WO2022025488A1 - Complexe d'hydrogel comprenant de la gélatine et un polymère synthétique et procédé de production correspondant - Google Patents

Complexe d'hydrogel comprenant de la gélatine et un polymère synthétique et procédé de production correspondant Download PDF

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WO2022025488A1
WO2022025488A1 PCT/KR2021/009045 KR2021009045W WO2022025488A1 WO 2022025488 A1 WO2022025488 A1 WO 2022025488A1 KR 2021009045 W KR2021009045 W KR 2021009045W WO 2022025488 A1 WO2022025488 A1 WO 2022025488A1
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gelatin
hydrogel
complex
synthetic polymer
reaction
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이재영
박중건
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광주과학기술원
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
    • C08K5/0025—Crosslinking or vulcanising agents; including accelerators
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/07—Aldehydes; Ketones
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/15—Heterocyclic compounds having oxygen in the ring
    • C08K5/151—Heterocyclic compounds having oxygen in the ring having one oxygen atom in the ring
    • C08K5/1515—Three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/16—Nitrogen-containing compounds
    • C08K5/29—Compounds containing one or more carbon-to-nitrogen double bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L101/00—Compositions of unspecified macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2300/00—Characterised by the use of unspecified polymers
    • C08J2300/14—Water soluble or water swellable polymers, e.g. aqueous gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2379/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen, or carbon only, not provided for in groups C08J2361/00 - C08J2377/00

Definitions

  • the present invention relates to a hydrogel complex and a method for preparing the same, and more particularly, to a hydrogel complex comprising gelatin and a synthetic polymer, and a method for preparing the same.
  • Hydrogels are widely used in biomedical engineering applications, cosmetics, and food due to their hydrophilic properties and high water content. In particular, it is used as a transplant and a cell culture material because of its similarity to the soft tissue of the living body. Hydrogels do not dissolve in water and retain their shape due to crosslinking by various chemical, physical, and ionic bonds of hydrophilic polymers, and are characterized by ductility.
  • natural polymers such as proteins such as gelatin, collagen, hyaluronic acid, cellulose derivatives, alginic acid and chitosan, nucleic acids such as DNA, and natural polymers such as lipids are used in the manufacture of hydrogels, and polyethylene glycol (Polyethylene glycol, PEG ), polyacrylic acid, polyacrylamide, polyvinyl alcohol, poly methyl methacrylate (PMMA), poly hydroxyethyl methacrylate (PHEMA), and other synthetic polymers are being used.
  • PEG polyethylene glycol
  • PMMA polymethyl methacrylate
  • PHEMA poly hydroxyethyl methacrylate
  • Synthetic polymers have a problem that bioactivity is low compared to natural polymers, and natural polymers have weak physical properties, which limits their use. Accordingly, various complexes and manufacturing technologies to improve the physical properties of the hard gel are being developed.
  • a hydrogel composite composed of two or more hydrophilic polymers has the advantage of being able to impart the properties of individual polymers constituting it to some extent, but there is a limitation that the simply prepared composite does not sufficiently contribute to the improvement of its physical properties.
  • Gelatin obtained through hydrolysis from animal tissues (skin, etc.) is widely used due to its excellent biocompatibility, degradability, and cell/tissue action.
  • Gelatin undergoes physical crosslinking at low temperatures to form a gel state having a certain shape, but exhibits a property of reversibly dissolving into a sol state when the temperature is increased. Accordingly, when used at room temperature or higher due to a simple mixing or crosslinking reaction of gelatin and other polymers, the properties of the material still show limitations.
  • Non-Patent Document 1 Ahmed A. Haroun et al., International Journal of Biological Macromolecules, 46 (2010), 310-316.
  • the inventors of the present invention overcame the problem of low mechanical properties when using a single synthetic polymer or gelatin hydrogel alone, and studied to improve the physical properties of a hydrogel obtained by mixing gelatin and polymer, the physical network of gelatin In the case of realizing a stable double network structure of gelatin and polymer complex by simultaneously or secondary inducing polymerization of synthetic polymers, hydrogel complexes exhibiting excellent mechanical (physical) and biological properties can be prepared. found
  • the present invention is a hydrogel complex (compoiste) containing gelatin and a synthetic polymer and a method for producing the hydrogel complex comprising the step of implementing a stable double network structure of the gelatin and polymer complex.
  • hydrogel complex comprising gelatin and a synthetic polymer.
  • the gelatin may be included in an amount of 30 to 500 mg/ml based on the hydrogel complex.
  • the synthetic polymer may be at least one selected from the group consisting of polyacrylamide, polyethylene glycol diacrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polymethyl methacrylate, and the synthetic polymer may be included in an amount of 1 to 30% (v/v) based on the hydrogel complex.
  • step (a) dissolving gelatin and a synthetic polymer monomer in water to obtain a hydrogel pre-solution; (b) adding a thermal initiator to the hydrogel pre-solution obtained in step (a) and performing a first reaction at a low temperature to obtain a first reactant in which a gelatin network is formed; And (c) a second reaction of the first reactant of step (b) at a temperature above room temperature to obtain a second reactant in which thermally initiated polymerization is formed, a method for producing a hydrogel complex comprising gelatin and synthetic polymer provided
  • the gelatin of step (a) may be dissolved at a concentration of 30 ⁇ 500 mg / ml.
  • the synthetic polymer monomer of step (a) is at least one selected from the group consisting of polyacrylamide, polyethylene glycol diacrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polymethyl methacrylate. It may be a monomer, and the synthetic polymer monomer may be dissolved in 1 to 30% (v/v).
  • the thermal initiator of step (b) may be at least one selected from the group consisting of ammonium persulfate, potassium persulfate and iron chloride, and the thermal initiator is added in an amount of 0.01 to 2% (v/v).
  • the thermal initiator is added in an amount of 0.01 to 2% (v/v).
  • At least one selected from the group consisting of a catalyst, a crosslinking agent, an adduct and a pore former may be additionally added in step (b).
  • the catalyst may be at least one selected from the group consisting of thymid, triethylamine, and butylamine, and the catalyst may be added in an amount of 0.01 to 2% (v/v).
  • the crosslinking agent is glutaraldehyde, formaldehyde, 1,4-butanediol diglycidyl ether (BDDE) and 1-ethyl-3-(3-dimethylamino) It may be at least one selected from the group consisting of propyl) carbodiimide (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide, EDC), and the crosslinking agent may be added in an amount of 0.01 to 1% (v/v). .
  • the low temperature of step (b) may be 0 ⁇ 10 °C.
  • the first reaction of step (b) may be performed for 1 to 200 minutes.
  • the temperature above room temperature in step (c) may be 15 ⁇ 60 °C.
  • the second reaction of step (c) may be performed for 1 to 200 minutes.
  • the gelatin/polymer hydrogel composite prepared so that the physical bonding of the gelatin network and the crosslinking of the polymer exist double exhibits excellent mechanical properties that cannot be obtained by a simple combination of gelatin and synthetic polymer.
  • the improved physical properties of elasticity and ductility and biological properties it is possible to solve the problems of hydrogels with weak physical properties and increase the interaction with cells/tissues by gelatin, which has been widely used in the past. It has been found that it can be utilized as an improved substitute for hydrogels.
  • the hydrogel complex comprising gelatin and synthetic polymer of the present invention and the method for preparing the hydrogel complex implementing the double network structure of the gelatin and polymer complex are tissue engineering scaffolds, human implants (inserts) in the field of hydrogel complexes. , cell cultures, pharmaceuticals, food, packaging, cosmetics, etc. can be usefully used as a biocompatible hydrophilic polymer.
  • 1 is an initial mixed aqueous solution (methyl methacrylate 5.11 (v/v)% and hydroxyethyl methacrylate 23.5 (v/v)%, pentaerythritol tetraacrylate 0.31 (v/v)% dissolved in DMF; Gelatin 100 mg/ml) as a graph measuring the elastic modulus displayed when the temperature changes according to the gelatin concentration, and the modulus means the elastic modulus, and indicates the degree of gelatin network formation.
  • Figure 2 is a graph measuring the change in modulus (Pa) according to the temperature change (conversion from 37 °C to 4 °C) of a mixed aqueous solution containing various concentrations of gelatin (50, 100, 150, 200 mg / ml) and monomers to be.
  • 3 is a graph measuring a change in modulus according to a temperature change (conversion from 5°C to 25°C) of a mixed aqueous solution containing PEGDA (polyethylene glycol diacrylate) having different gelatin concentrations.
  • PEGDA polyethylene glycol diacrylate
  • FIG. 4 is a graph showing the modulus of a hydrogel composite obtained by polymerizing a solution containing gelatin, acrylamide monomer, bisacrylamide, and a thermal initiator under 5 °C conditions, 25 °C conditions, and 5 °C to 25 °C conditions. .
  • FIG. 5 is a CD spectral spectrum of a gelatin hydrogel complex, in which a mixture containing gelatin, acrylamide monomer, bisacrylamide and a thermal initiator was mixed at 5 ° C. for 40 minutes (5 ° C.), 25 ° C. for 40 minutes (25 ° C.); The CD spectral spectrum of the sample was measured after polymerization at 5° C. for 20 minutes and at 25° C. for 20 minutes (5° C. & 25° C.). Absorbance at around 230 nm is an indicator of gelatin network formation, indicating the degree of formation of a triple helix structure of gelatin.
  • FIG. 6 is a graph showing the modulus of a hydrogel complex obtained by polymerizing a solution containing gelatin, polyethylene glycol diacrylate and a thermal initiator at 5 °C conditions, 25 °C conditions, and 5 °C to 25 °C conditions.
  • These are the modulus measurement results of the hydrogel complex obtained by forming a secondary network structure while the gelatin mixture reaction solution was adjusted to the same conditions other than temperature and time [I) 5°C/40min, II) 25°C/40min, III) 5° C./10 min + 25° C./30 min, IV) 5° C./20 min + 25° C./20 min, V) 5° C./30 min + 25° C./10 min].
  • hydrogel 7 is a hydrogel obtained by polymerizing a solution containing gelatin, polyhydroxyethyl methacrylate, polyethylene glycol-4-acrylate and a thermal initiator at 5 ° C., 25 ° C., and 5 ° C. to 25 ° C. It is a graph showing the modulus of the gel complex.
  • control group 9 is a polymer without gelatin (control group 1) and gelatin with and without fixation;
  • Kean hydrogel complex (control group 2) and a solution containing gelatin, acrylamide monomer, bisacrylamide, thermal initiator and chemical crosslinking agent were polymerized for 40 minutes while changing from 5 °C to 25 °C, a chemical crosslinking agent (glutaraldehyde) ) is a graph showing the modulus of the hydrogel complex obtained by changing the initial concentration of 0.1%, 0.2%, 0.3%.
  • the present invention provides a hydrogel complex comprising gelatin and a synthetic polymer.
  • the hydrogel complex of the present invention is composed of gelatin and a synthetic polymer, and optionally a thermal initiator, and consists of a primarily formed gelatin network and a secondary polymerized polymeric bond.
  • the hydrogel complex of the present invention including a chemical crosslinking agent, consists of a gelatin network formed through a stabilization process by chemical crosslinking after the primary gelatin network is formed.
  • the structure of the hydrogel composite of the present invention is shown in Scheme 1 below.
  • the gelatin may be included in an amount of 30 to 500 mg/ml based on the hydrogel complex, preferably 50 to 200 mg/ml.
  • the synthetic polymer may be at least one selected from the group consisting of polyacrylamide, polyethylene glycol diacrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol, and polymethyl methacrylate.
  • the synthetic polymer may be included in an amount of 1 to 30% (v/v), preferably 5 to 25% (v/v), based on the hydrogel complex.
  • the present invention comprises the steps of (a) dissolving gelatin and a synthetic polymer monomer in water to obtain a hydrogel pre-solution; (b) adding a thermal initiator to the hydrogel pre-solution obtained in step (a) and performing a first reaction at a low temperature to obtain a first reactant in which a gelatin network is formed; And (c) a second reaction of the first reactant of step (b) at a temperature above room temperature to obtain a second reactant in which thermally initiated polymerization is formed.
  • a method for producing a hydrogel complex comprising gelatin and a synthetic polymer to provide.
  • the preparation method of the present invention comprises a step of dissolving gelatin and a synthetic polymer monomer in water to obtain a hydrogel pre-solution [ie, step (a)].
  • gelatin should be prepared at a type and concentration of gelatin to form a physical cross-link and network in the mixed solution state before the reaction, and may be dissolved at a concentration of 30 to 500 mg/ml, preferably 50 It can be dissolved at ⁇ 200 mg/ml.
  • the synthetic polymer monomer of step (a) is at least one selected from the group consisting of polyacrylamide, polyethylene glycol diacrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polymethyl methacrylate. It may be a monomer.
  • the synthetic polymer monomer may be dissolved in 1 to 30% (v/v).
  • the preparation method of the present invention includes a step of obtaining a first reactant in which a gelatin network is formed by adding a thermal initiator to the hydrogel pre-solution obtained in step (a) and performing a first reaction at a low temperature [ie, step (b)].
  • Step (b) is a step of forming a gelatin network primarily at a low temperature.
  • the thermal initiator of step (b) may be at least one selected from the group consisting of ammonium persulfate, potassium persulfate and iron oxide chloride.
  • the thermal initiator may be added in an amount of 0.01 to 2% (v/v), preferably 0.1 to 1.5% (v/v).
  • At least one selected from the group consisting of a catalyst, a crosslinking agent, an adduct and a pore former may be additionally added in step (b).
  • the catalyst may be at least one selected from the group consisting of thymid, triethylamine, and butylamine.
  • the catalyst may be added in an amount of 0.01 to 2% (v/v), preferably 0.05 to 1% (v/v).
  • the crosslinking agent is 1 selected from the group consisting of glutaraldehyde, formaldehyde, 1,4-butanediol diglycidyl ether and 1-ethyl-3-(3-dimethylaminopropyl) carbodimide. may be more than one species.
  • the crosslinking agent may be added in an amount of 0.01 to 1% (v/v), preferably 0.05 to 0.5% (v/v), and most preferably 0.1 to 0.3% (v/v).
  • the low temperature of step (b) is possible as long as it is a low temperature at which a gelatin network is formed, for example, it may be 0 ⁇ 10 °C, preferably 3 ⁇ 6 °C, but is not limited thereto. .
  • the first reaction of step (b) may be carried out for a time during which the gelatin network formation reaction takes place, for example, it may be carried out for 1 to 200 minutes, preferably for 10 to 30 minutes. , but not limited thereto.
  • the preparation method of the present invention includes the step of obtaining a second reactant in which thermally initiated polymerization is formed by subjecting the first reactant of step (b) to a second reaction at a temperature above room temperature [ie, step (c)].
  • Step (c) is a step in which the polymerization reaction of the synthetic polymer is performed after the gelatin network is formed.
  • the polymerization reaction of the synthetic polymer is carried out by the thermal initiator added in step (b) when the temperature of the reactant is raised from a low temperature to a temperature above room temperature.
  • the polymerization temperature and time of the second reaction in step (c) are set to prevent a large loss of the physically formed gelatin network.
  • the temperature above room temperature may be 15 ⁇ 60 °C, preferably 20 ⁇ 38 °C.
  • the second reaction which is a polymerization reaction, may be performed for a time during which the polymerization reaction of the synthetic polymer takes place, for example, may be performed for 1 to 200 minutes, preferably for 10 to 30 minutes, but is not limited thereto. does not
  • the hydrogel prepared from the mold is removed and unreacted products and reaction by-products are washed and removed.
  • Hydrogel pre-solution was prepared by dissolving acrylamide 8% (v/v), bisacrylamide 0.28% (v/v) and gelatin 100 mg/ml in water. After that, 0.4 % (w/v) of ammonium persulfate as a thermal initiator and 0.2 % (v/v) of thymid as a catalyst are added, stirred quickly, and put the prepared solution in a mold maintained at 5 ° C. made it After 20 minutes, the mold containing the solution was moved to 25° C. and the reaction was allowed to proceed for 20 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • Hydrogel pre-solution was prepared by dissolving acrylamide 8% (v/v), bisacrylamide 0.28% (v/v) and gelatin 100 mg/ml in water. After that, 0.2% (v/v) of glutaraldehyde (GA), a crosslinking fixing agent, is added together with 0.4% (w/v) of ammonium persulfate as a thermal initiator and 0.2% (v/v) of thymid as a catalyst, followed by rapid stirring. The prepared solution was put into a mold maintained at 5 °C to proceed with the reaction. After 20 minutes, the mold containing the solution was moved to 25 °C and the rest of the reaction was allowed to proceed for 20 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • G glutaraldehyde
  • the hydrogel pre-solution was prepared by dissolving 5% (v/v) of polyethylene glycol diacrylate (Polyehtylene glycol diacrylate, molecular weight 700 Da) and 100 mg/ml of gelatin in water. Thereafter, 0.18% (w/v) of ammonium persulfate as a thermal initiator and 0.05% (v/v) of thymid as a catalyst were added, and after rapid stirring, the prepared solution was put into a mold maintained at 5° C. to proceed with the reaction. After 20 minutes, the mold containing the solution was moved to 25 °C and the rest of the reaction was allowed to proceed for 20 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • polyethylene glycol diacrylate Polyehtylene glycol diacrylate, molecular weight 700 Da
  • Hydrogel pre-solution was prepared by dissolving hydroxyethyl methacrylate 20% (v/v), ethylene glycol dimethacrylate 0.5% (v/v) and gelatin 100 mg/ml in water. Thereafter, 1% (w/v) of ammonium persulfate as a thermal initiator and 0.69% (v/v) of thymid as a catalyst were added, and the solution was put into a mold maintained at 5° C. after rapid stirring to proceed with the reaction. After 30 minutes, the mold containing the solution was moved to 25 °C and the rest of the reaction was allowed to proceed for 10 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • Hydrogel pre-solution was prepared by dissolving methyl methacrylate 10% (v/v), bisacrylamide 0.5% (v/v) and gelatin 100 mg/ml in water. Thereafter, 1.5% (w/v) of ammonium persulfate as a thermal initiator and 0.5% (v/v) of thymid as a catalyst were added, stirred quickly, and the prepared solution was put into a mold maintained at 5° C. to proceed with the reaction. After 30 minutes, the mold containing the solution was moved to 25 °C and the rest of the reaction was allowed to proceed for 10 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • Hydrogel pre-solution consisted of 5.11 (v/v) % methyl methacrylate and 23.5 (v/v) % hydroxy ethyl methacrylate, 0.41 (v/v) % ethylene glycol diacrylate, gelatin It was prepared by dissolving 100 mg/ml in water. Thereafter, 1.37 (w/v) % of ammonium persulfate as a thermal initiator and 0.69 (v/v) % of thymid as a catalyst were added, and the solution was put into a mold maintained at 5°C after rapid stirring, and the reaction proceeded. After 20 minutes, the mold containing the solution was moved to 25 °C and the reaction was carried out for 20 minutes. Thereafter, the prepared hydrogel was removed from the mold and washed in tertiary distilled water to obtain a double cross-linked hydrogel.
  • the prepared gel was measured using a rheometer at a temperature of 25 °C and a strain rate.
  • the elastic modulus was calculated using the shear modulus and the 1 Hz value in the frequency range from 0.1 to 10 Hz under the condition of 0.5%.
  • the triple helix structure of gelatin in the hydrogel was measured in the wavelength range of 190-240 nm at 25°C using CD spectroscopy.
  • the triple helical structure of gelatin and the degree of gelatin network formation were confirmed by values near the 230 nm wavelength band in the CD spectral spectrum of the sample.
  • the modulus means the modulus of elasticity, and indicates the degree of formation of the gelatin network.
  • FIG. 1 when gelatin was moved to a low temperature at a concentration of 50 mg/mL or more in a solution containing a monomer, a physical network was formed, and the modulus was increased. At this time, the temperature and time at which the gelatin network was formed were different according to the concentration of gelatin.
  • FIG. 2 shows the modulus (Pa) according to the temperature change (conversion from 37 °C to 4 °C) of a mixed aqueous solution containing various concentrations of gelatin (50, 100, 150, 100 mg/ml) and acrylamide monomer (10%) change is shown.
  • the modulus greatly increased within minutes, and then it was shown that the modulus continued to increase gradually.
  • FIG. 4 shows (a) a gelatin concentration of 50 mg/ml or (b) a mixed reaction solution having a gelatin concentration of 100 mg/ml and a solution containing acrylamide monomer, bisacrylamide, and a thermal initiator at 5 ° C. conditions, 25 ° C. conditions, and Modulus measurement results of the hydrogel composite obtained by polymerization under the conditions of changing from 5 °C to 25 °C are shown. As shown in FIG. 4 , it can be seen that the physical properties of the finally obtained hydrogel composite vary depending on the low temperature and room temperature reaction temperature.
  • the method of inducing polymer polymerization after the gelatin network formation condition improves the physical properties of the complex than the method of inducing the polymer polymerization condition on the gelatin network formation condition. That is, compared to the gelatin/polyacrylamide complex prepared by polymerization at low temperature (5 °C) and room temperature (25 °C) for 40 minutes, after reacting at low temperature (5 °C) for a predetermined time, the remaining time at room temperature (25 °C) The reaction time was the same for 40 minutes, but the mechanical properties of the composite prepared by changing the reaction temperature to 5 °C and 25 °C were found to be excellent.
  • FIG. 5 is a CD spectral spectrum of the gelatin hydrogel complex, in which a mixture containing gelatin, acrylamide monomer, bisacrylamide and a thermal initiator was mixed at 5 ° C. for 40 minutes (5 ° C.), 25 ° C. for 40 minutes (25 ° C.), The results of measuring the CD spectral spectrum of the sample after polymerization at 5°C for 20 minutes and at 25°C for 20 minutes (5°C & 25°C) are shown.
  • Absorbance at around 230 nm is an indicator of gelatin network formation, indicating the degree of formation of a triple helix structure of gelatin. As shown in FIG.
  • the gelatin network of the gelatin complex hydrogel was polymerized at 5 °C for 40 minutes (5 °C), at 5 °C for 20 minutes and at 25 °C for 20 minutes (5 °C & 25 °C). It can be seen that it is stably formed and maintained.
  • FIG. 6 shows the modulus of the hydrogel composite obtained by polymerizing a solution containing gelatin, polyethylene glycol diacrylate and a thermal initiator at 5 ° C., 25 ° C., and 5 ° C. to 25 ° C. The modulus is shown
  • FIG. A hydrogel complex obtained by polymerizing a solution containing gelatin, polyhydroxyethyl methacrylate, polyethylene glycol-4-acrylate and a thermal initiator under 5 °C conditions, 25 °C conditions, and 5 °C to 25 °C conditions. The modulus of is shown.
  • control group 9 shows a polymer without gelatin (control group 1), a hydrogel complex containing gelatin and not immobilized (control group 2), and a solution containing gelatin, acrylamide monomer, bisacrylamide, a thermal initiator and a chemical crosslinking agent at 5 ° C.
  • the modulus of the hydrogel complex obtained by changing the initial concentration of the chemical crosslinking agent (glutaraldehyde) to 0.1%, 0.2%, and 0.3% under the conditions of polymerization for 40 minutes at 25 °C is shown.
  • the mechanical strength of the finally obtained hydrogel composite is increased when a crosslinking agent capable of stabilizing the initial gelatin structure is added when the reaction temperature and time of low and room temperature are changed.

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  • Biological Depolymerization Polymers (AREA)

Abstract

La présente invention concerne un complexe d'hydrogel comprenant de la gélatine et un polymère synthétique et un procédé de production du complexe d'hydrogel mettant en œuvre une structure de double réseau de gélatine et un complexe polymère. Le complexe d'hydrogel produit par le procédé de production d'un complexe d'hydrogel mettant en œuvre une structure de double réseau de gélatine et un complexe polymère de la présente invention peut présenter des propriétés physiques améliorées d'une excellente élasticité et d'une excellente ductilité et d'excellentes propriétés biologiques en même temps, ce qui permet de résoudre les problèmes d'hydrogels existants présentant des propriétés physiques faibles et d'augmenter l'interaction avec des cellules/tissu au moyen de gélatine. Par conséquent, le complexe d'hydrogel de la présente invention peut être employé utilement en tant que polymère hydrophile biocompatible pour un échafaudage d'ingénierie tissulaire, un implant humain (implantation), une culture cellulaire, un produit pharmaceutique, un aliment, un matériau d'emballage, un produit cosmétique, etc. dans le domaine des complexes d'hydrogel.
PCT/KR2021/009045 2020-07-28 2021-07-14 Complexe d'hydrogel comprenant de la gélatine et un polymère synthétique et procédé de production correspondant WO2022025488A1 (fr)

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CN115252885A (zh) * 2022-07-26 2022-11-01 湖北大学 一种多重氢键交联的水凝胶敷料及其制备和应用
CN115317661A (zh) * 2022-08-29 2022-11-11 北京化工大学常州先进材料研究院 天然高分子复合水凝胶敷料
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CN116271186A (zh) * 2023-02-15 2023-06-23 上海瑞凝生物科技有限公司 一种可载药栓塞微球及其制备方法
CN117586462A (zh) * 2023-12-01 2024-02-23 西南民族大学 一种温度刺激响应型智能水凝胶材料的制备方法
CN118563455A (zh) * 2024-07-29 2024-08-30 四川大学华西医院 一种水凝胶纤维材料、制备方法

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CN114702691A (zh) * 2022-03-29 2022-07-05 浙江大学杭州国际科创中心 一种离子响应型、生物防污型水凝胶及其制备方法和应用
CN114702691B (zh) * 2022-03-29 2023-11-17 浙江大学杭州国际科创中心 一种离子响应型、生物防污型水凝胶及其制备方法和应用
CN115252885A (zh) * 2022-07-26 2022-11-01 湖北大学 一种多重氢键交联的水凝胶敷料及其制备和应用
CN115252885B (zh) * 2022-07-26 2023-08-22 湖北大学 一种多重氢键交联的水凝胶敷料及其制备和应用
CN115317661A (zh) * 2022-08-29 2022-11-11 北京化工大学常州先进材料研究院 天然高分子复合水凝胶敷料
CN115948013A (zh) * 2022-09-01 2023-04-11 浙江省医疗器械检验研究院(国家食品药品监督管理局杭州医疗器械质量监督检验中心) 一种快速成胶水凝胶及制备方法与应用
CN115948013B (zh) * 2022-09-01 2023-11-14 浙江省医疗器械检验研究院(国家食品药品监督管理局杭州医疗器械质量监督检验中心) 一种快速成胶水凝胶及制备方法与应用
CN116271186A (zh) * 2023-02-15 2023-06-23 上海瑞凝生物科技有限公司 一种可载药栓塞微球及其制备方法
CN116271186B (zh) * 2023-02-15 2024-08-09 上海瑞凝生物科技有限公司 一种可载药栓塞微球及其制备方法
CN117586462A (zh) * 2023-12-01 2024-02-23 西南民族大学 一种温度刺激响应型智能水凝胶材料的制备方法
CN118563455A (zh) * 2024-07-29 2024-08-30 四川大学华西医院 一种水凝胶纤维材料、制备方法

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