing material.
  • the protective sheet is removed prior to application of the composite dressing material to the wound.
  • the protective sheet can act as a barrier between the wound-facing side of the barrier active layer and the outer wrapper covering the dressing material.
  • the kit further includes a second protective sheet covering the opposite side of the active layer of the composite dressing material facing the wound.
  • the second protective sheet may be an effective barrier to substantially gas impermeable, vapor or liquid, thereby extending the shelf life of the dressing material.
  • the outer package housing encasing the composite dressing material is a pouch for receiving a dressing material.
  • the pouch is removed prior to applying the composite dressing material to the wound.
  • the outer casing is preferably substantially gas impermeable, vapor or liquid, preferably a vacuum wrap, thereby extending the shelf life of the dressing material.
  • closed casing materials include, but are not limited to, general plastic sheets, polyester films, polyethylene terephthalate (PET or MYLAR), which may be transparent, translucent, colored, or Metallized, preferably aluminum-plastic polyester composite film packaging bags, which are metallized with a thin layer of metal (usually aluminum).
  • the user can position the absorbent layer on the opposite side of the active layer of the composite dressing material to absorb excess wound fluid, serum or blood from the wound surface, including gauze, non-woven fabric, superabsorbent resin , hydrogel, hygroscopic foam such as polyurethane foam.
  • the present invention provides a method of making a composite dressing material of the present invention comprising the steps of impregnating a porous polymeric substrate with a semi-solid hydrophobic composition comprising a fatty acid and solid inorganic particles to provide solid inorganic The particles are substantially uniformly embedded in the matrix of the polymeric substrate.
  • the step of impregnating the porous polymeric substrate can be carried out at a temperature above 50 ° C, optionally at 60 ° C or above, at which temperature the semi-solid hydrophobic composition is substantially liquefied.
  • the step of impregnating the porous polymeric substrate is achieved by substantially uniformly introducing the liquefied hydrophobic composition onto the sheet of porous polymeric substrate by a precisely controlled mechanical manufacturing process, thereby averaging the hydrophobic composition impregnated in the substrate.
  • the thickness is about 0.1-10 mm, optionally 0.2-5 mm or 1-4 mm.
  • Figure 3 shows a patient treated with a burn wound using an embodiment of the dressing material of the present invention: male, 10 years old; left foot ankle is caused by boiling water to cause deep 2 degree burn; treated with a burn ointment for 4 days but the condition deteriorates followed by the present invention
  • An embodiment of the dressing material is treated and the dressing is changed every 1-2 days.
  • Figure 3A shows the presence of a large amount of necrotic tissue, eschar, and redness and inflammation of the wound and surrounding tissues before treatment.
  • the wound eschar was substantially liquefied by autolysis and debridement (Fig. 3B), and after washing with physiological saline, the wound surface became clean, leaving only a thin layer of suede (Fig. 3C). ), the inflammation of the wound and surrounding tissues subsided significantly.
  • the wound was completely healed without obvious scars (Fig. 3D, E, F, G).
  • Figure 4 illustrates the treatment of a patient with burn wounds using an embodiment of the dressing material of the present invention: male, 1 year and 5 months; right forearm and hand caused by boiling water to cause deep 2 to 3 degree burns; treatment with a burn ointment for 16 days
  • the condition deteriorated (due to the increased necrosis of the tissue exposed to the open air in the winter) and the fever was high for several days; then the treatment was carried out with the embodiment of the dressing material of the present invention, and the dressing was changed every 1-2 days.
  • Figure 4A shows that the wound surface is covered with a large amount of necrotic tissue, hard eschar, and severe redness and inflammation of the wound and surrounding tissues, accompanied by systemic inflammatory response.
  • the hard eschar of the wound is basically liquefied by autolysis and debridment, and after washing with physiological saline, the wound tends to be clean (Fig. 4B).
  • the wound tends to be clean (Fig. 4B).
  • fresh granulation tissue was exposed on the wound surface (Fig. 4C), and the inflammation of the wound surface and surrounding tissues was significantly ablated.
  • the skin was completely healed without skin grafting (Fig. 4D, E, F).
  • Figures 5 and 6 show the use of an embodiment of the dressing material of the present invention to treat two mothers and sons who were simultaneously burnt by boiling water: mother, 32 years old; deep burns caused by boiling water in the right foot and ankles; treatment with two burn ointments After 18 days, the condition deteriorated and the injury level became a 3 degree wound. The treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 5A shows the presence of a large amount of necrotic tissue, eschar, axillary ulceration, and redness and inflammation of the wound and surrounding tissues.
  • the wound eschar is basically softened and liquefied after being treated for one day.
  • the embodiment of the dressing material of the present invention is subjected to a healing process similar to that of the mother, and the wound eschar is substantially liquefied by autolysis and debridement within 1 day, and the wound is cleaned after washing with physiological saline (Fig. 6B), after 23 days of treatment. The wound was completely healed without obvious scars (Fig. 6C, D, E, F).
  • Figure 7 illustrates the treatment of a patient with burn wounds using an embodiment of the dressing material of the present invention: male, 4 years old; left lower leg and foot caused by boiling water to cause a deep 2-3 degree burn; treated with other burn therapy for 15 days but with worsening condition; The treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 7A shows the presence of a large amount of necrotic tissue, black eschar, and redness and inflammation of the wound and surrounding tissues on the wound before treatment.
  • the wound eschar was partially liquefied by autolysis, and the unliquefied black suede was also attached to the dressing and removed at the time of replacement (Fig. 7C), the wound was very Cleansing (Fig. 7B), the inflammation of the wound and surrounding tissues subsided significantly. After 6 days of treatment, the wound has healed by approximately 70% (Fig. 7D, E, F).
  • Figure 10 shows a patient with chronic refractory wounds treated with an embodiment of the dressing material of the present invention: male, 61 years old; varicose veins of the left lower leg for 10 years, 2 years ago due to itching and infection, gradually festering and deepening, forming Not getting chronic ulcers. Recently, the wounds worsened after the collision, the wounds were further enlarged and deepened, and the pain was lame; the treatment with other wound healing therapies was still unhealed; then the treatment of the dressing material of the present invention was followed, and the dressing was changed every 2-3 days.
  • Figure 10A shows the presence of necrotic tissue, pus, fibrotic hard palate on the wound before treatment, and redness and hyperpigmentation of the skin around the wound.
  • FIG. 10C shows that the wound eschar was liquefied by autolysis and debridement, and was attached to the dressing and removed at the time of replacement.
  • the wound was very clean (Fig. 10B), and the inflammation of the wound and surrounding tissues subsided significantly.
  • Figure 10C shows that the dressing locks the pus and the liquefied necrotic tissue, preventing it from spreading to the area around the wound where the damage is less and the secretion is less.
  • Figure 10D shows that after 12 days of treatment, the wound granulation tissue is fresh and the exudate is absorbed longitudinally through the dressing (Fig. 10E).
  • Figure 10F shows that the replaced dressing locks the exudate intermittently and prevents it from spreading around the wound. .
  • the wound has basically healed (Fig. 10G, H).
  • Figure 11 shows a patient treated with a burn wound using an embodiment of the dressing material of the present invention: female, 3 years old; the lower back, buttocks and lower extremities are caused by boiling water to cause deep 2 degree burns; treated with an burn cream for 1 day but condition deterioration.
  • the treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 11A shows the presence of a large amount of vesicles and necrotic tissue on the wound before treatment, and the wound and surrounding tissues are red, swollen and inflamed.
  • Figure 13 illustrates the treatment of a patient with a mechanical wound with an embodiment of the dressing material of the present invention: female, 6 years old; a motorcycle wheel wire wound to scratch the right heel, the wound deeper into the muscle layer. Treated with a wound cream for 20 days but the condition deteriorated. The treatment of the dressing material of the present invention is then followed and the dressing is changed every 1-2 days.
  • Figure 13A shows the presence of a large amount of hard fibrotic necrotic tissue on the wound before treatment, and the wound and surrounding tissues are red and swollen.
  • An embodiment of the dressing material of the present invention is applied to the wound surface (Fig. 13B) and then applied to a conventional gauze bandage (Fig. 13C).
  • the wound hard palate After applying the dressing material of the present invention for 2 days, the wound hard palate is softened and liquefied by autolysis, debriding, and adhered to the dressing, and is removed at the time of replacement, and the wound surface is very clean (Fig. 13D), the wound surface and the surrounding tissue. The inflammation subsided significantly. After 40 days of treatment, no skin grafting was required, the body regenerated the subcutaneous tissue, dermis and epithelium, and the wound completely healed (Fig. 13E, F). Fig. 13F shows that the healing skin was close to physiological healing without obvious scarring.
  • the preparation of an embodiment of the composite dressing material of the present invention can be carried out according to the following process: grinding and processing to a solid particle zinc oxide having a diameter of 200 ⁇ m or less and a calcium carbonate ratio of 1:1 by weight It is added to the vegetable oil so that it accounts for 20-30% by weight of each of the mixture.
  • the mixture was mixed by heating and stirring at 80 to 120 C, and then the melted beeswax was added to make it a 2-8% by weight ratio in the mixture.
  • the prepared mixture was filtered through a 120-240 mesh screen and cooled to room temperature to prepare a semi-solid hydrophobic composition.
  • the semi-solid hydrophobic composition is then heated and melted to 70-120 ° C, and then uniformly injected into one or several layers of viscose fiber/polyester hybrid nonwoven fabric by a machine, and cooled to room temperature to form a sheet-type composite dressing. material.
  • the composite dressing material can be cut into shapes of different sizes and then sealed.
  • the preparation of another embodiment of the composite dressing material of the present invention can be carried out according to the following process: grinding the solid particles of zinc oxide and calcium sulfate having a diameter of 80 ⁇ m or less to a 1:1 weight ratio to the sesame oil/olive oil In the mixed oil, it is each present in the mixture in a weight ratio of 20-30%.
  • the mixture was mixed by heating and stirring at 90 to 110 ° C, and then the melted beeswax was added to make it 2 to 8% by weight in the mixture.
  • the resulting mixture was filtered through a 200 mesh screen and cooled to room temperature to prepare a semisolid hydrophobic composition.
  • the semi-solid hydrophobic composition is then heated and melted to 80-100 ° C, and then uniformly injected into one or several layers of viscose/polyester hybrid nonwoven fabric by a machine, and cooled to room temperature to form a sheet-type composite dressing. material.
  • the preparation of another embodiment of the composite dressing material of the present invention can be carried out according to the following process: grinding the solid particles of zinc carbonate and calcium sulfate having a diameter of 100 ⁇ m or less into the rapeseed oil at a weight ratio of 1:1/ In a mixed oil such as olive oil, it is contained in the mixture in a weight ratio of 20-30% by weight.
  • the mixture was mixed by heating and stirring at 80 to 120 ° C, and then the melted beeswax was added to make it 2 to 8% by weight in the mixture.
  • the prepared mixture was filtered through a 120-240 mesh screen and cooled to room temperature to prepare a semi-solid hydrophobic composition.
  • the semi-solid hydrophobic composition is then heated and melted to 80-120 C, and then uniformly injected into one or several layers of viscose/bamboo fiber/polyester hybrid nonwoven fabric by a machine, and cooled to room temperature to form a thin sheet.
  • Type composite dressing material The composite dressing material can be cut into shapes of different sizes and then sealed in a vacuum package.
  • the preparation of another embodiment of the composite dressing material of the present invention can be carried out according to the following process: grinding the solid particles of zinc carbonate and calcium sulfate having a diameter of 100 ⁇ m or less into the tea seed oil in a weight ratio of 1:1. It is made to have a weight ratio of 20-30% in each of the mixtures. At 80-120 ° C The mixture was mixed by heating and stirring, and then the melted beeswax was added to make it a 2-8% by weight ratio in the mixture. The prepared mixture was filtered through a 120-240 mesh screen and cooled to room temperature to prepare a semi-solid hydrophobic composition.
  • the semi-solid hydrophobic composition is then melted by heating to 70-120 ° C, and uniformly injected into one or several layers of bamboo pulp fiber nonwoven fabric by a machine, and cooled to room temperature to form a sheet-type composite dressing material.
  • the composite dressing material can be cut into shapes of different sizes and then sealed.
  • the preparation of another embodiment of the composite dressing material of the present invention can be carried out according to the following process: grinding the solid particles of zinc carbonate and calcium sulfate having a diameter of 100 ⁇ m or less into the rapeseed oil at a weight ratio of 1:1/ In a mixed oil such as tea seed oil, it is made to have a weight ratio of 20-30% in each of the mixtures.
  • the mixture was mixed by heating and stirring at 70 to 120 ° C, and then the melted beeswax was added to make it 3 to 10% by weight in the mixture.
  • the prepared mixture was filtered through a 120-240 mesh screen and cooled to room temperature to prepare a semi-solid hydrophobic composition.
  • the semi-solid hydrophobic composition is then melted by heating to 70-120 ° C, and uniformly injected into one or several layers of bamboo fiber nonwoven fabric by a machine, and cooled to room temperature to form a sheet-type composite dressing material.
  • the composite dressing material can be cut into shapes of different sizes and then sealed in a vacuum package.
  • Figure 15 shows a patient treated with a burn wound using an embodiment of the dressing material of the present invention: male, 32 years old; 2 degrees burned with left thigh by boiling water; no improvement with 5 days of treatment with an burn plaster; followed by dressing of the present invention
  • One embodiment of the material is treated and the dressing is changed every 1-2 days. After 6 days of treatment, the wound has completely healed without obvious scarring.
  • Figure 16 illustrates the treatment of a patient having a burn wound with an embodiment of the dressing material of the present invention: male, 1 year and 6 months; right foot being boiled to cause a 2 degree burn; subsequently treated with an embodiment of the dressing material of the present invention, and Replace the dressing every 1-2 days. After 7 days of treatment, the wound has completely healed without obvious scarring.
  • Figure 17 shows a patient with burn wounds treated with an embodiment of the dressing material of the present invention: female, 5 years and 6 months; 14 days ago, the inner left and right hands of the left thigh were 2-3 degrees burned by boiling water; used in another hospital Other forms of treatment and skin graft failure; subsequent treatment with the examples of dressing materials of the present invention, and dressings changed every 1-2 days. After 17 days of treatment, the wound has basically healed without obvious scars.
  • Figure 18 illustrates the treatment of a patient with a chemical burn wound using an embodiment of the dressing material of the present invention: male, 58 years old; paper mill worker, with the right leg immersed in a storage tank containing a high temperature (130 ° C / 266 ° F) alkaline liquid, Rescued after a few minutes and was admitted to the hospital within 3 hours. He suffered a deep 2-3 degree burn (13% TBSA). Perform standard body burn management. He is treated topically with an embodiment of the dressing material of the present invention and the dressing is changed every 1-2 days. After 19 days of treatment, the wound has basically healed without obvious scars.
  • Figure 19 illustrates the treatment of a patient with a carbon burn wound using an embodiment of the dressing material of the present invention: male, 4 years old; right hand burnt charcoal to cause deep 2 degree burn; treated with a burn ointment for 3 days, but the condition deteriorated; An embodiment of the dressing material of the present invention is treated and the dressing is changed every 1-2 days. After 8 days of treatment, the wound has basically healed without obvious scars.
  • Figure 20 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention: male, 3 years old; right hand was opened by water to cause a deep 2 degree burn; treated with a burn ointment for 1 day, but the condition deteriorated; An embodiment of the dressing material is treated and the dressing is changed every 1-2 days. After 5 days of treatment, the wound has basically healed without obvious scars.
  • Figure 21 illustrates the treatment of a patient with a burn wound with an embodiment of the dressing material of the present invention: male, 1 year and 1 month; right leg is caused by boiling water to cause a deep 2 degree burn; delayed release of the pants deteriorates the condition; An embodiment of the dressing material is treated and the dressing is changed every 1-2 days. After 22 days of treatment, the wound has basically healed without obvious scars.
  • Figure 22 illustrates the treatment of a patient with burn wounds using an embodiment of the dressing material of the present invention: male, 1 year and 2 months; 1 day prior to the left knee and below being boiled to cause a 2-3 degree burn; subsequently using the dressing of the present invention
  • An example of the material is treated and the dressing is changed every 1-2 days. After 28 days of treatment, the wound has basically healed without obvious scars.
  • Figure 23 illustrates the treatment of a patient having an electrical burn wound with an embodiment of the dressing material of the present invention: male, 39 years old, electrician; hands causing electrical burns due to short circuit; subsequently using the embodiment of the dressing material of the present invention Treatment is given and the dressing is changed daily. After 13 days of treatment, the wound has basically healed without obvious scars.
  • Figure 24 shows a patient with an electric burn wound treated with an embodiment of the dressing material of the present invention: male, 60 years old, electrician; high-voltage electric burn on both hands (2-3 degrees) and face (2 degrees); An embodiment of the inventive dressing material is treated and the dressing is changed daily. After 14 days of treatment, the wound has basically healed without obvious scars.
  • Figure 25 illustrates the treatment of a patient having an electrical burn wound with an embodiment of the dressing material of the present invention: male, 52 years old, electrician; high voltage electrical burn on the right hand; followed by treatment with an embodiment of the dressing material of the present invention, and each Replace the dressing once a day. After 16 days of treatment, the wound has basically healed without obvious scars.
  • Figure 26 illustrates the treatment of a patient with leg venous ulcers with an embodiment of the dressing material of the present invention: female, 75 years old; venous stasis for 29 years in the left lower limb; 2 years ago, insect bites caused unhealed ulcers; An embodiment of the dressing material is treated and the dressing is changed every 2-3 days. After 4 weeks of treatment, the wound has healed by about 80%.
  • Figure 27 illustrates the treatment of a patient with leg venous ulcers using an embodiment of the dressing material of the present invention: male, 67 years old; venous stasis for more than 20 years in the left lower extremity; 2 years ago, suffering from an impact injury, which led to treatment of other therapies Ineffective ulceration; subsequent treatment with an embodiment of the dressing material of the present invention, and dressing changed every 1-2 days. After 10 weeks of treatment, the wound has completely healed.
  • Figure 28 illustrates the treatment of a patient with a non-healing surgical wound with an embodiment of the dressing material of the present invention: male, 39 years old; 20 years ago, suffered a car accident, resulting in an open fracture of the right calf tibia; removal of the plate implant This resulted in an unhealed wound from then on; the treatment of the dressing material of the present invention was subsequently followed and the dressing was changed every 2-3 days. After 8 weeks of treatment, the wound has basically healed.
  • Figure 29 illustrates the treatment of a patient with a non-healing surgical wound with an embodiment of the dressing material of the present invention: female, 38 years old; surgical wound on the right wrist, which failed to heal 18 days after the operation of the ganglion cyst; Dyeing and necrosis; treatment with the embodiment of the dressing material of the present invention followed by replacement of the dressing every 1-2 days. After 6 weeks of treatment, the wound has basically healed.
  • Figure 30 illustrates the treatment of a patient with unhealed surgical wounds using an embodiment of the dressing material of the present invention: male, 28 years old; skin cancer resection on the fourth toe of the left foot, leaving unhealed wounds, developing within 20 days For necrosis; toe amputation is recommended in another hospital, but he refuses; subsequent treatment with the embodiment of the dressing material of the present invention, and the dressing is changed every 1-2 days. After 5 weeks of treatment, the wound has healed by about 70%.
  • Figure 31 shows a patient with foot gangrene treated with an embodiment of the dressing material of the present invention: female, 70 years old; having coronary atherosclerosis, coronary artery disease, atrial fibrillation, hyperlipidemia for more than 10 years; 6 months ago
  • the development of the right toe is severe pain; the right foot develops into a dry gangrene; subsequent treatment with the embodiment of the dressing material of the present invention, and the dressing is changed every 1-2 days. After 15 weeks of treatment, the wound has healed by about 95%.

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Abstract

提供具有多功能、高效性仿生皮肤新材料。该材料以复合微孔隙纤丝网结构，模仿皮肤屏障功能，具有防污性、吸湿性、保湿性、透气性、柔韧性及黏附性，能有效吸收创面渗液、残滓而快速无痛自溶清创，双向调节保证充分引流，维持一个有利于创面修复性代谢及生理性愈合的半封闭、局部生理湿润环境，抑制炎症，减少渗出，有利于细胞内外响应，促进机体自身成纤维细胞和表皮细胞移行、伤口肉芽组织和上皮细胞再生，加速创面生理性愈合复原，减少复发。该敷料材料已被临床证明能够加速急性皮肤损伤及慢性溃疡创面的愈合，达到优良的愈合质量，最大程度避免或减少创伤性植皮，减少病人痛苦及瘢痕产生，恢复机体生理功能及容貌。

Description

作为再生性皮肤替代物的多功能皮肤或创面复合敷料
本发明申请要求申请号为62/168,124，申请日为2015年5月29日的美国临时专利申请的优先权和申请号为62/168,184，申请日为2015年5月29日的美国临时专利申请的优先权，该两项在先申请公开的全部技术内容纳入此处作为参考。
技术领域
本发明涉及一种皮肤或创面保护及愈合材料，以及其制备方法与使用方法，特别涉及作为再生性皮肤替代物的多功能皮肤或创面敷料及其在再生医学，创伤救护，伤口护理，医疗美容等领域的应用。
背景技术
创面愈合是一个非常井然有序的且复杂的过程。急性创面愈合通常遵循明确的过程，其被描述如下：凝血；发炎；细胞增殖和基质的修复；上皮化和瘢痕组织的重建。这些反应是通过细胞因子、趋化因子和生长因子，以及这些因子对细胞受体的作用而进行调控的。创面的形状和位置决定创面是否会愈合良好。对创面愈合的干扰也会导致并发症。这些影响因素可能包括营养不良、减少的血液供给、组织创伤、去神经化和感染。可能会导致的并发症包括增生性瘢痕和瘢痕疙瘩、挛缩、裂开、肉芽增生和粘连。
慢性创面是不能在合适的时间长度内恢复解剖和功能完整性的不充分修复的过程的结果。慢性创面在原本健康的个体中是很少见的。事实上，慢性创面的患者经常患有慢性疾病，如糖尿病、肥胖、心血管疾病、肾脏疾病和癌症。慢性创面通常被伪装成合并症，其实它是一种无声流行病，影响着世界上相当一大部分人口，并对全球公共健康和经济造成重大的，正在积聚的威胁。
糖尿病足溃疡长期不愈，特别是兼有神经病变/周围血管病的病人，其严重后果便是截肢。据估计世界范围内每年需要截肢的糖尿病患者超过了一百万，这就意味着平均每30秒世界上就有1例截肢手术发生。一端截肢后的五年生存率仅有50％。另一方面，随着世界人口的老龄化，与老年人密切相关的褥疮、肢端溃疡等慢性伤口护理在西方成为一个日益严重的卫生问题。据称，美国每年在治 疗慢性创面上花费高达250亿美元(Brem H等，分子医学2007；13：30-9)。除了美国等发达国家，世界各地糖尿病和肥胖的发生率均急剧上升，由于增加的健保成本、人口老龄化，治疗慢性创面的负担正在迅速增长。
最常见的慢性创伤为下肢溃疡。慢性静脉功能不全(CVI)占下肢溃疡的80％-90％且影响2％-5％的人口(Kane DP，慢性创面愈合和慢性创面处理，源自：慢性创面护理：医护专业人员的临床原始资料书，第四版，Malvern,PA：HMP Communications公司；2007：11-23)。其他类型的不愈创面是手术、糖尿病、动脉、烧伤、皮炎、脉管炎和辐射。
在生理层面，慢性创面的特征是长期炎症、细菌生物负荷和缺血。在慢性创面的分子环境中，存在多个不利于愈合的组成部分，如高水平的炎性细胞因子、蛋白酶和低水平的生长因子。这些改变终止了愈合过程并增加了脓毒性感染的可能性。所以，解决可能造成生理性创面改变的问题则可重新启动愈合过程。
市场上有各种创面护理产品，包括用于基础创面护理产品(绷带、干性敷料、清洗类)；高级创面护理产品(薄膜、泡沫敷料、胶原蛋白、藻酸盐、水胶体、水凝胶、超级吸收剂类)；生物活性创面护理产品(人工皮肤和皮肤替代物)；以及治疗仪器(负压创面治疗仪、减压仪、电刺激仪、紫外线治疗仪、供氧和高压氧舱设备、漩涡治疗仪、电磁治疗仪和超声治疗仪等)。
在各种治疗形式中，创面床的局部治疗是创面护理的最重要的方面。已开发出许多各种各样的创面护理局部产品以解决复杂的创面愈合过程的不同组成部分，包括抗菌/抗感染创面敷料、湿性创伤敷料、生物活性物质，如含生长因子的乳霜、具有保存的细胞外生物活性因子的脱细胞基质、羊膜和基于活细胞的皮肤替代物。
促进创面愈合的必要局部因子之一是保持创面床湿润。公认为湿润创面与较快的愈合、组织质量更高而且较少瘢痕形成、更少的疼痛相关联。然而，过度湿润会导致浸渍。在创建湿润的环境时，敷料通过将暴露的神经末梢浸于创面分泌物中舒缓了神经末梢，从而最大程度地减少或消除了疼痛并允许更自然地进行愈合。促进湿润创面环境的敷料包括薄膜、泡沫、藻酸盐、水胶体、亲水性纤维和水凝胶。水胶体通过与在创面床上的创面流体胶化而实现了湿润的创面环境。泡沫具有比薄膜和水胶体更好的吸收能力；然而，在创面渗出物少或已通过治疗减 少的情况下，除了那些被认为是“无创性”的泡沫之外的一些泡沫具有粘附至创面床的缺点。未开始的溶解的水胶体基质看起来像脓液或感染；且其通常产生特征性的臭味。水胶体敷料、膏和粉末难以从体腔和已形成窦道的创面移除。当与创面流体相接触时，藻酸盐从纤维转变为提供非粘附创面接触和用于愈合的湿润环境的凝胶。水凝胶在凝胶晶格中含有高水分，因此其不仅是非粘附的，而且为创面提供足够的水分。然而，水凝胶需要二级敷料。如果使用不当或在需要时没有及时更换敷料，藻酸盐则具有超饱和的风险，这可能浸渍周围皮肤或可能变干并与创面组织粘连。
对于“生物活性”的创面护理产品，其通常是非常昂贵的(每次应用费用高达1000美元)。基于活细胞的皮肤替代物(如APLIGRAF、DERMAGRAFT等)需要充分准备的创面床：无感染和健康的肉芽组织。在临床治疗患有挑战性创面病人的现实世界中，创面通常同时并发长期炎症、缺血、焦痂/无法存活的组织/纤维性组织、腐肉、大量的渗出液和耐抗生素治疗的细菌生物膜。有时，在花费一大笔资金后，移植昂贵的皮肤替代物(即使结合其他先进的创面护理形式一起使用)仍会失败，因为在这种创面床条件下移植细胞会失活。此外，对许多具有生物活性的创面护理产品和医疗器械的正确处理和操作，则需要对医疗服务工作者，有时为外科医生，多数时候为护士和/或家庭照顾者，进行广泛的技术培训。
在另一方面，纤维细胞的过度刺激或创面床的干燥造成的胶原蛋白过度沉积会导致广泛的瘢痕形成，从而对病人造成深刻的功能上和美学上的严重后果。通常烧伤后会发生增生性瘢痕形成。对于患者而言，瘢痕可能具有长期持久的功能性、美容性以及心理性后果。正常和增生性瘢痕二者依然是非常难以预防和治疗的。
因此，现有市场对于高端先进、高性能、高性价比的皮肤再生、创面愈合创新材料及创新产品仍存在很大需求，以期简化理顺整个创面护理治疗过程，化繁为简，加速愈合，防止截肢，减少瘢痕，提高愈合质量，从而减轻病人痛苦及医疗系统财政负担。
发明内容
本发明提供了可用于保护皮肤及愈合各种急性和慢性创面的创新性敷料材料。敷料为新颖复合材料，它具有用于有效保护皮肤及体表创面床的仿生皮肤 替代物的特性和属性，质地柔软且柔韧以顺应创面床的凹凸不平的轮廓，在换除时不会与创面床粘连不损伤新生的组织，不扰乱愈合动力学，而且能够保护创面基底部神经末梢，减少疼痛。同时并充当半封闭、透气的仿生皮肤屏障以创建有利于再生创面愈合的理想湿润平衡局部微环境。
本发明的敷料材料还具有多种功能：能够无创地/不经手术地自溶清创失活的或坏死的组织以控制微生物感染而减轻创面的生物负担，同时使对体内的健康活组织的损伤减到最轻，提供抗氧化舒缓并刺激微循环和组织再生，包括毛细血管和神经再生。本发明的敷料材料已被临床证明能够加速急性和慢性创面的愈合，而且达到优良的愈合质量和最大程度地减少瘢痕形成。
在本发明的一个方面中，提供了一种皮肤或创面复合敷料材料。在一个实施例中，所述敷料包括至少一层活性层，所述活性层的基材为多孔聚合物，多孔聚合物基材浸透了半固体疏水组合物；其中半固体疏水组合物包括脂肪酸和嵌入多孔聚合物基材中的固体无机颗粒。
进一步，作为本发明的一种实施方式，所述半固体疏水组合物通过机械加工使得脂肪酸基本均匀浸透多孔聚合物基材，固体无机颗粒基本均匀嵌入多孔聚合物基材中。
于本发明的一个实施例中，半固体疏水组合物基本均匀地浸透在聚合物基材中，共同形成厚度为0.1-10毫米的大致均匀的层。
作为本发明的一种实施方式，所述多孔聚合物具有网状结构，构成网状结构的材料本身包括具有束状结构的纤维，每条束状结构的纤维由多个微纤丝组成。
进一步，微纤丝彼此之间具有空隙。
可选的，所述微纤丝截面的最大直径为0.01-20微米。
本发明中，所述多孔聚合物可以选自源于棉、丝、亚麻、聚酯、尼龙、聚酰胺、聚丙烯、聚氨酯、聚四氟乙烯、粘胶纤维、竹原纤维、竹浆纤维、玉米、大豆、藻酸盐、壳聚糖、透明质酸、动物蛋白织造或非织造的纤维中的一种或多种。
作为本发明的一种实施方式，半固体疏水组合物含有小于复合创面敷料总重量5％的水。
可选的，半固体疏水组合物还包括固化剂，生物可吸收的组合物，水胶体中的一种或多种。
其中在本发明中，所述脂肪酸的浓度为复合创面敷料总重量的20-80％。
进一步，于本发明中，所述固体无机颗粒可以选自滑石、二氧化硅、氧化铝、氧化镁、氧化锌、铁氧化物、碳酸锌、碳酸钙、氯化钙、磷酸钙、硫酸钙和二氧化钛中的一种或多种。
作为本发明的不同实施方式，所述固体无机颗粒的平均尺寸为0.01-50微米，或至少80％的固体无机颗粒尺寸都小于50微米或30微米。
本发明中，可选的，所述固体无机颗粒的浓度为复合创面敷料总重量的20-80％。
进一步，所述复合创面敷料能够加速软化或液化创面上的坏死组织或焦痂，从而导致创面在1-4天之内自溶清创。
在本发明的另一个实施例中，复合敷料材料包括至少两个分离的层，其中第一层包括浸透了半固体疏水组合物的多孔聚合物基材，且第二层包括含有亲水组合物的聚合物基材。
根据该实施例，亲水组合物优选为包括水胶体，例如改性纤维素，如羧甲基纤维素和羟乙基纤维素或藻酸盐、几丁质、壳聚糖和透明质酸的组合物。
在又一个实施例中，复合敷料材料包括至少两个分离的层，其中第一层包括浸透了半固体疏水组合物的多孔聚合物基材，且第二层包括多孔的泡沫聚合物基材。
在本发明另一个实施例中，提供一种皮肤或创面复合敷料套件，所述套件包括上述的复合敷料；以及包覆敷料材料的外封装壳体。
进一步，套件还包括覆盖在复合创面敷料的活性层的面向创面的一侧的第一保护片材，和/或用于将敷料材料固定至哺乳动物的皮肤的粘合材料。
在本发明的另一个方面，提供了一种皮肤或创面复合敷料的制备方法，用包括脂肪酸和固体无机颗粒的半固体疏水组合物浸透多孔聚合物基材，从而使固体无机颗粒基本上均匀地嵌入聚合物基材中。
进一步，于本发明的一个实施例中，所述制备方法包括：将固体无机颗粒加工研磨，然后加入至脂肪酸中，加热搅拌混匀后制成室温状态呈半固体状的疏水组合物；半固体疏水组合物经加热融化后，由机器将其均匀注入一层或数层多孔聚合物基材内，冷却至室温即制成复合敷料材料。
在本发明的另一个方面，提供了一种皮肤或创面复合敷料用于治疗哺乳动物的创面的方法，包括：将上述的复合敷料材料定位以使其与创面部位相接触，并将此敷料材料固定在哺乳动物的皮肤上。
创面的类型包括但不限于急性手术和创伤性创面、烧伤(如热、电烧伤、辐射、化学、霜冻和风寒烧伤以及晒伤)、糖尿病性溃疡、静脉性溃疡、动脉溃疡、压疮(或被称为褥疮溃疡或褥疮)、混合病因的皮肤溃疡，例如因选自糖尿病、心血管疾病、周围性血管疾病、血管炎、中枢或周围神经损伤、肾脏疾病、自身免疫性疾病和癌症所组成的一组中的两个或多个疾病所导致的溃疡、瘘管、皮肤裂隙(由湿疹、接触性皮炎、牛皮癣/银屑病、毛囊炎、痤疮、红斑狼疮、带状疱疹等所导致的)以及其他慢性或坏死创面和炎症性病变和病症。根据本发明的材料主要旨在治疗感染性创面和非感染性创面(即，未显示感染的临床症状的创面)二者。创面不限于开放性的皮肤破裂创面，还包括皮肤完整但皮肤和/或皮下组织受损发炎的情况，例如放射性辐照(如癌症放射治疗法)或其他能量照射，体内或体表手术引起的皮肤发炎、组织纤维化、皮疹、红肿或水肿等。也可用于预防性治疗皮肤损伤，可将发明敷料提前覆盖在将要受影响的皮肤部位，然后再施予能量治疗，以防止或减轻能量辐照引起的组织炎症，纤维化，或其他形式的损伤。
在整个治疗过程中，敷料材料可用作与创面床直接接触的主敷料或与其他创面治疗方法配合使用，如与基于生物活性细胞的创面敷料、自体或异体皮肤移植物(包括自/异体植皮)、脱除细胞基质、羊膜、负压创面疗法和高压氧疗法相结合治疗。
本发明的创新敷料材料使用快速简便，一贴一换，不粘创面，可以无需繁琐的机器辅助治疗和技术训练。可以广泛应用于住院治疗、门诊治疗、康复护理院，养老院、家庭护理、以及野外、战场救护等极端情况。由于其卓越的疗效及愈合效果，此发明的产品特别适用于高端专科创面愈合中心、糖尿病管理中心、专业烧伤中心、整形外科、皮肤科、医疗美容医院等。
附图说明
现在将参照某些优选实施例的附图描述本发明的这些和其他特性和优点，其旨在阐明且不旨在限制本发明，其中相同的参考标号指代相同的组件，其中：
图1示出本发明敷料材料一个薄片型实施例的结构示意图。A：主视图结构示意图。B：纵截面结构示意图；C:图1A和图1B中纤维21的结构示意图。
图2示出本发明的敷料材料一个实施例在扫描电子显微镜下呈现的微观结构。A：在50μm标尺下多孔聚合物基材的网状结构；B：在10μm标尺下多孔聚合物基材中的微纤丝的束状结构。
图3示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图4示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图5示出用本发明敷料材料的实施例治疗被沸水烫伤的患者。
图6示出用本发明敷料材料的实施例治疗被沸水烫伤的患者。
图7示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图8示出本发明的敷料材料一个实施例中的一种固体无机颗粒在扫描电子显微镜下呈现的微观结构。A：在20μm标尺下固体无机颗粒微观结构；B：在3μm标尺下固体无机颗粒微观结构。
图9示出本发明的复合敷料材料一个实施例中的另一种固体无机颗粒在扫描电子显微镜下呈现的微观结构。A：在20μm标尺下固体无机颗粒微观结构；B：在2μm标尺下固体无机颗粒微观结构。
图10示出用本发明敷料材料的实施例治疗具有慢性难愈创面的患者。
图11示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图12(对比医例)示出用市场上一种烧伤膏治疗被沸水烫伤的儿童患者后的创面愈合状况。
图13示出用本发明敷料材料的实施例治疗具有机械创面的患者。
图14(对比医例)示出用另一种治疗方法治疗类似图13示出的具有机械创面的患者后的创面愈合状况。
图15示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图16示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图17示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图18示出用本发明敷料材料的实施例治疗具有化学烧伤创面的患者。
图19示出用本发明敷料材料的实施例治疗具有炭烧伤创面的患者。
图20示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图21示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图22示出用本发明敷料材料的实施例治疗具有烧伤创面的患者。
图23示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者。
图24示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者。
图25示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者。
图26示出用本发明敷料材料的实施例治疗具有腿部静脉溃疡的患者。
图27示出用本发明敷料材料的实施例治疗具有腿部静脉溃疡的患者。
图28示出用本发明敷料材料的实施例治疗具有非愈合性手术创面的患者。
图29示出用本发明敷料材料的实施例治疗具有非愈合性手术创面的患者。
图30示出用本发明敷料材料的实施例治疗具有非愈合性手术创面的患者。
图31示出用本发明敷料材料的实施例治疗具有足坏疽的患者。
具体实施方式
本发明提供了创新性敷料材料及其使用方法和含有所述敷料材料的套件或器械。
尽管已开发出许多各种各样的创面护理产品或医疗器械以处理多阶段创面愈合过程的特定问题。对于慢性创面而言，愈合过程可能更加复杂，其涉及许多细胞层面的参与者和环境因素。临床中的常用的创面敷料具有一些优点以及一些缺点，如1)不能防止微生物侵入(例如，基于细胞的皮肤替代物，皮肤移植物或脱细胞基质)；2)由于敷料与创面表面粘连，在移除时会导致患者的再次创伤(例如，在烧伤患者的高体温下干燥的普通纱布或一些含银的敷料)；3)敷料对创面渗出液的吸收量过低，会导致创面表面上的渗出液积聚而随后成为微生物攻击部位；4)未能提供合适的气体渗透性；5)仅可用于一般创面且不能用于慢性创面；以及6)太干或太湿—即不能保持生理湿润平衡的愈合环境。基于以上这些缺点，医疗人员必须采用多种不同的创面管理方式以解决在创面在逐步愈合过程中面临的各种复杂问题。
本发明提供的敷料材料是具有独特创新的多功能高效性的新材料，可作为“全程一站式”主要创面愈合敷料(One-Stop Primary Wound Dressing throughout the Wound Healing Process)无疼痛、无损伤再生修复各种创面。在优选的实施例 中，材料中独特的纳米级孔隙微粒与超微纤丝网有机结合，模仿皮肤屏障功能，具有防污性、吸湿性、保湿性、透气性、柔韧性及黏附性，既能吸收创面渗液而快速无痛自溶清创，双向调节保证充分引流，又能靶向性、区隔性地将渗液部分保留在敷料中，维持一个有利于创面修复性代谢及生理性愈合的半封闭、局部生理湿润环境，有利于细胞内外响应，促进身体自身成纤维细胞和表皮细胞移行、伤口肉芽组织和上皮细胞再生，加速创面生理性愈合复原，避免或尽少采用创伤性植皮，减少病人痛苦及瘢痕产生。
本发明提供的敷料材料可以灵活应用于开放性、或非开放性的急性创面及慢性创面愈合过程中各个阶段：凝血、发炎、细胞增殖、基质的修复、上皮化以及瘢痕组织的重建。复合敷料材料优选为片材形式且可按一次性即用形式进行封装，这对于不希望因材料的准备工作(例如，对冷冻的基于细胞的皮肤替代物进行解冻、对其进行清洗和保持在适于细胞的生存的窄小温度范围内)或预处理(例如，对干的含有治疗性粉末的敷料进行润湿)而感到烦恼的忙碌临床医生来说是非常需要的临床优势特征。
本发明在各个层面上也是具有成本效益的。由于敷料可以在室温储存，而且是方便的片材封装形式，临床医生、护理者和/或患者本人勿需经过复杂的技术训练或操作仪器，以最少疼痛和最佳愈合时间内管理、护理创面。该敷料对于机构性医疗保健提供者(例如，医院、诊所、创面护理中心、烧伤中心、专业护理机构、康复机构、长期护理机构、老年护理或辅助生活中心)来说具有成本效益，他们可能只需要将本发明敷料用作主敷料以管理许多不同类型的创面和皮肤病变或损伤，包括急性或慢性的。
本发明的敷料材料是一种复合材料，其具有用于保护皮肤或创面床的有效皮肤替代物的特性和属性:作为厚薄适宜的油质半固体状薄片，自然紧密地、熨贴地覆盖在体表创面上形成半封闭、模仿皮肤的物理屏障，有效阻隔环境中病原体污染创面，同时又形成保温、保湿缓冲环境，有效地覆盖和保护创面，减少创面因水分大量迅速挥发丢失而干燥结痂。
本发明的敷料材料柔软且柔韧以顺应创面床的凹凸起伏轮廓，且具有发明人认为对于有效控制微生物感染和炎症来说是至关重要的能力。与市场上许多类型的创面敷料相比，本发明的敷料材料可被轻压形成顺应创面床表面的“微细轮 廓”，从而使最大程度减小细菌可以茁壮成长的空隙和间隙，从而减少细菌感染和形成耐抗生素生物膜的风险。
在临床应用层面上，由于本发明的敷料材料质感柔韧油润、富有弹性，可自然紧密地贴附着于各种生理结构不平坦的创面，附着在创面上时因其高度的弯曲性及柔韧性使病人在机体活动时不易脱落，同时具有较大的肢体顺应性和舒适性。可以延长敷料保护创面的时间，从而减少更换敷料的频率，很受医护人员及患者的欢迎。
本发明的敷料材料在换除时不会与创面床粘连不损伤新生的组织，不扰乱愈合动力学，而且保护创面基底部神经末梢，减少疼痛。同时并充当半封闭、透气的仿生皮肤屏障以创建有利于再生创面愈合的理想湿润平衡微环境—不会太湿以导致浸渍，也不会太干以造成新生再生健康组织的干燥。敷料材料可在室温下存储至少12个月，在不进行任何预处理的情况下即可直接将敷料用在创面上。
如在本文所公开的临床病例中所表现的，敷料材料还是多功能的—能够经自体地溶解清创(自溶清创)失活的或坏死的组织以控制微生物感染(例如，无需借助于对坏死组织进行痛苦的外科手术清创)，提供了抗氧化舒缓以促进细胞增殖并刺激了微循环以促进组织再生，包括毛细管和神经再生。如在实例部分中所描述的，本发明的敷料材料已被临床证明能够加速急性和慢性创面的愈合，而且达到优良的愈合质量和最大程度地减少瘢痕形成。
在本发明的一个方面，提供了一种皮肤/创面复合敷料材料，其包括一层浸透了半固体疏水组合物的多孔聚合物基材的活性层，其中的组合物包括脂肪酸和嵌入聚合物基材的基质中的固体无机颗粒。
图1是本发明的复合敷料材料一个薄片型实施例的结构示意图。具体的，图1A为薄片型的复合敷料材料放置在水平面上时的俯视示意图。如图1A所示，复合敷料材料包括一层活性层10，在活性层10中可见多孔聚合物基材2的网状结构。本发明中，多孔聚合物基材2网状结构可以为规则的，也可以为不规则的。
本实施例的多孔聚合物基材2构成其网状结构的材料本身包括具有束状结构的纤维21。
活性层10中还可见嵌入多孔聚合物基材2中的固体无机颗粒3，固体无机颗粒3大致均匀的分布在多孔聚合物基材2中。由于图1A仅为示意图，仅反映固体无机颗粒3的位置分布，并不能真实反映其尺寸情况。
多孔聚合物基材2浸透了脂肪酸1。
图1B为图1A中薄片型实施例的纵截面结构示意图。由于薄片型的敷料材料其厚度非常薄，仅为0.1-10mm，因此图1B为了显示清楚其结构，对其进行放大，图1B中的结构仅反映辅料材料的基本结构，其尺寸及尺寸比例情况并不能真实反映。如图1A和图1B所示，脂肪酸1基本均匀地浸透在聚合物基材2中，共同形成大致均匀的层。脂肪酸1可以超出多孔聚合物基材2的上下表面。在本实施例中的多孔聚合物基材2直接进行机械加工的表面上，其脂肪酸1的厚度可以大于相对的表面上脂肪酸1的厚度。
图1C是图1A和图1B中纤维21的结构示意图。如图1C所示，每条具有束状结构的纤维21由多个微纤丝211组成。微纤丝211彼此之间具有间隙212。固体无机颗粒3大致均匀的分布在微纤丝211的表面。
在本发明的复合敷料材料这种实施例中，微纤丝截面的最大直径为0.01-20微米，优选为0.01-10微米或0.01-6微米。微纤丝彼此之间的空隙优选为0.01-10微米或0.01-3微米。
图2A和2B是本发明的复合敷料材料一个实施例在扫描电子显微镜下呈现的微观结构。图2A显示在50μm标尺下多孔聚合物基材的网状结构，还显示浸润了脂肪酸的聚合物基材，以及嵌入聚合物基材的基质中的固体无机颗粒。图2B显示在10μm标尺下多孔聚合物基材竹浆纤维中的微纤丝的束状结构，还显示了附着在微纤丝束上的固体无机颗粒。还可见微纤丝之间有大大小小的空隙，犹如毛细管可以有效吸收和蒸发水分。微纤丝的不同取向造成各种纳米至微米级的空隙，其独特结构使其具有优良的可呼吸性、保湿性和透气性。
本发明的复合敷料材料通过具有超微隙的聚合物微纤丝的毛细管效应，由其微纤丝束的中间的空隙及表面微细凹槽吸收水分，缓慢“呼吸”释放，防止创面渗液过度浸渍而阻碍皮肤再生。这样的保湿、透湿双向调节作用保持创面生理性湿润平衡，创造出最佳愈合局部环境。
这样的敷料覆盖在创面上，创造出半封闭的生理性湿润局部生态环境，利用机体自身的防御机制有效促进对坏死组织、焦痂有选择，周围皮肤无损伤的自溶清创—敷料能锁住伤口渗液，使坏死组织软化，同时创面渗液中释放并激活多种酶以及酶的活化因子(特别是蛋白酶和尿激酶)促进纤维蛋白和坏死组织溶解。渗液中还含有吞噬细胞和中性粒细胞，其自身产生的溶解素能有效地溶解坏死组织。溶解的坏死组织残滓随每次更换敷料时被清除出创面，避免或减少了使用选择性低、痛感强的手术清创。
本发明人还惊喜地观察到:使用本发明的复合敷料材料能够迅速软化、液化坏死组织、焦痂，在1-3天之内自溶清创，在更换敷料时将溶解的坏死组织残滓清除出创面，无创清洁创面，无损周围健康皮肤，从而减轻炎症反应，促进肉芽组织迅速再生。相比之下，现有技术中常用的促自溶清创敷料，如水凝胶、水胶体等，则需至少6-7天以上。用于酶解清创的胶原蛋白水解酶则因为对创面坏死组织及创面周围健康组织选择性差，在临床应用受到很大限制；加之是生化酶制剂，其昂贵的价格也给病人及医疗系统带来很大的负担。
图3示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，10岁；左足踝部被沸水造成深2度烧伤；用一种烧伤膏治疗4天但状况恶化随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图3A示出治疗前创面上存在大量坏死组织、焦痂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂经自溶清创基本液化(图3B)，用生理盐水冲洗后,创面趋于洁净，只剩下薄层痂皮(图3C)，创面及周围组织的炎症明显消退。经过14天的治疗，创面完全愈合，没有明显瘢痕(图3D,E,F,G)。
图4示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，1岁5个月；右前臂和手被沸水造成深2度至3度烧伤；用一种烧伤膏治疗16天但状况恶化(由于创面在冬季被暴露于露天中组织坏死加重)且高烧了几天；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图4A示出治疗前创面上满布大量坏死组织、坚硬焦痂，而且创面及周围组织严重红肿发炎，并伴有全身炎症反应。应用本发明敷料材料的实施例经过1天局部治疗，并辅以全身抗菌消炎治疗后，创面坚硬焦痂经自溶清创基本液化，用生理盐水冲洗后,创面趋于洁净(图4B)，治疗4天后创面露出鲜活肉芽组织(图4C)，创面及周围 组织的炎症明显消退。经过46天的局部治疗，无需植皮，创面完全愈合(图4D,E,F)。
图5、6示出用本发明敷料材料的实施例治疗同时被沸水烫伤的母亲及儿子两位患者：母，32岁；右足及足踝部被沸水造成深度烫伤；用了两种烧伤膏治疗18天但状况恶化，伤级加深成为3度创面。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图5A示出治疗前创面上存在大量坏死组织、焦痂，痂下溃烂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂基本软化、液化，用生理盐水冲洗、去除软化的痂皮后,创面洁净(图5B)，创面及周围组织的炎症明显消退，露出鲜活肉芽组织.经过17天的治疗，创面完全愈合，没有明显瘢痕(图5C，D,E,F)。其子，3岁，右足及足踝部伤级与其母类似，也经过同样的治疗过程，用了两种烧伤膏治疗18天后状况恶化，伤级加深成为3度创面(图6A)。应用本发明敷料材料的实施例经过与其母类似的愈合过程，在1天之内创面焦痂经自溶清创基本液化，用生理盐水冲洗后,创面洁净(图6B)，经过23天的治疗，创面完全愈合，没有明显瘢痕(图6C，D,E,F)。
本发明的复合敷料材料还具有高度吸附性，能够有效吸附掉自溶清创后创面渗液、脓液、坏死组织残滓，在换敷料时一并带走，有效充分引流以防止创面感染发炎，减少渗出。
如图7所示，用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，4岁；左小腿和脚被沸水造成深度2-3度烧伤；用其他烧伤疗法治疗了15天但状况恶化；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图7A示出治疗前创面上存在大量坏死组织、黑色焦痂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂经自溶清创有些液化，而未液化的黑色痂皮也附着在敷料上在更换时一并清除(图7C)，创面非常洁净(图7B)，创面及周围组织的炎症明显消退。经过6天的治疗，创面已大约70％愈合(图7D,E,F)。
图8A和8B是本发明的复合敷料材料一个实施例中的一种固体无机颗粒在扫描电子显微镜下呈现的微观结构。图8A显示在20μm标尺下固体无机颗粒微观结构，其呈现为大约长度在1-10μm的微粒。图8B显示在3μm标尺下固体无 机颗粒微观结构，可见长柱状微粒表面具有类似于图2B中微纤丝束的微细凹槽，凹槽大小分布大约在10-500nm左右。
图9A和9B是本发明的复合敷料材料一个实施例中的另一种固体无机颗粒在扫描电子显微镜下呈现的微观结构。图9A显示在20μm标尺下固体无机颗粒微观结构，其呈现为大约长度在1-10μm的微粒。图9B显示在2μm标尺下固体无机颗粒微观结构，可见其微粒呈薄片层状团聚体，表面可见由薄片集聚造成楔形毛细孔，孔径大小分布大约在10-300nm左右。
优选地，本发明的复合敷料材料中的固体无机颗粒的平均尺寸为0.01-50微米。更优选地，敷料材料中至少80％的固体无机颗粒尺寸都小于50微米，30微米，20微米，或10微米。
纳米材料通常是指基本结构三维空间中至少有一维处于纳米尺度范围(1～100nm)的材料,具有极大的比表面积和高孔隙率。普遍认为纳米材料具有量子尺寸效应、小尺寸效应、表面与界面效应与协同效应等性质，表现为比表面积大、表面活性中心多、表面反应活性高、吸附能力强、催化能力高等优势。
在本发明的复合敷料材料中采用如上例所包含的固体无机微粒，能够发挥纳米材料的独特优势，增强微粒的表面的有效吸附面积。这些再与多孔、比表面积较大的聚合物微纤丝网相结合，粘附力得以进一步强化，增加了明显抑菌的生物特性，能有效吸附掉自溶清创后创面渗液、脓液、坏死组织残滓，在换敷料时一并带走，有效充分引流以防止创面感染发炎，减少渗出。
在临床实践中，本发明人更进一步地发现本发明的复合敷料材料还具有靶向区隔护创作用。敷料对同一创面中深浅轻重不同的各部位具有靶向性、区隔性的保护作用。对损伤较深，分泌物较多的部位，敷料能定向吸收锁住多余渗液，阻止其扩散到周围损伤较浅，分泌物较少的部位，从而保护较浅创面不被过度浸渍而抑制愈合。
如图10所示，用本发明敷料材料的实施例治疗具有慢性难愈创面的患者：男，61岁；左小腿患静脉曲张10年，2年前因瘙痒抓破感染，逐渐溃烂加大加深，形成不愈慢性溃疡。近期因碰撞后症加重，创面进一步扩大加深，疼痛跛行；用其他创面愈合疗法治疗仍不愈；随后用本发明的敷料材料的实施例进行治疗，且每2-3天更换一次敷料。图10A示出治疗前创面上存在坏死组织、脓液、纤维 化硬痂，而且创面周围皮肤病变红肿，色素沉着。应用本发明敷料材料的实施例经过2天治疗后，创面焦痂经自溶清创已液化，附着在敷料上在更换时一并清除(图10C)，创面非常洁净(图10B)，创面及周围组织的炎症明显消退。而且图10C显示敷料区隔性地锁住脓液及液化的坏死组织，阻止其扩散到创面周围损伤较浅，分泌物较少的部位。图10D显示经过12天治疗后,创面肉芽组织鲜活，渗液纵向透过敷料被吸收(图10E)，图10F显示换下的敷料区隔性地锁住渗液，阻止其扩散到创面周围。经过32天的治疗，创面已基本愈合(图10G，H)
本发明人近一步地发现本发明的复合敷料材料有效地模仿皮肤屏障作用，在创面上创造的半封闭的生理性湿润环境，极大地有利于减少深层创面皮肤的瘢痕性愈合。在生理性湿润环境下(透明质酸增长更快，维持高浓度时间更长)，成纤维细胞游走性强，迁移速度快，成纤维细胞增殖与胶原蛋白合成同步，从而避免胶原蛋白无序排列，过度沉积。这样的创面愈合模式接近于早期胚胎皮肤无瘢痕愈合模式。
本发明的复合敷料材料的无机微粒微纤丝网能够及时有效吸附掉自溶清创后创面的渗液、脓液、坏死组织残滓，减少因细胞毒素及代谢物引起的炎性反应，从而避免因成纤维细胞的过度繁殖而导致的I型胶原蛋白过度增生，无序沉积而导致的深而厚纤维化瘢痕愈合。其中挛缩性瘢痕是以肢体或器官的功能受到影响而划分的一类瘢痕。它不仅有明显的功能障碍，也存在明显的外观改变。跨越关节部位的较深外伤即使创面愈合后，因为不断的张力影响也容易造成挛缩性瘢痕。由于自身的收缩和增生造成关节活动受限、器官变形和移位畸形。如特别是手足关节部位形成蹼状瘢痕，关节伸展受限。
临床实践中，本发明人观察到：应用本发明的复合敷料材料不但能够快速地愈合关节部位的深度创面(如深二度到三度的烧伤创面)，而且能够有效地防止挛缩性瘢痕的生成，极大程度的减少功能障碍，恢复创伤部位的生理功能及外观。这样的优势特征在整形外科，医疗美容领域具有重大意义，因为它能够避免多次瘢痕修复重建手术带来的痛苦和医疗费用负担。
图4，19，20，23，24和25示出用本发明敷料材料的实施例治疗具有手部深度烧伤创面的患者们。图3，5，6，7，13和14示出用本发明敷料材料的实施例治疗具有踝关节部深度烧伤创面的患者们。图16，18，30和31示出用本发明 敷料材料的实施例治疗具有足部深度烧伤创面的患者们。图11，21和22示出用本发明敷料材料的实施例治疗具有膝关节部位深度烧伤创面的患者们。可以看到他们的深度创面愈合后都没有形成挛缩性瘢痕，新生组织，包括皮肤，均柔软平实，几乎没有瘢痕增生。
不希望受到理论的束缚，发明人认为本发明的复合敷料材料一个实施例中含钙、锌的无机微粒可通过基质金属蛋白酶(MMPs)调控胶原蛋白的合成与分解，减少瘢痕。基质金属蛋白酶MMPs是含钙、锌的内源性多肽酶。钙、锌存在与MMPs分解胶原蛋白的活性密切相关。瘢痕疙瘩，增生性瘢痕与其自身正常皮肤相比,钙、锌、铜、铁，锰、硒等微量元素含量均减少。MMPs活性下降，胶原合成蛋白大于其分解，从而导致瘢痕增生。敷料中的钙、锌能有效调控MMP-1分解多余的I型胶原蛋白，且通过成纤维细胞表面钙离子通道抑制细胞活性，减少I型胶原蛋白过度增生。
复合敷料材料优选采用片材形式且包括根据本发明的敷料材料的活性层。活性层在使用中通常会是创面接触层，但在一些实施例中，其可通过一层直接接触创面的创面治疗物与创面隔开使用，如基于生物活性细胞的创面敷料、自体或异体皮肤移植物(包括自/异体植皮)、脱除细胞基质、羊膜等。
各个敷料片材的面积可被切割成任何大小或形状，其表面积优选为2-1600cm2、更优选为2-400cm2且最优选为4-100cm2。敷料片材的厚度优选为0.1-10mm，0.2-5mm,或0.4-2mm。
敷料片材可通过电离辐射如(钴-60、铯-137等)或通过化学灭菌，如环氧乙烷(EtO)和二氧化氮(NO2)气体而进行消毒。
聚合物基材优选为具有液体吸收性的，但非生物可吸收性的聚合物，其不可在哺乳动物体内充分降解和吸收。这种聚合物包括天然纤维或合成聚合物。天然纤维包括但不限于棉、丝和亚麻。合成聚合物包括但不限于由化学合成聚合物，如聚酯、尼龙、聚酰胺、聚丙烯、聚氨酯、聚四氟乙烯所制造的纤维，以及由天然可得的聚合物，如用于制造粘胶/人造丝/莱赛尔/天丝(TENCEL)/莫代尔(也被称为“人造丝”或“再生纤维素纤维及织物”)的源于木浆(如粘胶纤维等)或竹子(如竹原纤维，竹浆纤维等)所制造的纤维，源于植物蛋白(如玉米、大 豆、藻酸盐和花生)或源于动物蛋白(如源于牛奶的酪蛋白)的蛋白源的再生纤维、藻酸盐、几丁质、壳聚糖、透明质酸等。纤维可以是织造或非织造的。
聚合物基材优选为具有微纤丝的纤维，其微纤丝横截面可为任何形状，优选为圆柱或椭圆形，更优选为具有不规则表面纤丝。微纤丝的横截面最大直径优选为0.01–50μm，更优选为0.1–20μm，且最优选为1–10μm。微纤丝可以相互之间聚集结合成微纤丝，其纤丝之间可形成微孔隙，孔隙宽度大小优选为0.01–10μm，更优选为0.1–10μm，且最优选为0.1–5μm。
半固体疏水组合物优选为基本上匀质的，从而使其基本上均匀地浸透在聚合物基材的基质上以实现厚度为约0.1-10mm，可选为0.2-5mm，0.5-2mm或1-4mm这种浸渍聚合物基质的大致匀质的层。该效果可通过精确控制的机械制造工艺而实现。比如通过调节半固体疏水组合物的粘度、融化温度(比如高于60℃，或高于70℃-90℃，或于70℃-110℃，80℃-100℃)，以及调节将液化的疏水组合物施加于聚合物基质上的压力等。
组合物为疏水的，在其置于创面床上之前含有少于5％、优选为少于1％、最优选为少于0.2％(重量)的水(基于敷料材料的总重量)；且其含有基于敷料材料的总重量的20-80％、可选为30-70％或40-60％(重量)的脂肪酸。
脂肪酸可以是基于植物或动物油，优选为选自由大豆油、菜籽油、橄榄油、椰子油、茶树油、芝麻油、南瓜子油、玉米油、芥花油、蓖麻油、花生油、葵花籽油、棉籽油、奇亚籽油、亚麻籽油、红花油、西兰花籽油、杏仁油、番茄籽油、松子油、澳洲坚果油、山茶籽油、荷荷芭油、葡萄籽油、玫瑰果油、石榴籽油、牛油果脂、月见草油、薰衣草油以及迷迭香油所组成的一组的植物油。这种油可以是有助于提供敷料的柔性且柔软质地的塑化剂。塑化剂也可以是矿物油、凡士林/凡士林油、硅油、硬脂酸盐、氢化醚和酯以及对凡士林的天然植物基的替代物，如牛油树脂、可可油、未精制的椰子油、牛脂、羊毛脂和荷荷芭油。
组合物优选含有固化剂以使油凝固并使组合物在室温下为半固体且柔韧。固化剂优选为蜂蜡(黄色或白色)或乳化蜡，其为鲸蜡硬脂醇、聚山梨醇酯(例如，聚山梨醇酯60)、聚乙二醇(例如，PEG-150)硬脂酸酯、硬脂醇聚醚(由PEG和硬脂醇，如硬脂醇聚醚-20所组成的合成聚合物)等的组合物。
组合物可进一步包括合适的生物可吸收的聚合物，包括选自由胶原蛋白、弹力蛋白、生物可吸收的纤维素衍生物如氧化纤维素、半乳糖甘露聚糖如瓜尔胶/硼酸盐、糖胺聚糖如交联的透明质酸、聚交酯/聚乙交酯、聚羟基丁酸酯及其混合物所组成的一组的聚合物。用于实际应用的优选氧化纤维素是通过再生纤维素，如人造纤维的氧化而制备的氧化再生纤维素(ORC)，这是通过利用有利于减少手术后粘连的ORC的止血特性而实现的。
氧化再生纤维素(ORC)可通过在美国专利申请3，122，479中所描述的工艺而获得的，其全部内容通过引用并入本文。这种材料提供了许多优点，包括具有生物相容性、生物可降解、无免疫原性和容易市购得到的特性。可得到的ORC具有不同的氧化程度且因此具有不同的降解速率。ORC可按不溶性纤维的形式，包括织造、非织造和针织的织物，或按由ORC的碱水解获得的水溶性低分子量片段的形式而使用。
组合物可进一步包括水胶体以助于调整本发明的敷料材料的吸水性和透水性。合适的水胶体包括藻酸盐、果胶、树胶如瓜尔胶或黄原胶、改性纤维素如羧甲基纤维素和羟乙基纤维素、改性淀粉如羟基乙酸淀粉钠及其混合物。这种水胶体可在半固体疏水组合物的浸渍之前浸渍至本发明的敷料材料的聚合物基材的基质上，或可替代地与半固体疏水组合物进行预混合并随后被浸渍至聚合物基材的基质上。
在另一个实施例中，复合敷料材料包括至少两个分离的层，其中第一层包括浸透有半固体疏水组合物的多孔聚合物基材，且第二层包括含有亲水组合物的聚合物基材。
根据该实施例，亲水组合物优选为包括水胶体，如改性纤维素，如羧甲基纤维素和羟乙基纤维素或藻酸盐、几丁质、壳聚糖和透明质酸的组合物。
在另一个实施例中，复合敷料材料包括至少两个分离的层，其中第一层包括浸透有半固体疏水组合物的多孔聚合物基材，且第二层包括多孔的泡沫聚合物基材。
泡沫聚合物基材可以是泡沫敷料，其包括泡沫聚合物，如由聚氨酯、藻酸盐、水胶体或聚丙烯酸酯制成的聚合物。
双层配置在制造根据本发明的复合敷料材料的不同实施例时是非常通用的。例如，其中的第二层包括水胶体组合物或泡沫聚合物基材的敷料可用于对具有过多渗出物的那些创面施加敷料以吸收流体至敷料的最大容量，从而防止创面周边区域的泄漏或浸蚀。
在另一个实施例中，复合敷料材料还包括在浸透有半固体疏水组合物的多孔聚合物基材的活性层上延伸的背衬片，所述背衬片位于活性层的面向创面的反面。优选地，背衬片面积大于活性层，从而具有宽度为0.2-10cm，可选为0.5-5cm的边缘区域在活性层周围延伸以形成所谓的海岛敷料。在这种情况下，背衬片优选为至少在其边缘区域中涂覆压敏医用级粘合剂。
背衬片优选为基本上为不透液的，更优选为半透的，即可使水蒸气透过但不能使液体水或创面渗出物透过的，从而在不使创面周围皮肤发生浸渍的情况下允许敷料下的创面在湿润条件下愈合。优选地，背衬片还是微生物不能透过的。合适的连续一致的背衬片的实例包括聚氨酯、聚烷氧烷基丙烯酸酯和甲基丙烯酸酯。
嵌入根据本发明的敷料材料的固体颗粒优选为无机矿物颗粒，如滑石(硅酸镁)、二氧化硅、氧化镁(MgO)、氧化铝、氧化锌(ZnO)、铁氧化物(FeO、Fe2O3、Fe3O4、Fe4O5、Fe4O3等)、氯化钙、碳酸钙(CaCO3)、碳酸锌(ZnCO3)、磷酸钙(Ca3(PO4)2)、硫酸钙(CaSO4)和二氧化钛(TiO2)。
固体颗粒优选被微粉化或研碎和碾碎成小的细颗粒。颗粒的平均尺寸优选为0.01-50微米、更优选为0.05-20微米、最优选为0.1-10微米。在敷料材料中的固体颗粒的浓度优选为基于敷料材料的总重量的20-80％，可选为30-70％或40-60％(重量)。
细颗粒具有足够小的尺寸以便在接触或摩擦后不造成创面的疼痛。由于其被包含在半固体疏水组合物中并嵌入聚合物基材的基质中，因此这种配置可防止干颗粒再次摩擦脆弱的创面床。该半固体疏水性组合物还可防止肉芽组织过度生长至敷料中，因为这样会在移除敷料后造成疼痛、损坏新生的再生组织并阻碍创面愈合过程。由于颗粒分散在聚合物基材的基质中，其创建了可使气体和水蒸气透过但却不能使微生物透过的网状透气基质，从而有效地保护了创面床以免受到源于环境的细菌和其他有害微生物，以及其他环境因素，如灰尘的侵入。
人类细胞的直径一般在10～20微米，细胞器的直径则从几纳米至数百纳米不等，因此纳米粒子可以很容易地以非侵袭性的方式与细胞内外的生物分子进行信息交流。不希望受到理论的束缚，发明人认为当在聚合物基材的基质上浸渍时，固体颗粒(特别是当小于0.1微米(100纳米)时)可能提供用于组织再生的生物相容支架，其更类似于形成天然细胞支持组织，如作为构建单元用于毛细血管内皮细胞从而再生血管，以及用于神经元从而在皮肤中再生神经末梢。作为神经细胞外基质(ECM)的主要成分的层粘连蛋白、胶原蛋白和纤连蛋白的大小具有相同的数量级，为约60纳米。这些纳米颗粒不仅可以模拟天然组织的粗糙度，而且还由于其独特的表面活力和与蛋白的相互作用(通过选择蛋白的增强吸附和增强的细胞功能而实现)可有效地促进组织再生。
如图2，8，9所示，本发明的复合敷料材料一个实施例在扫描电子显微镜下呈现的微观结构显示出其微观三维空间中基材的微纤丝束的中间的空隙及表面微细凹槽，无机微粒的楔形孔隙及表面微细凹槽至少有一维处于纳米尺度范围(<100nm)，具有极大的比表面积和高孔隙率高度类似细胞外基质，利于细胞的黏附、分化和增殖。此材料中的超细纤维及无机微粒可作为组织支架基底，为细胞提供较适宜的黏附、繁殖和分化环境，有利于组织再生。此材料具有较大的比表面积，能非常容易地实现酶类及其他生物催化剂的固定化。另外，其很高的孔隙率及孔洞内连通性都有利于固定创面上酶和生物催化剂,维持较高的存活率。
发明人还认为通过将这些微小固体颗粒结合至聚合物基材的基质中，敷料材料在被施加至创面后可顺应创面床的轮廓(当机械变形时)，敷料材料可生成瞬时电势，即所谓的压电效应。由于已表明低至10mV/mm的电刺激能够促进神经元的生长，因此认为这种压电材料可有效刺激创面床上的细胞活动，从而加强创面组织再生而不需要任何外部电刺激。这些微粒还可吸附创面床上的细菌，改变其细胞之间粘连形态和密度，从而扰乱细菌菌落或其生物膜的形成，从而减少创面的生物负荷。
如在实例部分中的临床研究中所示，本发明敷料似乎具有一种有效皮肤替代物的特性和属性——其柔软、柔韧且灵活地顺应创面床的轮廓以保护创面床，而且能充当半封闭和透气的皮肤屏障以创建有利于再生创面愈合的理想湿润平衡 微环境，有利于细胞内外响应，促进身体自身成纤维细胞和表皮细胞移行、伤口肉芽组织和上皮细胞再生，加速创面生理性愈合复原，避免或尽少采用创伤性植皮，防止或减少瘢痕产生，极大程度地减少病人生理及心理创伤，恢复机体生理功能及容貌。
图11示出用本发明敷料材料的一个实施例治疗具有烧伤创面的患者：女，3岁；后腰部、臀部及双下肢被沸水造成深2度烧伤；用一种烧伤膏治疗1天但状况恶化。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图11A示出治疗前创面上存在大量泡皮及坏死组织，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过15天的治疗，泡皮及坏死组织经自溶清创，无需植皮，身体再生出真皮及上皮，创面基本愈合(图11B，C)。23天后，创面完全愈合(图11D)。38天后随访，图11E显示愈合的皮肤接近生理性愈合，没有明显瘢痕。
相比之下，本发明人观察到用其他敷料或烧伤外用药治疗后的伤级类似的烫伤儿童病人，则容易造成疤痕增生。如图12A，B，C所示，10个月前在某医院用一种烧伤膏治疗被沸水烫伤的儿童患者(男，2岁；前后腰部、臀部及双下肢部被沸水造成深2度烧伤),基本上所有创面都是增生瘢痕累累。
图18示出用本发明敷料材料的实施例治疗具有严重化学烧伤创面的患者：男，58岁；造纸厂工人，右腿陷入含有高温(130℃/266°F)碱性液体的储罐中，几分钟后救出并在3小时内入院。他遭受了深度2-3度烧伤(TBSA为13％)。进行标准的全身烧伤管理。用本发明的敷料材料的实施例对他进行局部创面治疗，且每1-2天更换一次敷料。图18A，18B示出治疗前创面上存在大量泡皮及坏死组织。应用本发明敷料材料的实施例经过19天的治疗，泡皮及坏死组织经自溶清创去除(图18C)，大量鲜活肉芽组织繁殖铺满创面(图18D)，无需植皮，身体迅速再生出真皮及上皮，创面基本愈合。图18E显示愈合的皮肤接近生理性愈合，没有明显瘢痕。
图13示出用本发明敷料材料的一个实施例治疗具有机械创面的患者：女，6岁；摩托车轮钢丝绞刮伤右脚后跟部，创面深达肌层。用一种创伤膏治疗20天但状况恶化。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图13A示出治疗前创面上存在大量坚硬纤维化坏死组织，而且创面及周 围组织红肿发炎。应用本发明敷料材料的实施例覆盖在创面上(图13B)，然后施予普通纱布绷带包扎(图13C)。应用本发明敷料材料的实施例经过2天治疗后，创面硬痂经自溶清创软化、液化，附着在敷料上在更换时一并清除，创面非常洁净(图13D)，创面及周围组织的炎症明显消退。经过40天的治疗，无需植皮，身体再生出皮下组织、真皮及上皮，创面完全愈合(图13E，F)，图13F显示愈合的皮肤接近生理性愈合，没有明显瘢痕。
相比之下，本发明人观察到用其他敷料或创伤外用药治疗后的伤处及伤级类似的创伤病人，则需要植皮，不仅愈合困难，而且导致瘢痕增生。如图14A，B所示，1月前在某医院治疗的一儿童患者(男，6岁；摩托车轮钢丝绞刮伤右脚后跟部及外侧，创面深达肌层)住院28天，先后做过清创、转移皮瓣植皮术2次。因植皮失败伤口缺损扩大加深，院方安排再做植皮术。但家属见历经三次手术，不仅植皮坏死，供皮区又损伤，拒绝接受再做取、植皮手术。应用本发明敷料材料的一实施例经过43天治疗后，创面硬痂在2-3天内经自溶清创软化、液化，附着在敷料上在更换时一并清除，无需植皮，身体再生出皮下组织、真皮及上皮，创面完全愈合(图14C)，供皮区的皮肤状况也有所改善。
不希望受到理论的束缚，发明人认为嵌入复合敷料材料中的脂肪酸被施加至活的哺乳动物从而被半封闭的湿润环境中的皮肤温热时，油可透过创面表面并通过皂化过程将坏死组织分解成颗粒，从而通过自溶清创机制尽快地在1周内，有时在1-3天，1-4天，或3-5天内液化或软化坏死组织。在换药后，可通过移除本发明的敷料(其吸收了液化的创面残滓)而轻易地移除液化或软化的坏死组织，使新生再生创面床保持洁净且受到最少干扰。与可能不加选择地削除失活的和健康的细胞的手术清创相比，这种自溶清创的模式是非侵入性的且最大程度地保留了细胞在创面床中的活性，包括那些在受损伤后处于滞淤阶段但如果不能及时复苏则失活的细胞。因此，创面的深度可控制得尽可能地浅，从而实现更快的愈合。通过快速自溶清创坏死或失活的组织，可重新激活和强力启动愈合受阻的创面以生成新的肉芽组织并最终实现创面愈合。
本发明的敷料材料还可包括抗氧化剂。不希望受到理论的束缚，发明人认为长期氧化应激可能阻碍创面的愈合和组织再生，因为其会产生慢性炎症，在损害组织重建的情况下将可用的能量供给转向抗氧化防御从而提高了使肉芽组织分 解的基质金属蛋白酶的水平。在慢性创面中，活性氧化物的长期升级可导致过氧化氢诱导的衰老或凋亡或组织坏死，从而导致创面再生延迟。
这样的抗氧化剂或活性氧清除剂可以是天然存在的化学物质或天然材料的提取物，如植物和动物成分，优选为维他命A、维他命C、维他命E、类视黄醇、泛醇、谷胱甘肽、类胡萝卜素、含有多酚(例如，儿茶素、表儿茶素、儿茶素、没食子儿茶素没食子酸酯、没食子儿茶素和表没食子儿茶素没食子酸酯(EGCG))的绿茶提取物、叶绿素、叶绿酸和在最终的提取物粉末中含有至少50％的多酚的甜茶(通用名：甜茶)叶的水：乙醇提取物。这些天然材料也可对创面施加某些抗炎和/或抗过敏作用，其对愈合慢性创面是特别有利的。
抗氧化剂或活性氧清除剂还可以是合成的抗氧化剂，包括但不限于芪、苯胺染料、吖啶染料、硫堇染料，如龙胆紫、苯胺蓝、亚甲基蓝、结晶紫、吖啶黄、靛蓝、亮绿、台盼蓝、台盼红、孔雀绿、扎克林、甲基紫、甲基橙、甲基黄、乙基紫、酸性橙、酸性黄、酸性蓝和酸性红。
抗氧化剂可存在于本发明的敷料材料中，其含量为基于敷料材料的干重的约0.01％至约10％(重量)，优选为0.1至约5％。
本发明的敷料材料还可包括抗菌剂或防腐剂以防止或治疗创面感染。抗微生物可以是天然存在的或合成的成分，如胶体银、银盐、磺胺嘧啶银、硫糖铝、季铵盐、抗生素(如四环素、青霉素、土霉素、红霉素、杆菌肽、新霉素、多粘菌素B、莫匹罗星、克林霉素及其混合物)、肽类抗菌剂(如防御素、马加宁、其合成衍生物)、氯己定、聚维酮碘和三氯生。天然存在的抗菌剂也可以是植物的提取物，如牡丹皮、黄连根、紫草根、生地黄根、黄柏皮或黄芩根，其优选为油提取物；或鱼腥草全植物的提取物、忍冬(日本金银花)花提取物或菘蓝(大青叶)根或叶的提取物，其优选为乙醇：水提取物。
此抗菌剂可存在于本发明的敷料材料中，其含量为基于敷料材料的总重量的约0.01％至约10％(重量)，优选为0.1至约5％。
本发明的敷料材料可进一步包括止痛药以减少创面的疼痛。这种止痛药可以是天然存在的或合成的成分，如非类固醇抗炎药(NSAID，如布洛芬、对乙酰氨基酚)、抗炎类固醇如前列腺素、可待因、二氢可待因酮、吗啡、芬太尼、哌替啶、美沙酮、羟考酮和纳洛酮。天然存在的止痛药也可以是植物提取物，如延胡 索(延胡索)的茎提取物，冰片(从植物，如香樟提取的或合成的)或罂粟(罂粟)的干胶囊，其优选为油提取物。
止痛药可存在于本发明的敷料材料中，其含量为基于敷料材料的总重量的约0.001％至约20％(重量)，优选为0.01至约5％。
在本发明的另一个方面，提供了一种用于治疗哺乳动物的创面的方法，其包括：将复合敷料材料定位以使其与创面部位相接触，并将此敷料材料固定在哺乳动物的皮肤上。
哺乳动物可以是人或选自由狗、猫、猪、牛、马、绵羊、山羊、老虎、狮子、狼、大象、兔、豚鼠、仓鼠、大鼠和小鼠所组成的一组的哺乳动物。
创面的类型包括但不限于急性手术和创伤性创面、烧伤(如热、电烧伤、辐射、化学、霜冻和风寒烧伤以及晒伤)、糖尿病性溃疡、静脉性溃疡、动脉溃疡、压疮(或被称为褥疮溃疡或褥疮)、混合病因的皮肤溃疡，例如因选自糖尿病、心血管疾病、周围性血管疾病、血管炎、中枢或周围神经损伤、肾脏疾病、自身免疫性疾病和癌症所组成的一组中的两个或多个疾病所导致的溃疡、瘘管、皮肤裂隙(由湿疹、接触性皮炎、牛皮癣/银屑病、毛囊炎、痤疮、红斑狼疮、带状疱疹等所导致的)以及其他慢性或坏死创面和炎症性病变和病症。根据本发明的材料主要旨在治疗感染性创面和非感染性创面(即，未显示感染的临床症状的创面)二者。创面不限于开放性的皮肤破裂创面，还包括皮肤完整但皮肤和/或皮下组织受损发炎的情况，例如放射性辐照(如癌症放射治疗法)或其他能量照射，体内或体表手术引起的皮肤发炎、组织纤维化、皮疹、红肿或水肿等。也可用于预防性治疗皮肤损伤，可将发明敷料提前覆盖在将要受影响的皮肤部位，然后再施予能量治疗，以防止或减轻能量辐照引起的组织炎症，纤维化，或其他形式的损伤。
在一个实施例中，提供了一种用于治疗人的慢性创面的方法，其包括：将本发明的复合敷料材料定位以使其与一人的创面部位相接触，并将此敷料材料固定在该人的皮肤上，其中该人具有未愈合创面至少2个月，可选为至少3-6个月或至少一年。可选地，该人之前已使用选自由基于活细胞的皮肤替代物、植皮、脱除细胞基质、含银敷料、酶清创剂、生长因子、羊膜、负压创面疗法、超声疗法、电刺激疗法和高压氧疗法所组成的一组的创面护理形式进行治疗。
在另一个实施例中，提供了一种用于治疗人的慢性创面的方法，其包括：将本发明的复合敷料材料定位以使其与一人的创面部位相接触，并将此敷料材料固定在该人的皮肤上，其中创面的面积在4周的治疗中减少了至少50％。
敷料材料在整个治疗过程中可被用作与创面床直接接触的主敷料。用户可方便地将敷料材料敷在创面床上并通过使用胶布绷带将其固定至创面床。
替代地，本发明的敷料材料可与其他创面治疗方法相结合使用，如基于生物细胞的创面敷料、自体或异体皮肤移植物(包括自/异体植皮)、脱除细胞基质、负压创面疗法(NPWT)和高压氧疗法。本发明的敷料材料可充当覆盖在植皮、基于生物细胞的创面敷料、脱除细胞基质、基于胶原蛋白的敷料等一级敷料之上的二级敷料。这种构架是有利的，这是因为本发明的敷料材料可提供洁净且生理湿润平衡的愈合环境以保护生物性敷料以免由于微生物感染/污染或由于创面床的干燥而因失活发生降解。
此外，由于本发明的敷料材料可以是透气的，其还可在负压创面疗法(NPWT)中使用的泡沫敷料下使用以保护新生的再生创面床免受机械性损伤以及以免使创面床干燥。
此外，替代地，本发明的敷料材料可与促组织再生的生长因子结合使用。生长因子可以选自由表皮生长因子(EGF)、成纤维细胞生长因子(FGF)、血小板衍生的生长因子(PDGF)、转化生长因子β(TGF-β)、血管内皮生长因子(VEGF)和类胰岛素生长因子(IGF)及其混合物所组成的一组。生长因子可被局部施用于创面床或全身性施加到具有创面的患者上。例如，液体形式的生长因子可被直接喷洒至创面床，接着将本发明的敷料材料施加至创面床。这样的组合可以是协同的以通过减少深度创面的瘢痕形成而进一步加速创面愈合并增强愈合质量。
此外，替代地，本发明的敷料材料可与含银敷料相结合使用。例如，本发明的敷料材料可被直接施加至创面，然后施加含银敷料(如纳米银创面敷料、含银泡沫敷料等)以进一步地保护创面以免受到感染和/或从创面吸收过多的渗出物。
此外，替代地，本发明的敷料材料可广泛应用于整形外科及医疗美容。多数情况下深二度以上烧伤，手术及其它创面按常规治疗往往是瘢痕愈合。患者往往需要经过多次愈后瘢痕修复重建手术以期达到减轻生理运动功能障碍和最大限 度恢复容貌效果。本发明的敷料材料可直接覆盖在瘢痕皮肤表面以促进皮肤的更新代谢，褪去瘢痕组织，取而代之的是新生的更正常的皮肤组织。也可以结合外科手术以及其它医疗器械，比如激光，红外线，声波，超声波，电磁波，机械磨皮等仪器，协同地达到最佳治疗效果。此外，还可以结合化学脱皮方法，将本发明的敷料材料直接覆盖在经化学脱皮后(如果酸换肤等)的皮肤表面以迅速抑制皮肤的炎症，提供理想的生理湿润愈合局部环境，减少热源损伤及因炎症带来的色素沉着，促进瘢痕修复，磨皮换肤后的皮肤再生愈合。
在本发明的又一个方面，提供了一种皮肤或创面复合敷料套件，所述套件包括上述的本发明的复合敷料；以及包覆敷料材料的外封装壳体。
进一步，套件还包括覆盖在复合创面敷料的活性层的面向创面的一侧的第一保护片材，和/或用于将敷料材料固定至哺乳动物的皮肤的粘合材料。
在一个实施例中，套件还包括覆盖在复合敷料材料的活性层的面向创面的一侧的第一保护片材。在将复合敷料材料施加至创面前，移除保护片材。保护片材可充当隔离活性层的面向创面的一侧与包覆敷料材料的外封装材料之间的屏障。
可选地，套件还包括覆盖在复合敷料材料的活性层的面向创面的反面的第二保护片材。第二保护片材可以是基本上不透气体、蒸气或液体的有效屏障，从而延长敷料材料的保存期限。
在另一个实施例中，包覆复合敷料材料的外封装壳体是用于容纳敷料材料的小袋。在将复合敷料材料施加至创面前，移除该小袋。外部壳体优选为基本上不透气体、蒸气或液体的，优选为真空包装袋，从而延长敷料材料的保存期限。这种封闭壳体材料的实例包括但不限于一般的塑料片材、聚酯薄膜、聚对苯二甲酸乙二醇酯(PET或MYLAR)，其可以是透明的、半透明的、有色的或以金属(通常为铝)薄层进行金属化的，优选为铝塑聚酯复合膜包装袋。
对于渗出的创面，用户可将吸收层定位在复合敷料材料的活性层的面向创面的反面上以从创面吸收过多的创面流体、血清或血液，包括纱布、无纺布、高吸水性树脂、水凝胶、吸湿泡沫如聚氨酯泡沫。
在进一步的方面，本发明提供了一种制造本发明的复合敷料材料的方法，其包括下列步骤：用包括脂肪酸和固体无机颗粒的半固体疏水组合物浸透多孔聚合物基材，从而使固体无机颗粒基本上均匀地嵌入聚合物基材的基质中。
根据本方法，浸透多孔聚合物基材的步骤可在50℃以上的温度进行，可选为60℃或80℃以上，在该温度上，半固体疏水组合物基本上被液化。浸透多孔聚合物基材的步骤通过精确控制的机械制造工艺基本上均匀地将液化疏水组合物注入在多孔聚合物基材的片材上而实现，从而使基材中浸透的疏水组合物的平均厚度为约0.1-10mm，可选为0.2-5mm或1-4mm。
将理解的是，本文中描述的关于本发明的任何一个方面的任何特性或实施例也可被应用于本发明的任何其他方面。
现在将在下列实例中进一步地描述本发明的某些特定实施例。
实例
实例1
图3示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，10岁；左足踝部被沸水造成深2度烧伤；用一种烧伤膏治疗4天但状况恶化随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图3A示出治疗前创面上存在大量坏死组织、焦痂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂经自溶清创基本液化(图3B)，用生理盐水冲洗后,创面趋于洁净，只剩下薄层痂皮(图3C)，创面及周围组织的炎症明显消退。经过14天的治疗，创面完全愈合，没有明显瘢痕(图3D,E,F,G)。
实例2
图4示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，1岁5个月；右前臂和手被沸水造成深2度至3度烧伤；用一种烧伤膏治疗16天但状况恶化(由于创面在冬季被暴露于露天中组织坏死加重)且高烧了几天；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图4A示出治疗前创面上满布大量坏死组织、坚硬焦痂，而且创面及周围组织严重红肿发炎，并伴有全身炎症反应。应用本发明敷料材料的实施例经过1天局部治疗，并辅以全身抗菌消炎治疗后，创面坚硬焦痂经自溶清创基本液化，用生理盐水冲洗后,创面趋于洁净(图4B)，治疗4天后创面露出鲜活肉芽组织(图4C)，创面及周围组织的炎症明显消退。经过46天的局部治疗，无需植皮，创面完全愈合(图4D,E,F)。
实例3
图5、6示出用本发明敷料材料的实施例治疗同时被沸水烫伤的母亲及儿子两位患者：母，32岁；右足及足踝部被沸水造成深度烫伤；用了两种烧伤膏治疗18天但状况恶化，伤级加深成为3度创面。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图5A示出治疗前创面上存在大量坏死组织、焦痂，痂下溃烂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂基本软化、液化，用生理盐水冲洗、去除软化的痂皮后,创面洁净(图5B)，创面及周围组织的炎症明显消退，露出鲜活肉芽组织.经过17天的治疗，创面完全愈合，没有明显瘢痕(图5C，D,E,F)。其子，3岁，右足及足踝部伤级与其母类似，也经过同样的治疗过程，用了两种烧伤膏治疗18天后状况恶化，伤级加深成为3度创面(图6A)。应用本发明敷料材料的实施例经过与其母类似的愈合过程，在1天之内创面焦痂经自溶清创基本液化，用生理盐水冲洗后,创面洁净(图6B)，经过23天的治疗，创面完全愈合，没有明显瘢痕(图6C，D,E,F)。
实例4
图7示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，4岁；左小腿和脚被沸水造成深度2-3度烧伤；用其他烧伤疗法治疗了15天但状况恶化；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图7A示出治疗前创面上存在大量坏死组织、黑色焦痂，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过1天治疗后，创面焦痂经自溶清创有些液化，而未液化的黑色痂皮也附着在敷料上在更换时一并清除(图7C)，创面非常洁净(图7B)，创面及周围组织的炎症明显消退。经过6天的治疗，创面已大约70％愈合(图7D,E,F)。
实例5
图10示出用本发明敷料材料的实施例治疗具有慢性难愈创面的患者：男，61岁；左小腿患静脉曲张10年，2年前因瘙痒抓破感染，逐渐溃烂加大加深，形成不愈慢性溃疡。近期因碰撞后症加重，创面进一步扩大加深，疼痛跛行；用其他创面愈合疗法治疗仍不愈；随后用本发明的敷料材料的实施例进行治疗，且每2-3天更换一次敷料。图10A示出治疗前创面上存在坏死组织、脓液、纤维化硬痂，而且创面周围皮肤病变红肿，色素沉着。应用本发明敷料材料的实施例经 过2天治疗后，创面焦痂经自溶清创已液化，附着在敷料上在更换时一并清除(图10C)，创面非常洁净(图10B)，创面及周围组织的炎症明显消退。而且图10C显示敷料区隔性地锁住脓液及液化的坏死组织，阻止其扩散到创面周围损伤较浅，分泌物较少的部位。图10D显示经过12天治疗后,创面肉芽组织鲜活，渗液纵向透过敷料被吸收(图10E)，图10F显示换下的敷料区隔性地锁住渗液，阻止其扩散到创面周围。经过32天的治疗，创面已基本愈合(图10G，H)。
实例6
图11示出用本发明敷料材料的一个实施例治疗具有烧伤创面的患者：女，3岁；后腰部、臀部及双下肢被沸水造成深2度烧伤；用一种烧伤膏治疗1天但状况恶化。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图11A示出治疗前创面上存在大量泡皮及坏死组织，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例经过15天的治疗，泡皮及坏死组织经自溶清创，无需植皮，身体再生出真皮及上皮，创面基本愈合(图11B，C)。23天后，创面完全愈合(图11D)。38天后随访，图11E显示愈合的皮肤接近生理性愈合，没有明显瘢痕。
实例7
图13示出用本发明敷料材料的一个实施例治疗具有机械创面的患者：女，6岁；摩托车轮钢丝绞刮伤右脚后跟部，创面深达肌层。用一种创伤膏治疗20天但状况恶化。随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。图13A示出治疗前创面上存在大量坚硬纤维化坏死组织，而且创面及周围组织红肿发炎。应用本发明敷料材料的实施例覆盖在创面上(图13B)，然后施予普通纱布绷带包扎(图13C)。应用本发明敷料材料的实施例经过2天治疗后，创面硬痂经自溶清创软化、液化，附着在敷料上在更换时一并清除，创面非常洁净(图13D)，创面及周围组织的炎症明显消退。经过40天的治疗，无需植皮，身体再生出皮下组织、真皮及上皮，创面完全愈合(图13E，F)，图13F显示愈合的皮肤接近生理性愈合，没有明显瘢痕。
实例8
本发明的复合敷料材料的一种实施例的制备可以按照以下工艺流程制造出来：将加工研磨至直径200μm以下的固体颗粒氧化锌与碳酸钙按1:1的重量比 加入到植物油中，使其在此混合物中各自占20-30％的重量比。在80-120C下加热搅拌混匀此混合物，然后加入融化后的蜂蜡，使其在此混合物中占2-8％的重量比。制作的混合物经120-240目网筛过滤后，冷却至室温即制成半固体疏水组合物。此半固体疏水组合物然后经加热融化至70-120℃后，由机器将其均匀注入一层或数层粘胶纤维/聚酯混合无纺布内，冷却至室温即制成薄片型复合敷料材料。此复合敷料材料可裁切成大小不同规格的形状，然后进行密封包装。
实例9
本发明的复合敷料材料的另一种实施例的制备可以按照以下工艺流程制造出来：将加工研磨至直径80μm以下的固体颗粒氧化锌与硫酸钙按1:1的重量比加入到芝麻油/橄榄油等混合油中，使其在此混合物中各自占20-30％的重量比。在90-110℃下加热搅拌混匀此混合物，然后加入融化后的蜂蜡，使其在此混合物中占2-8％的重量。制作的混合物经200目网筛过滤后，冷却至室温即制成半固体疏水组合物。此半固体疏水组合物然后经加热融化至80-100℃后，由机器将其均匀注入一层或数层粘胶纤维/聚酯混合无纺布内，冷却至室温即制成薄片型复合敷料材料。
实例10
本发明的复合敷料材料的另一种实施例的制备可以按照以下工艺流程制造出来：将加工研磨至直径100μm以下的固体颗粒碳酸锌与硫酸钙按1:1的重量比加入到菜籽油/橄榄油等混合油中，使其在此混合物中各自占20-30％的重量比。在80-120℃下加热搅拌混匀此混合物，然后加入融化后的蜂蜡，使其在此混合物中占2-8％的重量。制作的混合物经120-240目网筛过滤后，冷却至室温即制成半固体疏水组合物。此半固体疏水组合物然后经加热融化至80-120C后，由机器将其均匀注入一层或数层粘胶纤维/竹浆纤维/聚酯混合无纺布内，冷却至室温即制成薄片型复合敷料材料。此复合敷料材料可裁切成大小不同规格的形状，然后进行密封真空包装。
实例11
本发明的复合敷料材料的另一种实施例的制备可以按照以下工艺流程制造出来：将加工研磨至直径100μm以下的固体颗粒碳酸锌与硫酸钙按1:1的重量比加入到茶籽油中，使其在此混合物中各自占20-30％的重量比。在80-120℃下 加热搅拌混匀此混合物，然后加入融化后的蜂蜡，使其在此混合物中占2-8％的重量比。制作的混合物经120-240目网筛过滤后，冷却至室温即制成半固体疏水组合物。此半固体疏水组合物然后经加热融化至70-120℃后，由机器将其均匀注入一层或数层竹浆纤维无纺布内，冷却至室温即制成薄片型复合敷料材料。此复合敷料材料可裁切成大小不同规格的形状，然后进行密封包装。
实例12
本发明的复合敷料材料的另一种实施例的制备可以按照以下工艺流程制造出来：将加工研磨至直径100μm以下的固体颗粒碳酸锌与硫酸钙按1:1的重量比加入到菜籽油/茶籽油等混合油中，使其在此混合物中各自占20-30％的重量比。在70-120℃下加热搅拌混匀此混合物，然后加入融化后的蜂蜡，使其在此混合物中占3-10％的重量。制作的混合物经120-240目网筛过滤后，冷却至室温即制成半固体疏水组合物。此半固体疏水组合物然后经加热融化至70-120℃后，由机器将其均匀注入一层或数层竹纤维无纺布内，冷却至室温即制成薄片型复合敷料材料。此复合敷料材料可裁切成大小不同规格的形状，然后进行密封真空包装。
实例13
图15示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，32岁；左大腿被开水造成2度烫伤；用一种烧伤膏治疗5天无改善；随后用本发明的敷料材料的一个实施例进行治疗，且每1-2天更换一次敷料。经过6天的治疗，创面已完全愈合，没有明显瘢痕。
实例14
图16示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，1岁6个月；右脚被开水造成2度烫伤；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过7天的治疗，创面已完全愈合，没有明显瘢痕。
实例15
图17示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：女，5岁6个月；14天前，左大腿内侧和右手被开水造成2-3度烧伤；在另一家医院用其他形式治疗且植皮失败；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过17天的治疗，创面已基本愈合，没有明显瘢痕。
实例16
图18示出用本发明敷料材料的实施例治疗具有化学烧伤创面的患者：男，58岁；造纸厂工人，右腿陷入含有高温(130℃/266°F)碱性液体的储罐中，几分钟后救出并在3小时内入院。他遭受了深度2-3度烧伤(TBSA为13％)。进行标准的全身烧伤管理。用本发明的敷料材料的实施例对他进行局部治疗，且每1-2天更换一次敷料。经过19天的治疗，创面已基本愈合，没有明显瘢痕。
实例17
图19示出用本发明敷料材料的实施例治疗具有炭烧伤创面的患者：男，4岁；右手被烧炭造成深2度烧伤；用一种烧伤膏治疗3天，但状况恶化；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过8天的治疗，创面已基本愈合，没有明显瘢痕。
实例18
图20示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，3岁；右手被开水造成深2度烧伤；用一种烧伤膏治疗1天，但状况恶化；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过5天的治疗，创面已基本愈合，没有明显瘢痕。
实例19
图21示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，1岁1个月；右腿被开水造成深度2度烧伤；延迟的脱裤恶化了状况；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过22天的治疗，创面已基本愈合，没有明显瘢痕。
实例20
图22示出用本发明敷料材料的实施例治疗具有烧伤创面的患者：男，1岁2个月；1天前，左膝及以下被开水造成2-3度烧伤；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过28天的治疗，创面已基本愈合，没有明显瘢痕。
实例21
图23示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者：男，39岁，电工；双手因电路短路而导致电烧伤；随后用本发明的敷料材料的实施例进 行治疗，且每日更换一次敷料。经过13天的治疗，创面已基本愈合，没有明显瘢痕。
实例22
图24示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者：男，60岁，电工；双手(2-3度)和面部(2度)上具有高压电烧伤；随后用本发明的敷料材料的实施例进行治疗，且每日更换一次敷料。经过14天的治疗，创面已基本愈合，没有明显瘢痕。
实例23
图25示出用本发明敷料材料的实施例治疗具有电烧伤创面的患者：男，52岁，电工；右手上具有高压电烧伤；随后用本发明的敷料材料的实施例进行治疗，且每日更换一次敷料。经过16天的治疗，创面已基本愈合，没有明显瘢痕。
实例24
图26示出用本发明敷料材料的实施例治疗具有腿部静脉溃疡的患者：女，75岁；左下肢具有静脉淤滞29年；2年前，昆虫叮咬导致不愈溃疡；随后用本发明的敷料材料的实施例进行治疗，且每2-3天更换一次敷料。经过4周的治疗，创面已约80％愈合。
实例25
图27示出用本发明敷料材料的实施例治疗具有腿部静脉溃疡的患者：男，67岁；左下肢具有静脉淤滞20年以上；2年前，遭受冲击伤，这导致了其他疗法的治疗失效的不愈溃疡；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过10周的治疗，创面已完全愈合。
实例26
图28示出用本发明敷料材料的实施例治疗具有不愈手术创面的患者：男，39岁；二十年前，遭受车祸，导致了右小腿胫骨的开放性骨折；移除钢板植入物后导致了从那时开始的不愈创面；随后用本发明的敷料材料的实施例进行治疗，且每2-3天更换一次敷料。经过8周的治疗，创面已基本愈合。
实例27
图29示出用本发明敷料材料的实施例治疗具有不愈手术创面的患者：女，38岁；右手腕上具有手术创面，其在腱鞘囊肿手术后18天未能愈合；其受到感 染并坏死；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过6周的治疗，创面已基本愈合。
实例28
图30示出用本发明敷料材料的实施例治疗具有不愈手术创面的患者：男，28岁；在左脚的第四趾进行了皮肤癌切除，留下了不愈创面，在20天内发展为坏死；在另一家医院建议进行脚趾截肢，但他拒绝了；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过5周的治疗，创面已约70％愈合。
实例29
图31示出用本发明敷料材料的实施例治疗具有足坏疽的患者：女，70岁；其具有冠状动脉粥样硬化、冠状动脉疾病、房颤、高血脂症10年以上；6个月前，发展为右脚趾剧烈疼痛；右脚发展为干性坏疽；随后用本发明的敷料材料的实施例进行治疗，且每1-2天更换一次敷料。经过15周的治疗，创面已约95％愈合。
虽然以上描述是本发明的优选实施例的示例性描述，但相关领域中的普通技术人员将认识到，许多变化、变更、修改、替换等也是很容易实现的，特别是根据本说明书和附图而实现。在任何情况下，由于本发明的范围比任何特定实施例的范围广泛，以上的详细描述不应被解释为限制本发明的范围，本发明的范围仅由随附权利要求限定。

Claims (20)

  1. 一种作为再生性皮肤替代物的多功能皮肤或创面复合敷料，其特征在于，所述敷料包括至少一层活性层，所述活性层的基材为多孔聚合物，多孔聚合物基材浸透了半固体疏水组合物；其中半固体疏水组合物包括脂肪酸和嵌入多孔聚合物基材中的固体无机颗粒。
  2. 根据权利要求1所述的复合敷料，其特征在于，所述半固体疏水组合物通过机械加工使得脂肪酸基本均匀浸透多孔聚合物基材，固体无机颗粒基本均匀嵌入多孔聚合物基材中。
  3. 根据权利要求2所述的复合敷料，其特征在于，半固体疏水组合物基本均匀地浸透在聚合物基材中，共同形成厚度为0.1-10毫米的大致均匀的层。
  4. 根据权利要求1所述的复合敷料，其特征在于，所述多孔聚合物具有网状结构，构成网状结构的材料本身包括具有束状结构的纤维，每条束状结构的纤维由多个微纤丝组成。
  5. 根据权利要求4所述的复合敷料，其特征在于，微纤丝彼此之间具有空隙。
  6. 根据权利要求4所述的复合敷料，其特征在于，所述微纤丝截面的最大直径为0.01-20微米。
  7. 根据权利要求1所述的复合敷料，其特征在于，所述多孔聚合物选自源于棉、丝、亚麻、聚酯、尼龙、聚酰胺、聚丙烯、聚氨酯、聚四氟乙烯、粘胶纤维、竹原纤维、竹浆纤维、玉米、大豆、藻酸盐、壳聚糖、透明质酸、动物蛋白的织造或非织造的纤维中的一种或多种。
  8. 根据权利要求1所述的复合敷料，其特征在于，半固体疏水组合物含有小于复合敷料总重量5％的水。
  9. 根据权利要求1所述的复合敷料，其特征在于，半固体疏水组合物还包括固 化剂，生物可吸收的组合物，水胶体中的一种或多种。
  10. 根据权利要求1所述的复合敷料，其特征在于，所述脂肪酸的浓度为复合敷料总重量的20-80％。
  11. 根据权利要求1所述的复合敷料，其特征在于，所述固体无机颗粒选自滑石、二氧化硅、氧化铝、氧化镁、氧化锌、铁氧化物、碳酸锌、碳酸钙、氯化钙、磷酸钙、硫酸钙和二氧化钛中的一种或多种。
  12. 根据权利要求1所述的复合敷料，其特征在于，所述固体无机颗粒的平均尺寸为0.01-50微米，或至少80％的固体无机颗粒尺寸都小于50微米或30微米。
  13. 根据权利要求1所述的复合敷料，其特征在于，所述固体无机颗粒的浓度为复合敷料总重量的20-80％。
  14. 根据权利要求1所述的复合敷料，其特征在于，所述复合敷料能够加速软化或液化创面上的坏死组织或焦痂，从而导致创面在1-4天之内自溶清创。
  15. 一种皮肤或创面复合敷料套件，其特征在于，所述套件包括权利要求1-14任意一项所述的复合敷料；以及包覆敷料材料的外封装壳体。
  16. 根据权利要求15所述的复合敷料套件，其特征在于，套件还包括覆盖在复合敷料的活性层的面向创面的一侧的第一保护片材，和/或用于将敷料材料固定至哺乳动物的皮肤的粘合材料。
  17. 一种皮肤或创面复合敷料的制备方法，其特征在于，用包括脂肪酸和固体无机颗粒的半固体疏水组合物浸透多孔聚合物基材，从而使固体无机颗粒基本上均匀地嵌入聚合物基材中。
  18. 根据权利要求17所述的制备方法，其特征在于，所述制备方法包括：将加 工研磨后的固体无机颗粒加入至脂肪酸中，加热搅拌混匀后制成室温状态呈半固体状的疏水组合物；半固体疏水组合物经加热融化后，由机器将其均匀注入一层或数层多孔聚合物基材内，冷却至室温即制成复合敷料材料。
  19. 一种皮肤或创面复合敷料用于治疗哺乳动物的皮肤或创面的方法，其特征在于，其包括：将如权利要求1所述的复合敷料定位以使其与需要治疗的皮肤或创面部位相接触，并将此敷料固定在哺乳动物的皮肤上。
  20. 根据权利要求19所述的治疗哺乳动物的皮肤或创面的方法，其特征在于，其哺乳动物的创面选自源于手术和创伤性创面、烧伤、烫伤、热源性皮肤损伤、化学烧伤、电烧伤、晒伤、冻伤、糖尿病性溃疡、静脉性溃疡、动脉溃疡、压疮、混合病因的皮肤损伤、瘘管、皮肤炎症、疱疹、裂隙中的一种或多种。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3448396A4 (en) * 2017-04-14 2020-01-22 President and Fellows of Harvard College METHOD FOR PRODUCING A MICROFILAMENT NETWORK FROM CELLS

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10596388B2 (en) * 2016-09-21 2020-03-24 Epistar Corporation Therapeutic light-emitting module
CN106377011A (zh) * 2016-11-17 2017-02-08 温州医科大学 一种糖尿病足的专用鞋垫
CN106806933B (zh) * 2017-01-14 2020-04-21 成都医学院 聚酰胺纱布作为创面敷料的用途
US11298391B1 (en) * 2017-04-27 2022-04-12 Lorenol Laboratories, Inc. Topical skin health improvement compositions and administrations thereof
CN107397975A (zh) * 2017-06-29 2017-11-28 苏州凌科特新材料有限公司 抗感染医用创面敷料及其制备方法
CN110025818A (zh) * 2019-03-11 2019-07-19 温州大学 一种壳聚糖压电薄膜及其制备方法与应用
CN111001028B (zh) * 2019-12-29 2021-09-10 北京工商大学 亚甲基蓝抗氧化修复高分子纳米纤维膜及制备方法
CN111870732B (zh) * 2020-07-20 2022-06-14 卓阮医疗科技（苏州）有限公司 一种可诱导组织再生修复的止血颗粒及其制备方法和应用
WO2022091102A1 (en) * 2020-11-02 2022-05-05 Medcu Technologies Ltd Method for reducing post-operative scar formation using materials comprising copper, zinc and/or silver compounds applied under peripheral pressure
CN113332489B (zh) * 2021-06-24 2022-06-03 天津中医药大学 一种白及-黄连复方海绵敷料及其制备方法和应用
CN113952497B (zh) * 2021-09-28 2022-07-29 振德医疗用品股份有限公司 细菌黏附性抗感染创面敷料
CN113925994B (zh) * 2021-09-30 2022-11-29 振德医疗用品股份有限公司 一种负压封闭引流敷料及其制备方法
EP4186532B1 (de) 2021-11-29 2024-04-10 Asetreat GmbH & Co.KG Elektret-basierte wundauflage
CN114344549A (zh) * 2021-12-13 2022-04-15 动之医学技术(上海)有限公司 复合羊膜敷料及其制备方法
CN114306726A (zh) * 2021-12-17 2022-04-12 广西萌大夫生物技术有限公司 一种可注射仿生抗氧化水凝胶的制备方法和使用方法
CN114504636B (zh) * 2022-01-27 2023-09-26 华南理工大学 一种杏仁油烫伤膏及其制备方法与应用
US20230255880A1 (en) * 2022-02-16 2023-08-17 Guild Associates Inc. Immobilized enzyme-based wound debridement
CN114904056B (zh) * 2022-04-15 2023-10-13 上海理工大学 一种基于人胎盘脱细胞基质的复合水凝胶及其制备方法
CN115591009B (zh) * 2022-10-27 2023-09-26 江苏阳生生物股份有限公司 促进皮肤创面快速修复的敷料

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102813957A (zh) * 2012-09-14 2012-12-12 上海白衣缘生物工程有限公司 一种促愈合生物膜及其制备方法
CN102858379A (zh) * 2009-10-08 2013-01-02 欧麦德公司 粘合剂组合物
CN103189035A (zh) * 2010-08-16 2013-07-03 瑞士商麦斯特医疗股份有限公司 可变吸收性防沾粘海藻酸盐阻隔材料
CN103200971A (zh) * 2010-08-30 2013-07-10 哈佛大学校长及研究员协会 高强度壳多糖复合材料及其制造方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6099866A (en) * 1986-01-31 2000-08-08 Slimak; K. M. Compositions for topical application and other products from fresh beeswaxes
US5652274A (en) * 1991-03-01 1997-07-29 Martin; Alain Therapeutic-wound healing compositions and methods for preparing and using same
US6060461A (en) * 1999-02-08 2000-05-09 Drake; James Franklin Topically applied clotting material
US20060083776A1 (en) * 2003-10-27 2006-04-20 Bott Richard R Preparations for topical application and methods of delivering an active agent to a substrate
US7858123B2 (en) * 2005-04-04 2010-12-28 The Regents Of The University Of California Inorganic materials for hemostatic modulation and therapeutic wound healing
US8921244B2 (en) * 2005-08-22 2014-12-30 The Procter & Gamble Company Hydroxyl polymer fiber fibrous structures and processes for making same
US20080317830A1 (en) * 2007-06-25 2008-12-25 Liolabs Llc Compositions and Methods for the Treatment of Wounds and Scar Tissue
CN102357258B (zh) * 2011-10-27 2014-02-05 上海美宝生命科技有限公司 一种结合湿润烧伤膏治疗烧伤的敷料的制备方法
CN102430145B (zh) * 2011-12-24 2014-06-11 四川大学 不对称型聚氨酯/纳米TiO2薄膜创伤敷料及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102858379A (zh) * 2009-10-08 2013-01-02 欧麦德公司 粘合剂组合物
CN103189035A (zh) * 2010-08-16 2013-07-03 瑞士商麦斯特医疗股份有限公司 可变吸收性防沾粘海藻酸盐阻隔材料
CN103200971A (zh) * 2010-08-30 2013-07-10 哈佛大学校长及研究员协会 高强度壳多糖复合材料及其制造方法
CN102813957A (zh) * 2012-09-14 2012-12-12 上海白衣缘生物工程有限公司 一种促愈合生物膜及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3305335A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3448396A4 (en) * 2017-04-14 2020-01-22 President and Fellows of Harvard College METHOD FOR PRODUCING A MICROFILAMENT NETWORK FROM CELLS
JP2020516593A (ja) * 2017-04-14 2020-06-11 プレジデント アンド フェローズ オブ ハーバード カレッジ 細胞由来のマイクロフィラメントネットワークの生成方法
US11185568B2 (en) 2017-04-14 2021-11-30 President And Fellows Of Harvard College Methods for generation of cell-derived microfilament network

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