WO2014079198A1 - Matériau dégradable de réparation de blessures et son procédé de préparation - Google Patents

Matériau dégradable de réparation de blessures et son procédé de préparation Download PDF

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Publication number
WO2014079198A1
WO2014079198A1 PCT/CN2013/074697 CN2013074697W WO2014079198A1 WO 2014079198 A1 WO2014079198 A1 WO 2014079198A1 CN 2013074697 W CN2013074697 W CN 2013074697W WO 2014079198 A1 WO2014079198 A1 WO 2014079198A1
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factor
solution
crosslinking
composite
repairing material
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PCT/CN2013/074697
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English (en)
Chinese (zh)
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谭荣伟
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深圳兰度生物材料有限公司
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Publication of WO2014079198A1 publication Critical patent/WO2014079198A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/64—Use of materials characterised by their function or physical properties specially adapted to be resorbable inside the body
    • 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
    • A61L15/40—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing ingredients of undetermined constitution or reaction products thereof, e.g. plant or animal extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention relates to the field of biomedical materials and biomedical engineering technology, and in particular, to a degradable wound repairing material and a preparation method thereof.
  • Skin is one of the most important organs of the human body. It is an important barrier between the human body and the external environment, and one of the most vulnerable organs. The repair of skin wounds is also one of the oldest medical problems in humans.
  • the dermis layer of the skin is rich in collagen fibers and glycoproteins, which is rich in blood supply and has strong regeneration and repair ability. Therefore, in the design of wound repair materials, high-molecular scaffolds with good biocompatibility and excellent degradation properties provide sites for early cell attachment, which can promote their proliferation and migration more effectively. Supplemented with the necessary antibacterial ingredients and growth-promoting growth factors, it can reduce the early infection of wound repair and accelerate wound healing.
  • degradable wound repair materials have been applied for skin wound repair treatment.
  • the clinically used degradable wound repair materials are mainly collagen sponges, which have good biocompatibility, are one of the important components of human tissues, and have excellent degradability and degradation.
  • the process can guide tissue proliferation and migration.
  • this type of material degrades too quickly, and it is easy to lose the mechanical support structure prematurely.
  • the wound is susceptible to infection, and such stents are also difficult to load with antibacterial agents and factors that promote wound healing. Therefore, the development of components and structures that are more similar to natural skin and diverse in morphology, and the ability to load a variety of components to prevent infection and promote wound repair has far-reaching significance.
  • the technical problem to be solved by the present invention is to provide a degradable wound repairing material with good biocompatibility.
  • a further technical problem to be solved by the present invention is to provide a method for preparing a degradable wound repairing material to obtain a biodegradable biodegradable wound repairing material.
  • a degradable wound repairing material comprising a matrix component, the matrix component comprising a protein component, the protein component is derived from a mammal
  • the raw material of the degradable wound repairing material further comprises an auxiliary component, wherein the auxiliary component comprises at least one of an antibacterial agent and an active factor, wherein the antibacterial agent is a synthetic antibacterial drug, an inorganic antibacterial agent, and an organic An antibacterial agent or a natural antibacterial agent; the active factor is at least one of the following active factors: epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, platelet activating factor, insulin-like growth factor, tumor necrosis factor, leukocyte-mediated Prime, Colony stimulating factor-1, various bone morphogenetic proteins or transforming growth factors.
  • the active factor is at least one of the following active factors: epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, platelet activating factor, insulin-like growth factor, tumor necrosis factor, leukocyte-mediated Prime, Colony stimulating factor-1, various bone morphogenetic proteins or transforming growth factors.
  • the matrix component further includes a polysaccharide component, the polysaccharide component comprising at least one of the following components: hyaluronic acid, chitin and chitosan derived from the arthropod shell, source Alginic acid or sodium alginate in seaweed or kelp or chondroitin sulfate extracted from organs of pigs, cattle, sheep or sharks.
  • hyaluronic acid chitin and chitosan derived from the arthropod shell
  • source Alginic acid or sodium alginate in seaweed or kelp or chondroitin sulfate extracted from organs of pigs, cattle, sheep or sharks.
  • the mass ratio of the protein component to the sum of all other raw material components is 1/350 to 4000/1.
  • the present invention provides a method for preparing a degradable wound repairing material according to any of the above, comprising the following steps;
  • the composite is subjected to a molding process to obtain a desired material form.
  • the step of preparing the base material mixing the respective matrix component solutions under stirring conditions, and performing a pore-forming process to obtain a composite with a support pore structure as a matrix material, wherein the pore-forming process is as follows At least one of: particle leaching, stirred foaming or defoaming, initial concentration adjustment or complex concentration.
  • a composite auxiliary component step is further performed between the preparation of the base material and the molding step, and at least one of an antibacterial agent and an active factor is loaded onto the composite having the pore structure of the stent, wherein the antibacterial agent
  • the loading mode is any one of the following modes: grafting, physical blending, adsorption or microsphere encapsulation
  • the loading method of the active factor is any one of the following modes: grafting, physical blending, adsorption Or microspheres are embedded.
  • the molding step adopts a flow film forming process or a film forming process or a granulation process, and after the forming step, a crosslinking step is further performed, and the crosslinked composite is washed and dried to obtain the following One of the composites of the state: a dry sponge, a wet sponge, a dry granule or a wet granule, the crosslinking step using a physical crosslinking process, a crosslinking process involving a chemical crosslinking agent, or a natural crosslinking agent Cross-linking process, wherein
  • the physical crosslinking process is any one of the following processes: a vacuum high temperature crosslinking process, an ultraviolet irradiation process, a Y irradiation process, a high energy electron beam irradiation, and the like;
  • the crosslinking agent used in the crosslinking process involving the chemical crosslinking agent is any one of the following components: an aldehyde crosslinking agent, an imide crosslinking agent or a diisocyanate crosslinking agent;
  • crosslinking agent used in the crosslinking process involving natural crosslinking agents is genipin.
  • the molding step uses a gel process or a compound solution dilution process to obtain an injectable gel or a sprayable solution of a degradable wound repair material, respectively.
  • the preparation method further includes a terminal sterilization step as a last step, the obtained material is sterilized to obtain a finished product, and the terminal sterilization step adopts any one of the following sterilization processes.
  • Species High-energy electron beam irradiation process, Y-radiation process, filtration process, gas sterilization process.
  • the present invention has at least the following beneficial effects: by using collagen derived from mammalian skin or Achilles tendon or silk fibroin derived from silk or silk fibroin modified by derivatization As a protein component, it has good biocompatibility and is more conducive to degradation and absorption.
  • the loading of the active factor component can also be biologically active on the basis of satisfying the degradable property, and can better promote wound repair; and the anti-infective property of the product is improved by loading the antibacterial agent on the basis of the matrix component.
  • FIG. 1 is a flow chart of a method for preparing a degradable wound repairing material of the present invention.
  • FIG. 2 is a schematic view showing the path of a dispersion of a solution of a living factor or a suspension of a sustained release carrier onto a formed sponge block in the method for preparing a degradable wound repairing material of the present invention.
  • the present invention provides a degradable wound repairing material, the raw materials of which include:
  • Protein-based components including various types of collagen derived from skins such as cows, sheep, pigs, and the like, and derivatives of silk fibroin or silk fibroin derived from silk, such as:
  • the collagen may be type I, type II, type III, type IV, type V, type VI, type VD, type VIII, type IX, type X, type XI, type ⁇ , type X IV, type XV, type X VI , ⁇ type,
  • a polysaccharide component chitin and chitosan derived from the arthropod shell, alginic acid or sodium alginate derived from seaweed or kelp, chondroitin sulfate extracted from various organs of pig, cow, sheep and shark, and transparent Acidic acid, etc.
  • the above protein components and polysaccharide components may be regarded as the matrix component of the degradable wound repairing material of the present invention, but in preparation, the two are still different, and the protein component is an indispensable matrix component, and more The sugar component can be selectively added according to the needs of product differentiation.
  • the wound repairing material of the present invention may optionally be added with one or more of the following antibacterial agents:
  • Synthetic antibacterial drugs such as: penicillins, cephalosporins, other beta-lactamase inhibitors, aminoglycosides, amides, glycopeptides, macrolides, tetracyclines, sulfonamides, quinolones , furans, antifungals, nitrazoles;
  • Inorganic antibacterial agents such as: nano-silver, nano-titanium dioxide, zinc oxide, copper oxide, ammonium dihydrogen phosphate, lithium carbonate, etc.
  • organic antibacterial agents such as: vanillin, ethyl vanillin, acyl aniline, imidazole, Thiazoles, isothiazolone derivatives, quaternary ammonium salts, biguanides, phenols, etc.
  • Natural antibacterial agents such as: chitin, mustard, castor oil, wasabi, etc.
  • one or more of the following active factors may be optionally added to the wound repair material of the present invention: epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet Derived growth factor (PDGF), platelet activating factor (PAF), insulin-like growth factor (IGF), tumor necrosis factor (TNF), interleukin (IL-1, IL-3, IL-4, IL-6, etc.) , colony stimulating factor-1, various bone morphogenetic proteins (BMPs) and other transforming growth factors (TGF).
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • PDGF platelet Derived growth factor
  • PAF platelet activating factor
  • IGF insulin-like growth factor
  • TNF tumor necrosis factor
  • IL-1, IL-3, IL-4, IL-6, etc. colony stimulating factor-1
  • BMPs bone morphogenetic proteins
  • TGF transforming growth factors
  • the core of the innovation of the present invention is that the above-mentioned raw materials are prepared into a porous scaffold material according to the method to be described below, and as the raw materials used, in addition to protein components, other raw materials are required.
  • the amount of the component may be in any ratio, and in the case where other raw material components are added in addition to the protein component, the mass ratio of the protein component to the sum of all other raw material components is 1/350 to 4000/1.
  • the preparation method of the degradable wound repairing material of the present invention includes the main steps as will be described in detail below.
  • Preparation of solution Select one or more of the above raw materials to prepare a solution.
  • the solution concentration (mass fraction concentration) and solvent are as follows: Collagen: 0.01% ⁇ 10%, acid (mass percentage is 0.05) Aqueous solution or pure water of % ⁇ 10% acetic acid or hydrochloric acid; silk fibroin: 0.02% ⁇ 10%, pure water; polysaccharide: 0.001% ⁇ 15%, acid (0.001% ⁇ 10% acetic acid or hydrochloric acid, etc.) or pure water.
  • Control hole structure Particle leaching method, stirring foaming or defoaming method, initial concentration adjustment method or composite liquid concentration method may be selected as the pore forming process. If particle leaching is used, porogens (sodium, potassium and ammonium salts such as NaCl, KN0 3 , NH 4 C1) are added, and the pore structure can be controlled by the content of the porogen.
  • the mass ratio of the composite liquid prepared in step 2 is 1/100 ⁇ 20/100; the pore structure of the support can also be controlled by stirring or defoaming, for example, the step poly 2 solution compound is stirred and stirred at a certain stirring speed.
  • the composite may also be selectively compounded with an antibacterial agent or an active factor, or both may be selected as an auxiliary component, as follows:
  • soluble antibacterial drugs select a suitable solvent (see Table 1) to dissolve, the concentration of which can be determined according to the dosage of the drug; for ionic or granular antibacterial agents, choose a suitable dispersion medium for dispersion; And an ionic or granular antibacterial agent, which can be optionally embedded in a sustained-release carrier (polymer microspheres, microcapsules, particles, etc.), and then prepared into a dispersion;
  • the solution or dispersion of the antibacterial agent prepared in the step 1 is added to the complex prepared in the first step under stirring.
  • the dose of the antibacterial agent should take into account the pharmacodynamic and pharmacokinetic parameters, as well as the difference between the concentration-dependent drug and the time-dependent drug.
  • Various active factors may also be selected by first-dissolving various solvents listed in Table 1.
  • the active factors may be embedded in a sustained-release carrier (polymer microspheres, microcapsules, particles, etc.), sustained-release carrier.
  • the preparation method includes a microemulsion method, a spray drying method, etc., and the base material of the prepared sustained-release carrier can be selected from the polymer materials shown in Table 2;
  • the solution of the active factor prepared in the step 2 of the method 1 or the dispersion of the sustained-release carrier is added dropwise to the matrix material obtained in the first step in a row-by-row manner, and can be fully adsorbed by means of a negative pressure, specific
  • the dropping path is as shown by the arrow in Fig. 2, and is dropped back and forth from the first line.
  • Step three the molding step:
  • the molding process of the wound repairing material of the present invention may be selected from, but not limited to, one of the following processes: flow film formation, film formation, granulation, gelation, and dilution of a composite solution. And with freeze drying, air conditioning at room temperature.
  • the molding of the composite obtained in the second step may select one of the following routes:
  • the process parameters of the route the temperature during freezing is -5 ⁇ -150 °C; the temperature during freeze-drying is -65 ⁇ 45 °C, and the pressure is 0.1 ⁇ Pa.
  • the process parameters of the route the temperature during freezing is -5 ⁇ -150 °C; the temperature during freeze-drying is -65 ⁇ 45 °C, the pressure is 0.1 ⁇ 200Pa; the pressure when pressed into film is 5Pa ⁇ 5000MPa, time It is 0.5 ⁇ 168h.
  • the process parameters of the route the temperature at room temperature is 5 ⁇ 45 °C; the pressure when pressed into film is 5Pa ⁇ 5000MPa.
  • the process parameters of the route the temperature during freezing is -5 ⁇ -150 °C; the temperature during freeze-drying is -65 ⁇ 45 °C, and the pressure is 0.1 ⁇ Pa.
  • the pore size of the filter is lm ⁇ 10mm; when the granulation is carried out, the flow rate of the pump head is 0.05 ⁇ 200mL/min, and the flow of the pump head can be selected from air, nitrogen or other inert gas, and the pumped composite droplets are filled with hydrocarbons.
  • the temperature of the collection tank is maintained at -40 to -2 °C.
  • the pore size of the filter is lm ⁇ 10mm; when the granulation is carried out, the flow rate of the pump head is 0.05 ⁇ 200mL/min, and the flow of the pump head can be selected from air, nitrogen or other inert gas, and the pumped composite droplets are filled with organic A collection tank of a mixture of solvent and water (such as alcohol and water), the temperature of the collection tank is maintained at -40 to -2 ° C; the temperature during freeze-drying is -65 to 45 ° C, and the pressure is 0.1 to 200 Pa. [0041] Route 7, composite solution gel
  • the composite solution obtained in the second step is allowed to stand in an environment of 1 to 8 ° C, or diluted in a certain ratio, and then allowed to stand in an environment of 1 to 8 ° C to obtain a composite gel.
  • the composite solution obtained in the second step is diluted in a certain ratio to obtain a composite sprayable solution.
  • Step four cross-linking steps:
  • the crosslinking method of the wound repairing material of the invention may be selected but not limited to: physical crosslinking method such as vacuum high temperature crosslinking, ultraviolet irradiation, Y irradiation, high energy electron beam irradiation, or various chemical crosslinking agents (aldehyde Cross-linking agent: Glyoxal, glutaraldehyde, formaldehyde, etc., imine cross-linking agent: carbodiimide, etc., diisocyanate cross-linking agent: diisocyanate, carbamate derivative, etc.
  • a cross-linking method involving natural cross-linking agents such as Genipin.
  • the sample of the dried composite obtained by the route 1-6 in the third step may be crosslinked by one or more crosslinking methods.
  • the crosslinking method includes: physical crosslinking method such as vacuum high temperature crosslinking, ultraviolet irradiation, Y irradiation, high energy electron beam irradiation, or various chemical crosslinking agents (aldehyde crosslinking agent: glyoxal, glutaraldehyde, Formaldehyde, etc., imine cross-linking agent: carbodiimide, etc., diisocyanate cross-linking agent: diisocyanate, carbamate derivative, etc.) and natural cross-linking agent [eg Genipin (Genipin) ) etc.] Participate in the cross-linking method.
  • the specific crosslinking conditions are as follows:
  • the crosslinking temperature is 50 to 200 ° C
  • the crosslinking time is 2 to 120 hours
  • the vacuum pressure during crosslinking is 0.1 to 200 Pa
  • the irradiation time is 5 minutes in the ultraviolet irradiation crosslinking. ⁇ 48 hours, the irradiation intensity is 10 ⁇ 100mW/cm 2 ; the dose of Y irradiation is l ⁇ 40KGy; the dose of high energy electron beam irradiation is l ⁇ 50KGy.
  • the dried composite film sample is immersed in a solution of various concentrations of various crosslinking agents for a certain period of time.
  • the mass fraction of the carbodiimide solution is 1 ⁇ g/mL ⁇ 100 mg/mL, the crosslinking time is 5 minutes to 72 hours; the mass fraction concentration of the glyoxal, glutaraldehyde, and formaldehyde solution is 0.01 to 10%,
  • the crosslinking time is 1 to 168 hours; the mass fraction concentration of the diisocyanate crosslinking agent solution is 0.1 to 8%, the crosslinking time is 30 minutes to 84 hours; the mass fraction concentration of the Genipin solution is 0.05 ⁇ 8%, the crosslinking time is 2 to 168 hours.
  • the final morphology of the wound repair material obtained by the cross-linking of the cross-linking agent after the cross-linking agent can be prepared into one of the following states: dry sponge, wet sponge, injectable coagulation Glue, dry or wet granules, sprayable solution.
  • Step 5 sterilization treatment:
  • the sterilization method of the wound repairing material of the present invention may be one of the following methods: terminal sterilization process, for example: high energy electron beam irradiation, Y radiation, filtration, gas sterilization (ethylene oxide, formaldehyde vapor, ethanol, etc.) or Other terminal sterilization processes; process aseptic processes can also be employed.
  • terminal sterilization process for example: high energy electron beam irradiation, Y radiation, filtration, gas sterilization (ethylene oxide, formaldehyde vapor, ethanol, etc.) or Other terminal sterilization processes; process aseptic processes can also be employed.
  • the aseptic mode of the composite in various states obtained in the fourth step can be selected by using both the process aseptic process and the terminal sterilization.
  • the aseptic process of the process that is, the entire preparation process is carried out in a clean room of a suitable degree, and aseptic control is carried out.
  • Terminal sterilization refers to the terminal sterilization process after the composite produced in the clean workshop, such as: high energy electron beam irradiation, Y radiation, filtration, gas sterilization (ethylene oxide, formaldehyde vapor, ethanol, etc.) or Other sterilization methods are sterilized.
  • the dry sponge, the wet sponge, the dry particles or the wet particles, and the gel state composite may be sterilized by one of high energy electron beam or Y radiation, and the sterilization dose is 5 to 35 KGy.
  • the dry sponge and the dry granules may be sterilized by a gas sterilization method (ethylene oxide, formaldehyde vapor, ethanol, etc.), and the sterilization parameters are determined according to the state of the product and the purpose to be achieved.
  • the gel-state and solution-state complexes may be sterilized by a filter sterilization method, and the pores of the filter membrane should be less than or equal to 0.22 ⁇ m.
  • a 1% collagen solution was prepared by using 3% aqueous acetic acid as a solvent, and a 0.001% chitosan solution was prepared using 0.001% aqueous acetic acid as a solvent. Then, 4 parts by mass of the type I collagen solution was taken and stirred at 500 rpm, and 1 part by mass of chitosan solution was added at a rate of 2 ml/min. After the completion of the addition, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to chitosan in the obtained composite solution was 4000:1.
  • VEGF-loaded PBS solution was added to the composite solution and stirred and uniformly mixed so that the mass ratio of the active factor to the dry weight of the composite in the resulting composite was 1/100.
  • the resulting composite solution was defoamed under vacuum of 20 Pa for 20 min.
  • a carbodiimide solution having a concentration of 100 g/L was prepared, and the film obtained above was immersed therein and immersed for 30 hours. Thereafter, after washing with water for 5 times, a wet spongy material was obtained. It was sterilized by irradiation in Y-rays at a sterilization dose of 25 KGy.
  • a 10% type III collagen solution was prepared by using 0.05% aqueous acetic acid as a solvent, and a 0.02% silk fibroin solution was prepared using a pure aqueous solution as a solvent. Then, 6 parts by mass of the type III collagen solution was taken, and while stirring at 100 rpm, 1 part by mass of the silk fibroin solution was added at a rate of 0.5 ml/min, and after the completion of the addition, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to silk fibroin in the resulting composite solution was 3000:1.
  • a volume of 5 parts by volume of a pure aqueous dispersion of gentamicin-loaded PLGA microspheres (2 g/L) was added to the composite solution, and the mixture was stirred and homogenized. The resulting composite solution was defoamed for 10 min under a vacuum of 10 Pa.
  • the defoamed composite liquid was weighed in a mold and then air-dried at room temperature (30 ° C), and the air-dried film was continuously pressed at a static pressure of 5 MPa for 168 hours to obtain a pressed film.
  • the sterility of the resulting film is controlled by using a "process aseptic process.”
  • a 0.5% V-type collagen solution was prepared by using 10% aqueous acetic acid as a solvent, and a 1% chondroitin sulfate solution was prepared by using 0.5% aqueous acetic acid as a solvent. Then, 4 parts by mass of the collagen solution was taken and stirred at 800 rpm, and 1 part by mass of chondroitin sulfate solution was added at a rate of 0.02 mL/min. After the addition was completed, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to chondroitin sulfate in the obtained composite liquid was 2:1.
  • a 0.1% VD-type collagen solution was prepared by using 5% aqueous acetic acid as a solvent, and a 1% hyaluronic acid solution was prepared using water as a solvent. Then, 4 parts by mass of the collagen solution was taken and stirred at 200 rpm, and 1 part by mass of hyaluronic acid solution was added at a rate of 5 mL/min. After the completion of the addition, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to hyaluronic acid in the obtained composite liquid was 2:5.
  • the pure water dispersion of the PCL microspheres containing riiBMP-2 is added to the composite liquid to be uniformly mixed, so that the mass ratio of the active factor to the dry weight of the composite in the resulting composite is 1/5*10 4 .
  • the resulting composite solution was defoamed under vacuum at 12 Pa for 20 min.
  • the film was crosslinked by a high temperature vacuum, the crosslinking temperature was 200 ° C, the crosslinking time was 2 h, and the vacuum pressure at the time of crosslinking was 0.1 Pa.
  • a solution of 0.01% glyoxal was prepared, and the film obtained above was immersed therein and immersed for 48 hours. Thereafter, after washing 5 times, a wet spongy material was obtained. Then, it was frozen at -150 ° C for 4 hours, and then lyophilized in a freeze dryer (temperature of -40 ° 45, 45 ° ⁇ , pressure: 5 Pa) to obtain a sponge-like film.
  • Sterilization was carried out using ethylene gas sterilization using a gas sterilization method at a temperature of 60, a humidity of 50%, and a concentration of 600 mg/mL.
  • Example 5 A 0.2% type II collagen solution was prepared by using 0.5% aqueous hydrochloric acid as a solvent, and a 2% chitin solution was prepared by using 10% aqueous acetic acid as a solvent. Then, 2 parts by mass of the collagen solution was taken, and while stirring at 1000 rpm, 5 parts of a mass of chitin solution was added at a rate of 2 mL/min, and after the completion of the addition, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to chitin in the obtained composite liquid was 2:50.
  • the composite liquid after defoaming is filtered (the pore diameter of the sieve is 1 mm), and then granulated, the granulation conditions: the flow rate of the pump head is 0.05 mL/min, the air flow of the pump head circulation selects air, and the pumping compound
  • the droplets were placed in a hexane-containing collection tank, and the temperature of the collection tank was maintained at -40 °C. A wet gel particle composite is obtained after granulation.
  • a 0.01% type I collagen solution was prepared by using 3% aqueous hydrochloric acid as a solvent, and a 1.5% chondroitin sulfate solution was prepared by using 0.5% aqueous hydrochloric acid as a solvent. Then, 2 parts by mass of the collagen solution was taken and stirred at 450 rpm, and 5 parts by mass of chondroitin sulfate solution was added at a rate of 0.01 ml/min. After the completion of the addition, stirring was continued to form a uniform composite liquid. The mass ratio of collagen to chondroitin sulfate in the obtained composite solution was 1:350.
  • the composite liquid after defoaming is filtered (the pore size of the sieve is 1 ⁇ ⁇ ), and then granulated, the granulation conditions: the flow rate of the pump head is 200 mL/min, the gas flow of the pump head is selected, the helium gas is pumped out.
  • the composite droplets were transferred to a collection tank containing octane, and the temperature of the collection tank was maintained at -2 °C. After granulation, the wet gel particles were frozen in a refrigerator at -65 °C for 3 h, and then lyophilized (the temperature at lyophilization was -30 ° C after 20 ° C, the pressure was lOPa). Particle complex.
  • the high energy electron beam sterilization was carried out at a sterilization dose of 50 KGy.
  • the crosslinking was then carried out by ultraviolet irradiation for 48 hours, and the irradiation intensity was 1000 mW/cm 2 .
  • a carbodiimide solution having a concentration of 100 g/L was prepared, and the film obtained above was immersed therein and immersed for 30 hours. Thereafter, after washing with water for 5 times, a wet spongy material was obtained. It was sterilized by irradiation in Y-rays at a sterilization dose of 25 KGy.
  • a pure aqueous dispersion (20 g/L) of 2 parts by mass of nano-titanium-loaded chitin microspheres was added to the composite liquid, and the mixture was stirred and uniformly mixed.
  • the resulting composite solution was degassed under vacuum at 20 Pa for 20 min.
  • a glutaraldehyde solution having a concentration of 0.5% was prepared, and the film obtained above was immersed therein and immersed for 168 hours. After washing with water for 6 times, a wet spongy material was obtained, which was then frozen in a refrigerator at -50 ° C for 3 h, and then lyophilized in a freeze dryer (temperature: -45 ° C, 45 ° C, pressure: 10 Pa). .
  • a 10% silk fibroin solution was prepared by using water as a solvent, and a 1% chitosan solution was prepared by using 1% acetic acid aqueous solution as a solvent. Then, 2 parts of the silk fibroin solution was taken and stirred at 400 rpm, 5 parts of chitosan solution was added at a rate of 3 ml/min, and stirring was continued to form a uniform composite liquid. The mass ratio of collagen to chitosan in the obtained composite liquid was 4:1.
  • a carbodiimide solution having a concentration of 100 g/mL was prepared, and the film obtained above was immersed therein and immersed for 30 hours. After washing with water for 5 times, a wet spongy material was obtained.
  • a 0.01% type I collagen solution was prepared by using 0.5% aqueous acetic acid as a solvent.
  • a pure aqueous dispersion of vanillin-loaded PHA microspheres (50 mg/ml) was added to the collagen solution and stirred and mixed uniformly.
  • the resulting composite solution was degassed under vacuum at 20 Pa for 20 min.
  • the prepared composite liquid was allowed to stand in a refrigerator at 4 ° C for 72 hours to obtain a composite gel.

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Abstract

La présente invention concerne un matériau dégradable de réparation de blessures et son procédé de préparation, la matière première du matériau dégradable de réparation de blessures comprenant des composants matriciels et des composants auxiliaires, les composants matriciels comportant des composants protéiniques et les composants auxiliaires comprenant au moins l'un des agents microbiens et un facteur actif, l'agent antimicrobien étant un médicament antimicrobien synthétique, un agent antimicrobien inorganique, un agent antimicrobien organique ou un agent naturel antimicrobien ; le facteur actif est au moins l'un des suivants : un facteur de croissance épidermique, un facteur de croissance de l'endothélium vasculaire FGF, un facteur de croissance dérivé plaquettaire, un facteur d'activation plaquettaire, un facteur d'activation plaquettaire, un facteur de croissance analogue à l'insuline, un facteur de nécrose de tumeur, un interleukine, un facteur-1 stimulant les colonies, diverses protéines morphogénétiques osseuses ou un facteur de croissance de transformation. L'agent antimicrobien et le facteur actif sont chargés sur les bases des composants matriciels et, de ce fait, la présente invention peut aussi posséder une activité biologique en se basant sur des conditions de biodégradabilité satisfaisantes afin d'améliorer la réparation de blessures et affiche une bonne performance anti-infectieuse lors du processus d'application.
PCT/CN2013/074697 2012-11-21 2013-04-25 Matériau dégradable de réparation de blessures et son procédé de préparation WO2014079198A1 (fr)

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