WO2019124653A1 - Procédé de production d'hydrogel libérant de l'oxygène pour bioinjection et utilisation biomédicale associée - Google Patents

Procédé de production d'hydrogel libérant de l'oxygène pour bioinjection et utilisation biomédicale associée Download PDF

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WO2019124653A1
WO2019124653A1 PCT/KR2018/006346 KR2018006346W WO2019124653A1 WO 2019124653 A1 WO2019124653 A1 WO 2019124653A1 KR 2018006346 W KR2018006346 W KR 2018006346W WO 2019124653 A1 WO2019124653 A1 WO 2019124653A1
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hydrogel
oxygen
calcium
gum
releasing
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PCT/KR2018/006346
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Korean (ko)
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박경민
강전일
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인천대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • 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
    • 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
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the present invention relates to a method for producing a bioinjected oxygen-releasing hydrogel using calcium peroxide and a biomedical use thereof, and more particularly to a method for producing a bioinjected oxygen-releasing hydrogel using calcium peroxide. More particularly, the in situ bridged hydrogel is used in a previously reported method for preparing alginate- The present invention relates to a new type of injection-type polymer hydrogel which can be produced through ionic crosslinking of divalent cations using calcium peroxide and capable of releasing high-concentration oxygen in a formed hydrogel matrix.
  • the present invention can be manufactured by a simple method using a natural polymer, alginate, without chemical modification of a polymer, compared with a conventional method of manufacturing a bioinjectable hydrogel, and the physical / chemical / There is an advantage that the characteristic can be easily controlled.
  • Polymer hydrogels composed of a three-dimensional network of hydrophilic polymers are used in a variety of biomedical applications due to their biocompatibility, high water content, good permeability of nutrients and metabolites, structural similarity with natural tissues and multi-tunable properties Has been widely used.
  • in situ bridged hydrogels have been extensively studied as drug / cell carriers, tissue fillers, or tissue engineering supports based on minimally invasive techniques.
  • These in situ bridged hydrogels can be prepared using natural and synthetic polymers, and hydrogels can be formed through various chemical and physical crosslinks.
  • Alginate is an anionic polysaccharide derived from brown algae, and is excellent in biocompatibility and biodegradability and has been applied in various fields in biomedical applications. Ionotropic crosslinking occurs in the presence of divalent cations such as calcium (Ca 2+ ), magnesium (Mg 2+ ), or zinc (Zn 2+ ) ions in the alginate polymer main chain to form a three-dimensional hydrogel network
  • divalent cations such as calcium (Ca 2+ ), magnesium (Mg 2+ ), or zinc (Zn 2+ ) ions
  • CaCO 3 calcium carbonate
  • CaCl 2 calcium chloride
  • ZnCO 3 zinc carbonate
  • Oxygen acts as a metabolic substrate and a signal molecule, which plays an important role in homeostasis maintenance and wound healing.
  • hyperbaric oxygen promotes cell proliferation by temporarily increasing oxygen partial pressure in the cell, increasing reactive oxygen species, and promoting collagen synthesis and processing by oxygen-based lysyl oxidase Promotes angiogenesis. It also promotes angiogenesis and wound healing by causing secretion of growth factors that promote angiogenesis or by allowing stem cells to migrate from the bone marrow.
  • several technologies are recently being developed to transport oxygen.
  • HBOT hyperbaric oxygen therapy
  • PFC perfluorocarbon
  • the present invention meets the above-mentioned conventional demands and reports new researches that have not been reported so far.
  • the present invention provides a method for producing a sustained release oxygen-containing injection-type hydrogel which can easily control biological characteristics, and its various biomedical uses.
  • the present invention relates to a method for producing an ionic cross-linking agent, wherein the natural alginate polymer composed of mannuronic acid and glutaric acid, which is not chemically modified, Based cross-linked polymer hydrogel that produces a crosslinked alginate-based hydrogel and at the same time releases a high concentration of oxygen by decomposition of calcium peroxide in an aqueous solution.
  • the bioinjection type oxygen release which can easily control the physical / chemical / biological properties of hydrogels such as hydrogel mechanical strength, hydrogen peroxide release, oxygen release behavior and the like by controlling composition and concentration of alginate, calcium peroxide and catalase A method for producing a hydrogel is provided.
  • the present invention also provides an implant material for tissue regeneration and filling comprising an alginate-based in situ crosslinked oxygen releasing hydrogel.
  • the present invention also provides a material for tissue adhesion and hemostasis comprising an alginate-based in situ crosslinked oxygen releasing hydrogel.
  • the present invention also provides a carrier for a physiologically active substance or drug carrier, which comprises an alginate-based in situ crosslinked oxygen releasing hydrogel.
  • the new type of in situ crosslinked hydrogel according to the present invention is characterized in that hydrogels formed by calcium ions generated by the decomposition of calcium peroxide and the release behavior of high concentration oxygen generated in the hydrogel can be controlled.
  • the present invention has the novelty of inventing a new alginate hydrogel using calcium peroxide, which has not been reported in studies on the preparation of hydrogels using divalent cations, and can overcome the limitations of oxygen generating hydrogels Based on excellent biocompatibility, various biomedical applications (eg tissue regeneration, artificial tissue preparation, wound healing material, tissue adhesive material, drug delivery system, etc.) are possible.
  • various biomedical applications eg tissue regeneration, artificial tissue preparation, wound healing material, tissue adhesive material, drug delivery system, etc.
  • FIG. 1 is a schematic view showing the formation of a hydrogel for generating oxygen based on alginate.
  • FIG. 2 is an image of decomposition of calcium peroxide and formation of a hydrogel according to a buffer solution.
  • FIG. 3 is a graph showing the hydrogel formation using calcium peroxide and the mechanical strength varying with the concentration of alginate and calcium peroxide (A: alginate, C: calcium peroxide).
  • FIG. 4 is a graph showing hydrogen peroxide decomposition behavior using catalase (A: alginate, C: calcium peroxide).
  • FIG. 5 is a graph showing the oxygen release behavior with addition of calcium oxide concentration and catalase (A: alginate, C: calcium peroxide).
  • Fig. 6 is a diagram showing cell fitness of a hydrogel (A: alginate, C: calcium peroxide).
  • the present inventors have found that a new type of in situ formed hydrogel using calcium peroxide is produced, and a high concentration of oxygen (more than 80%) is generated in such a hydrogel, 25% or more) continued for 48 hours.
  • a polymer hydrogel material capable of releasing oxygen at a high concentration in a simple manner without chemical modification of the polymer can be manufactured, and physical / chemical / biological properties can be easily controlled.
  • the present invention employs calcium peroxide for natural / synthetic polymers with anions to induce ionic interactions and thereby produce oxygen-releasing in situ hydrogels.
  • alginate having a gluconic acid monomer unit having an anion is a natural polymer without chemical modification.
  • the polymer main chain may be selected from the group consisting of Arabic Gum, Tamarind Gum, Karaya Gum, Guar Gum, Locust Bean Gum, Quince Seed Gum, Xanthan Gum, Cyclodextrin, Casein, Tara Gum, Tragacanth Gum, Glucomannan, Glucosamine, Gum Ghatti, Furcelleran, Pullulan, Gellan Gum, Pectin, Agar, Alginate, Carrageenan, Dextrin, Poly Sodium alginate, sodium polyacrylate, propylene glycol alginate, methyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, ), Sodium alginate (Sodiu m Alginate, and sodium caseinate.
  • the present invention is not limited thereto.
  • the oxygen-releasing hydrogel can be produced by in situ crosslinking of a polysaccharide main chain having an anionic glucuronic acid unit by inducing ionic interaction by release of calcium ions in a solution containing calcium peroxide have.
  • DPBS which is a commonly used buffer solution
  • DPBS does not form a hydrogel because calcium ionization is limited
  • Tris-HCl buffer solution A hydrogel is formed by utilizing the fact that calcium ions are released. This was also applicable to calcium hydroxide with low solubility in water to form a hydrogel.
  • the present invention also provides a tissue regeneration, tissue engineering support and implant implant material comprising an oxygen-releasing in situ crosslinked hydrogel.
  • These materials include cartilage regeneration, bone regeneration, alveolar regeneration, skin regeneration, cardiac tissue regeneration, artificial intraocular lens, spinal nerve A regeneration and augmentation, a barrier for adhesion, a urinary incontinence treatment, a filler for wrinkle removal, a burn A wound dressing, a tissue augmentation, and an intervertebral disc treatment.
  • the present invention is not limited thereto.
  • the present invention also provides a material for tissue adhesion and hemostasis comprising the oxygen-releasing in situ crosslinked hydrogel.
  • the material for hemostasis includes at least one of neurosurgical surgery including a vascular surgery area, orthopedic surgery including adhesion of bone, hemostasis of a laceration patient, suture of a femoral artery, cataract incision suture, cartilage healing, skin joining, Gastrointestinal tract differentiation, and tendon / ligament healing.
  • neurosurgical surgery including a vascular surgery area
  • orthopedic surgery including adhesion of bone, hemostasis of a laceration patient, suture of a femoral artery, cataract incision suture, cartilage healing, skin joining, Gastrointestinal tract differentiation, and tendon / ligament healing.
  • orthopedic surgery including adhesion of bone, hemostasis of a laceration patient, suture of a femoral artery, cataract incision suture, cartilage healing, skin joining, Gastrointestinal tract differentiation, and tendon / ligament healing.
  • the present invention is not limited thereto.
  • the present invention also provides a carrier for a physiologically active substance or a drug delivery carrier comprising the oxygen-releasing in situ crosslinked hydrogel.
  • the physiologically active substance or drug may be any one or more selected from the group consisting of a peptide or protein drug, an antibacterial agent, an anti-cancer agent, and an anti-inflammatory agent, but is not limited thereto.
  • the peptide or protein drug may be a fibroblast growth factor (FGF), a vascular endothelial growth factor (VEGF), a transforming growth factor (TGF), a bone morphogenetic factor protein, BMP), human growth hormone (hGH), porcine growth hormone (pGH), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO) , Macrophage colony-stimulating factor (M-CSF), tumor necrosis factor (TNF), epidermal growth factor (EGF), platelet-derived growth factor , Interferon- ⁇ , ⁇ , ⁇ , interleukin-2 (IL-2), calcitonin, nerve growth factor (NGF), growth hormone Factor, angiotensin, luteinizing hormone releasing hormone (luteinizin (LHRH agonist), insulin, thyrotropin-releasing hormone (TRH), angiostatin, endostatin, somatostatin, glucagon, endorphin, But
  • said antimicrobial agent is selected from the group consisting of minocycline, tetracycline, oproxacin, phosphomycin, mergein, proproxacin, ampicillin, penicillin, doxycycline, thienamycin, cephalosporin, noradocin, gentamicin, neomycin, It may be advantageous to use a compound selected from the group consisting of paromomycin, micronomycin, amikacin, tobramycin, dibecasin, cytotoxic, sepracur, erythromycin, cyprofloxacin, levofloxacin, enoxasin, vancomycin, imipenem, foscidic acid and mixtures thereof , But the present invention is not limited thereto.
  • the anticancer agent is selected from the group consisting of paclitaxel, texothier, adriamycin, endostatin, angiostatin, mitomycin, bleomycin, cispletin, carboplatin, doxorubicin, daunorubicin, dirubicin, 5-fluorouracil, methotrexate, Actinomycin-D, and mixtures thereof, but is not limited thereto.
  • the anti-inflammatory agent is selected from the group consisting of acetaminophen, aspirin, ibuprofen, diclofenac, indomethacin, piroxycam, fenoprofen, plubiprofen, ketoprofen, naproxen, Camphor, tenoxicam, and mixtures thereof, but is not limited thereto.
  • Alginic acid sodium salt, calcium peroxide (CaO 2 ), calcium hydroxide (Ca (OH) 2 ) and catalase were purchased from Sigma Aldrich (St. Louis, Mo., USA) , UltraPure TM 1M Tris-HCI (pH 8.0) buffer was purchased from Invitrogen (Carlsbad, CA, USA).
  • DMEM penicillin-streptomycin
  • P / S penicillin-streptomycin
  • trypsin / EDTA and DPBS
  • DPBS Dibbecco's modified phosphate buffered saline
  • NBCS newborn fetal serum Calf Serum
  • the hydrogel was prepared by mixing a solution of the alginate polymer dissolved in DPBS at 37 DEG C and calcium peroxide (0 to 0.75 wt%).
  • the type of solvent was changed to DPBS (250 ⁇ l) or Tris-HCl (250 ⁇ l) under a constant composition of Alginate (2 wt%) and CaO 2 (0.75 wt%).
  • the mechanical strength of the alginate hydrogel was measured using a rheometer, and the change in mechanical strength was evaluated by adjusting the concentrations of alginate and calcium peroxide.
  • the concentration of alginate was varied to 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, and 3.0 wt% under a constant composition of the concentration of calcium peroxide (0.3 wt%).
  • the mechanical strength of the hydrogel can be controlled by controlling the concentration of the alginate, and the range was 4 to 1600 Pa.
  • the concentration of calcium peroxide was changed to 0 wt%, 0.15 wt%, 0.3 wt%, 0.45 wt%, 0.6 wt%, 0.75 wt%, and 0.9 wt% under a constant composition of alginate concentration (2.0 wt%). It was confirmed that the mechanical strength of the hydrogel was controllable by controlling the concentration of calcium peroxide, and the range was from 200 to 4000 Pa. On the other hand, when the concentration of calcium peroxide was set to 0 wt%, the hydrogel could not be formed. This is because there is no calcium peroxide and the formation of ionic bond between the calcium ion and the carboxylate functional group of glutaric acid is not achieved.
  • the concentration of calcium peroxide was changed to 0% by weight, 0.15% by weight, 0.45% by weight and 0.75% by weight under a constant composition of alginate (2.0% by weight) %, 0.6 wt%, 0.3 wt%, 0 wt%. It was confirmed that the mechanical strength of the hydrogel can be similarly controlled by adjusting the concentration of calcium peroxide and the amount of calcium ion released by the supplement of calcium hydroxide, and the range was from 1800 to 2100 Pa.
  • the concentration of catalase was changed to 0 U / ml, 50 U / ml, and 100 U / ml to prepare a polymer solution for the hydrogel preparation.
  • hydrogel 100 ⁇ l was prepared using a uniform mold, and 10 minutes later, it was placed in a 1.5 ml EP tube together with the medium (600 ⁇ l) The amount of hydrogen peroxide after 24 hours was measured.
  • the amount of hydrogen peroxide in the medium containing hydrogel could be controlled to 10 ⁇ 520 ⁇ M by controlling the concentration of calcium peroxide.
  • concentration of calcium peroxide increased, because the concentration of calcium peroxide, which is the cause of hydrogen peroxide, increased, and more hydrogen peroxide was generated inside the hydrogel.
  • the amount of hydrogen peroxide in the hydrogel containing 50 U / ml and 100 U / ml catalase could be adjusted to 9 ⁇ 16 ⁇ M, and no significant difference was observed between the groups regardless of the increase in the concentration of calcium peroxide Respectively. This is because hydrogen peroxide produced by calcium peroxide is decomposed into water and oxygen by catalysis.
  • the oxygen release behavior of the hydrogel according to the concentration of calcium peroxide was confirmed for 2 days using an oxygen sensor.
  • the effect of decomposition of hydrogen peroxide generated by the decomposition of calcium peroxide on the oxygen release behavior was analyzed by using catalysis.
  • the concentration of catalase was changed to 0 U / ml and 50 U / ml to prepare a polymer solution for the hydrogel preparation.
  • Hydrogel 300 ⁇ l was prepared to measure the amount of dissolved oxygen in the media containing the hydrogel, and the medium (600 ⁇ l) was added 10 minutes later, and the amount of dissolved oxygen in the medium was measured.
  • the maximum dissolved oxygen level of the medium containing hydrogel prepared with 50 U / ml of catalase could be adjusted to 22.83 ⁇ 81.03%.
  • concentration of calcium peroxide increased, the maximum dissolved oxygen amount of the medium containing hydrogel increased,
  • the oxygen environment was maintained for 24 hours to 48 hours. This is because the concentration of calcium peroxide, which is the oxygen generating factor, increases, and the catalysis increases the oxygen concentration in the hydrogel while decomposing the hydrogen peroxide produced by the calcium peroxide into water and oxygen.
  • the oxygen release time is prolonged and the oxygen concentration is maintained for a long time.
  • human dermal fibroblasts hHDFs
  • hHDFs human dermal fibroblasts
  • the concentration of the cells used in the experiment was 3.0 ⁇ 10 3 cells / well.
  • the cells were cultured for 24 hours at 37 ° C. in 5% CO 2 atmosphere. After 24 hours of hydrogel-loaded eluate was diluted 10 times in the medium, After 24 hours, cell viability was measured using WST-1 assay and Live / Dead Viability / Cytotoxicity Kit.
  • Hydrogel disks were prepared by mixing catalase (0 ⁇ 100 U / ml) for the decomposition of hydrogen peroxide produced during hydrogel formation.
  • Live / Dead analysis is a method of assessing the cytotoxicity by showing the cells killed by cytotoxicity as red and living cells as green.
  • the hydrogel showed similar cell densities regardless of calcium peroxide concentration, and showed cell viability above 105% of that of the control.
  • the hydrogel showed similar cell densities regardless of calcium peroxide concentration, and showed cell viability of over 98% compared to the control. These results show that the ratio of living cells is similar in Live / Dead assay results.

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Abstract

La présente invention concerne la production d'un hydrogel libérant de l'oxygène pour bioinjection. Un nouveau type d'hydrogel réticulé libérant de l'oxygène in situ ainsi produit est formé sous la forme d'un hydrogel par induction, au moyen d'ions calcium libérés par décomposition du peroxyde de calcium, d'un couplage ionique avec un polymère chargé négativement, et génère et libère de l'oxygène hautement concentré à l'intérieur de l'hydrogel. De plus, la présente invention est innovante car elle est issue de la première des études sur la formation d'un hydrogel au moyen d'alginates existants pour produire un hydrogel au moyen de peroxyde de calcium, elle est capable d'améliorer les limites des systèmes d'administration d'oxygène existants, permet la production d'hydrogel libérant de l'oxygène pour bioinjection par un procédé simple et rapide sans synthèse chimique, et présente l'avantage supplémentaire de permettre de contrôler facilement les caractéristiques physiques, chimiques et biochimiques de l'hydrogel en fonction des conditions de production.
PCT/KR2018/006346 2017-12-19 2018-06-04 Procédé de production d'hydrogel libérant de l'oxygène pour bioinjection et utilisation biomédicale associée WO2019124653A1 (fr)

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KR10-2017-0175152 2017-12-19

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CN111603608A (zh) * 2020-05-15 2020-09-01 南通大学 普鲁兰多糖-透明质酸-微纤维脊髓支架及其制备方法

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