WO2020252957A1 - 一种促进组织原位再生的可降解再生医学材料及其制备方法 - Google Patents

一种促进组织原位再生的可降解再生医学材料及其制备方法 Download PDF

Info

Publication number
WO2020252957A1
WO2020252957A1 PCT/CN2019/106736 CN2019106736W WO2020252957A1 WO 2020252957 A1 WO2020252957 A1 WO 2020252957A1 CN 2019106736 W CN2019106736 W CN 2019106736W WO 2020252957 A1 WO2020252957 A1 WO 2020252957A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
degradable regenerative
degradable
regenerative medicine
foam
Prior art date
Application number
PCT/CN2019/106736
Other languages
English (en)
French (fr)
Inventor
郭创洲
胡方
仇越秀
于晓丽
Original Assignee
北京幸福益生再生医学科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京幸福益生再生医学科技有限公司 filed Critical 北京幸福益生再生医学科技有限公司
Priority to US17/596,627 priority Critical patent/US20220296785A1/en
Priority to EP19934179.3A priority patent/EP3988136A4/en
Publication of WO2020252957A1 publication Critical patent/WO2020252957A1/zh

Links

Images

Classifications

    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by 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
    • 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
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

  • the invention relates to the technical field of biomedical materials, in particular to a degradable regenerative medical material that can promote tissue regeneration in situ and a preparation method thereof.
  • Regenerative medicine is a comprehensive application of the principles and methods of life sciences, material sciences, and clinical medicine. It is a cutting-edge interdisciplinary subject that researches and develops theoretical techniques for replacing, repairing, reconstructing or regenerating various tissues and organs of the human body. It has been widely used The treatment of congenital genetic defect diseases and various tissue and organ damage is a leap in the development of human medicine; it has become a new frontier in the field of medical biology, and has extremely important theoretical and applied significance for the development of medical biology. Value; the development of regenerative medicine puts forward higher requirements for biomedical materials.
  • Biomaterials refer to materials that, for medical purposes, help patients achieve rehabilitation or enhance their physical functions through diagnosis, repair, treatment or replacement of human tissues and organs.
  • Traditional biomaterials are mainly bio-inert materials, which have good biocompatibility with the human body and low foreign body reaction, which makes the quality of life of patients implanted with biomaterials significantly improved in five to 25 years.
  • bio-inert materials can no longer meet the multiple clinical treatment needs of patients.
  • the focus of medical research has also changed from the original biocompatibility research to biological activity and bioremediation.
  • biological materials can be degraded so that they can be completely replaced by new tissues of the human body, so that there is no obvious difference between biological materials and the tissues of the human body.
  • Regenerative medicine materials must have similar components and structures to human tissues or organs, have good biocompatibility and inducibility, and can trigger the body's self-repair mechanism after being implanted in the human body.
  • tissue engineering materials are implanted into the damaged parts of human tissues and organs, so that the biological materials are absorbed by the body, and the body is constantly stimulated. Some of the cells regenerate to form new tissues to replace the cell tissues in the damaged parts, helping the body to achieve repair and reconstruction.
  • Tissue engineering material products have been used in some clinical treatments, such as dermatology, articular cartilage, vascular system repair and so on. The other is in-situ tissue regeneration materials.
  • in-situ tissue regeneration refers to the introduction of some biological materials in the form of powder, solution or microparticles into the human body to release some growth factors in the form of ions to induce the rapid regeneration of the damaged tissue's own cells and realize the in-situ repair function of the original tissue. For example, injecting regenerative medical biomaterials into the injured body will allow the original bone structure to rebuild new bone tissue.
  • Inorganic regenerative medical biomaterials have good biocompatibility, biological response characteristics, gene activation characteristics and the function of promoting the formation of new tissues due to their similar composition and structural characteristics of inorganic minerals in human hard tissues.
  • the academic and clinical circles attach great importance to it and have important applications in human tissue repair.
  • the stability of the composition of inorganic regenerative medicine biomaterials makes the materials have low biological activity and slow degradation in the body, making it difficult to meet the requirements of regenerative medicine.
  • the main purpose of the present invention is to provide a degradable regenerative medical material that promotes in-situ regeneration of tissues and a preparation method thereof.
  • the method realizes the growth in the process of gelation and molding of inorganic regenerative medical biological materials.
  • the foam is simultaneously solidified to form a microscopic foam, and then the foam is calcined at a high temperature to remove the solvent to form an inorganic regenerative medical biological material with a microscopic three-dimensional network structure. Its foaming ratio is high, the pore size is uniform, and the specific surface area is large. It can realize active groups. Fully contact with body fluids to achieve high biological activity and increase degradation rate.
  • a thickener, foam stabilizer, foaming agent, foam fixing agent and other additives to a mixed sol composed of silicate, phosphate and soluble metal salt rich in metals, phosphorus and silicon. After heating, foaming, and solid foaming, drying and calcination are carried out to form a microscopic porous material with biological activity.
  • a degradable regenerative medical material that promotes tissue regeneration in situ.
  • the degradable regenerative medical material is formed by chemical bonding of Si, P, O and metal elements containing calcium, and has a nano-scale mesoporous structure.
  • the material is used as a regular three-dimensional network structure formed by the skeleton, and the regular three-dimensional network structure is uniformly distributed with micron-sized macropores communicating with the pores.
  • the raw materials for preparing the degradable regenerative medicine materials include:
  • the silicate is used as the silicon source, and the amount should be appropriate. If too much, the material system will degrade slowly, and too little will not meet the requirement of carrier components.
  • Phosphate esters as the phosphorus source provider of the material system, control the degradation rate of the formed material, too much or too little is not conducive to degradation regulation;
  • the pH value of the material will be higher, and too little will affect the ratio of metal to phosphorus and thus the formation rate of hydroxyapatite.
  • the silicate is at least one of methyl orthosilicate, ethyl orthosilicate, and propyl orthosilicate;
  • the phosphate ester is at least one of phosphate monoester, phosphate diester, phosphate triester, glycerophosphate and phytate;
  • the soluble metal salt is at least one of inorganic salts and alkoxides of calcium, strontium, copper, and zinc; in the above-mentioned degradable regenerative medicine material, as a preferred embodiment, the water is deionized water;
  • the catalyst is an acid or a base; wherein the acid is an inorganic acid or an organic acid, and the inorganic acid is preferably nitric acid, hydrochloric acid or sulfuric acid, and
  • the organic acid is preferably at least one of acetic acid, oxalic acid, maleic acid and citric acid;
  • the base is an inorganic base or an organic amine, wherein the inorganic base is preferably sodium hydroxide, ammonia and sodium bicarbonate.
  • the organic amine is preferably at least one of ethylenediamine and n-propylamine.
  • the alcohol solvent is at least one of methanol, ethanol, ethylene glycol, diethylene glycol and glycerol; preferably, the alcohol solvent is methanol A mixture of at least one of ethanol, ethylene glycol and diethylene glycol with glycerol.
  • the thickener is at least one of water-soluble polyvinyl alcohol, hydroxymethyl cellulose and polyethylene glycol 6000;
  • the foam stabilizer is a silicon carbon type surfactant, sodium lauryl sulfonate, fatty acid polyoxyethylene ether, glyceryl stearate, PEG -75 stearate, cetyl ether-20, ceteareth-6, ceteareth-25, PEG-100 stearate, cetearyl glucoside and At least one of C20-22 alcohol phosphate sodium;
  • the foam fixative is at least one of corn gluten powder, whey protein powder, starch and methyl cellulose;
  • the blowing agent is a physical blowing agent, preferably, the blowing agent is pentane, hexane, heptane, petroleum ether, chlorofluoro One or more mixtures of methane, dichlorodifluoromethane and dichlorotetrafluoroethane.
  • the degradable regenerative medicine material has a mesoporous structure of 3-10 nm and a regular three-dimensional structure with pores of 20-100 ⁇ m (the pores forming a three-dimensional network structure). Network structure.
  • the specific surface area of the degradable regenerative medicine material is 740-1500 m 2 /g.
  • the degradable regenerative medicine material has a three-dimensional network structure formed by chemical bonds of Si, P, O, and metal elements, using SiO 2 , P 2 O 5 ,
  • the content of SiO 2 is 46.4-75.4%
  • the content of P 2 O 5 is 3.4-9.4%
  • the content of metal oxides is 21.2-44.2%.
  • a method for preparing the above-mentioned degradable regenerative medicine material for promoting tissue regeneration in situ including:
  • Steps of preparing mixed sol adding catalysts in water and stirring uniformly, then adding silicate and phosphate esters for pre-hydrolysis reaction, hydrolyzing until the mixed liquid becomes transparent, adding soluble metal salt, and stirring until completely dissolved to obtain mixed sol;
  • Foaming and curing step disperse the thickener with an alcohol solvent and add it to the mixed sol, stir until it is completely swollen and dissolved, then add foam stabilizer and foam fixative and stir evenly, then age, then add foaming agent and stir The mixture is uniformly obtained, and then the mixture is heated and foamed and solidified, and then the solidified foam is dried to obtain a foam; wherein the thickener can not only play a thickening role, but also can be used in the foaming process. It helps to form a film.
  • the calcining step calcining the foam to completely remove organic matter to obtain a degradable regenerative medical material that has a three-dimensional network structure and promotes tissue regeneration in situ.
  • the mechanism of the pre-hydrolysis reaction is: the silicate and phosphate esters in the formula are hydrolyzed in the solvent system under the action of a catalyst to generate silanol and hydroxyphosphorus monomer , And then the monomers generated by hydrolysis shrink and polymerize each other into a network structure in which silicon, oxygen, and phosphorus are covalently bonded.
  • the metal ions are interspersed in the network and combined with ionic bonds to achieve molecular-level mixing of various elements to form a material composition. main structure.
  • the aging in the method for preparing the degradable regenerative medicine material, as a preferred embodiment, in the foaming and curing step, is room temperature aging, preferably, the aging refers to aging to viscosity Reach 6000-20000cp (such as 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000cp). If the viscosity is too low, it is easy to break the foam during the foaming process, resulting in low boiling point physical development.
  • the foaming agent escapes; if the viscosity is too high, it is difficult to foam and the foaming ratio is too small; then the temperature is lowered to below 25°C (because the foaming agent is a low boiling point substance, so when adding the foaming agent, ensure that the system temperature is below 25°C to prevent
  • the blowing agent is directly vaporized; preferably, the stirring speed after adding the blowing agent is 120-300r/min (such as 130, 150, 170, 200, 220, 150, 270, 290r/min); preferably, the heating
  • the temperature of foaming and curing is 60-100°C (65, 70, 75°C, 80°C, 85°C, 90°C, 95°C), and the time is 0.5-1h (because the boiling point of the blowing agent is 36-50°C, If the temperature of heating foaming and curing is too low, the foaming agent cannot vaporize and foam.
  • the heating, foaming and curing is carried out in a container whose volume is five times greater than the volume of the mixture; preferably, the drying temperature is 100-200°C, and drying to the moisture content of the system Not more than 5%.
  • the temperature of the calcination is 500-1000°C (such as 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 800, 850, 900, 960°C), the time is 1-3h (such as 1.5, 2.0, 2.5h), too much calcination temperature will cause the material to melt partially, affecting the micro Structure, the calcination temperature is too low to completely remove the organic matter and cause impurity residue; too short calcination time will cause incomplete calcination, too long time is meaningless (a waste of time and energy).
  • the present invention has the following positive effects:
  • the present invention is simple and feasible.
  • foaming, solidifying and uniform pore formation are realized by adding foaming aids, foam stabilizing aids, etc., and the formed material has a mesoporous structure of 3-10 nm and The regular three-dimensional network structure with 20-100 ⁇ m pores connected by foaming is conducive to orderly climbing of cells.
  • the regenerative medicine material of the present invention has a huge specific surface area, the material has strong biological activity, and can form carbonate hydroxyapatite within 4 hours.
  • the pH of the regenerative medicine material of the present invention is stable and controllable, and the pH of the material can be controlled between 7.4 and 10.0, which has high biological safety and has the effect of promoting cell proliferation.
  • the regenerative medicine material of the present invention has controllable degradation performance, can realize material degradation and cell proliferation synchronization, and the material degradation rate can reach about 30% in 5 days, can induce the rapid regeneration of damaged tissues' own cells, and realize the function of tissue repair in situ .
  • Figure 1 is the surface topography of the sample of Example 2.
  • Figure 2 is a comparison diagram of samples of Examples 1-4 before and after mineralization in the SBF simulated body fluid.
  • Fig. 3 is a morphology diagram of hydroxyapatite carbonate formed after the sample of Example 2 is mineralized.
  • Fig. 4 is an animal experimental model and process record diagram of sample efficacy verification in Example 2 of the present invention.
  • Fig. 5 is an analysis diagram of a pathological section of an animal experiment to verify the efficacy of a sample in Example 2 of the present invention.
  • a degradable regenerative medical material with a three-dimensional network structure that promotes tissue regeneration in situ includes:
  • the dried foam is placed in a muffle furnace and calcined at 800° C. for 1 hour to completely remove organic matter.
  • the resulting material is the final product.
  • the silicate is ethyl orthosilicate
  • the phosphate esters are glycerophosphate
  • the soluble metal salt is a mixture of calcium chloride, zinc lactate, and strontium chloride in a molar ratio of 100:5:2.
  • Trace elements such as strontium and zinc can promote wound repair and osteoblast growth. Strontium, zinc, etc. are added Trace elements can improve material performance;
  • the catalyst is hydrochloric acid with a mass fraction of 36%
  • the alcohol solvent is a mixture of ethylene glycol and glycerol at a mass ratio of 1:1; the compatibility of each material in the system can be increased according to the difference in the structure of each (ethylene glycol and glycerin);
  • the thickener is water-soluble polyvinyl alcohol PVA1788;
  • the foam stabilizer is H-203 polysiloxane type surfactant (Zhongshan Shandong Jun Chemical);
  • the foam fixing agent is a mixture of corn gluten meal and starch in a mass ratio of 1:1;
  • the blowing agent is a mixture of n-pentane and hexane in a mass ratio of 1:1.
  • the material synthesized in this embodiment is a composite structure formed by chemical bonding of each element composed of Si, P, O, and metal elements, expressed by the molar content of SiO 2 , P 2 O 5 , and metal oxide.
  • the material composition is 75.4% SiO 2 , 3.4% P 2 O 5 , 21.2% calcium, zinc, and strontium metal oxides; the final material structure has 3-20nm mesopores and 40-100 ⁇ m micron-sized macropores.
  • a degradable regenerative medical material with a three-dimensional network structure that promotes tissue regeneration in situ, in terms of mole fraction includes:
  • the mixed sol add 150 parts of water to the reactor, add 0.4 parts of catalyst and stir evenly, then add 60 parts of silicate and 15 parts of phosphate for pre-hydrolysis reaction, hydrolyze until the mixture becomes transparent and clear Add 30 parts of soluble metal salt and stir until completely dissolved to obtain a mixed sol;
  • the dried foam is placed in a muffle furnace and calcined at 700° C. for 1.5 hours to completely remove organic matter.
  • the resulting material is the final product.
  • the silicate is ethyl orthosilicate
  • the phosphate esters are glycerophosphate
  • the soluble metal salt is a mixture of calcium acetate, zinc lactate, and strontium nitrate at a molar ratio of 100:5:2;
  • the catalyst is nitric acid with a mass fraction of 50%;
  • the alcohol solvent is a mixture of ethylene glycol and glycerol in a mass ratio of 1:1;
  • the thickener is water-soluble polyvinyl alcohol PVA1788;
  • the foam stabilizer is a mixture of PEG-75 stearate and H-203 polysiloxane type surfactant at a mass ratio of 1:1;
  • the foam fixing agent is a mixture of whey protein powder and methyl cellulose at a mass ratio of 1:1;
  • the blowing agent is a 1:1 mixture of n-pentane and hexane by mass.
  • the material synthesized in this embodiment is a composite structure formed by the chemical bonding of each element of Si, P, O, and metal elements. It is expressed by the molar content of SiO 2 , P 2 O 5 , and metal oxide.
  • the compositions are respectively 61.5% SiO 2 , 7.7% P 2 O 5 , 30.8% calcium, zinc, and strontium metal oxides; the final material structure has 3-7nm mesopores and 30-100 ⁇ m micron-sized macropores.
  • a degradable regenerative medical material with a three-dimensional network structure that promotes tissue regeneration in situ, in terms of mole fraction includes:
  • the dried foam is placed in a muffle furnace and calcined at 700° C. for 1.5 hours to completely remove organic matter.
  • the resulting material is the final product.
  • the silicate is ethyl orthosilicate
  • the phosphate esters are glycerophosphate
  • the soluble metal salt is a mixture of calcium nitrate, zinc nitrate, and strontium acetate at a molar ratio of 100:5:2;
  • the catalyst is nitric acid with a mass fraction of 50%;
  • the alcohol solvent is a mixture of ethylene glycol and glycerol in a mass ratio of 1:1;
  • the thickener is water-soluble polyvinyl alcohol PVA1788;
  • the foam stabilizer is a mixture of PEG-75 stearate and H-203 polysiloxane type surfactant at a mass ratio of 1:1;
  • the foam fixative is a mixture of whey protein powder and starch in a mass ratio of 1:1;
  • the blowing agent is a mixture of n-pentane and hexane in a mass ratio of 1:1.
  • the synthesized material is a composite structure formed by chemical bonding of each element of Si, P, O, and metal elements, expressed by the molar content of SiO 2 , P 2 O 5 , and metal oxide.
  • the material composition is 61.5% SiO 2 , 7.7% P 2 O 5 , 30.8% calcium, zinc, and strontium metal oxides; the final material structure has 3-7nm mesopores and 20-80 ⁇ m micron-sized macropores.
  • a degradable regenerative medical material with a three-dimensional network structure that promotes tissue regeneration in situ, in terms of mole fraction includes:
  • the dried foam is placed in a muffle furnace and calcined at 600° C. for 2 hours to completely remove organic matter.
  • the resulting material is the final product.
  • the silicate is ethyl orthosilicate
  • the phosphate is dimethyl phosphate
  • the soluble metal salt is a mixture of calcium nitrate, zinc acetate, and strontium nitrate with a molar mass ratio of 100:5:1;
  • the catalyst is an aqueous solution of citric acid with a mass fraction of 50%;
  • the alcohol solvent is a mixture of ethylene glycol and glycerol in a mass ratio of 1:1;
  • the thickener is water-soluble polyvinyl alcohol PVA1788;
  • the foam stabilizer is a mixture of stearic acid triglyceride and sodium lauryl sulfonate in a mass ratio of 1:1;
  • the foam fixing agent is a mixture of corn gluten meal and starch in a mass ratio of 1:1;
  • the blowing agent is a mixture of n-pentane and hexane in a mass ratio of 1:1.
  • the material synthesized in this embodiment is a composite structure formed by the chemical bonding of each element of Si, P, O, and metal elements. It is expressed by the molar content of SiO 2 , P 2 O 5 , and metal oxide.
  • the composition is 46.4% SiO 2 , 9.4% P 2 O 5 , 44.2% calcium, zinc, and strontium metal oxides; the final material structure has 3-7nm mesopores and 30-100 ⁇ m micron-sized macropores.
  • Regenerative medicine material testing In order to verify whether the present invention achieves the expected effect, the three-dimensional network structure, mesoporous and macroporous structure, specific surface area, biological activity, degradation performance, etc. of the samples of the present invention are tested and analyzed, as follows:
  • Test Example 1 Three-dimensional network structure test of regenerative medicine materials
  • the SEM test was performed on the samples obtained in Examples 1-4, and the results showed that the samples obtained in each of the Examples formed a regular three-dimensional network structure, with uniform pore diameters, and pores communicating with each other.
  • the SEM test result of the sample obtained in Example 2 is as shown in FIG. 1.
  • the sample obtained in Example 2 forms a regular three-dimensional network structure with uniform pore diameters and the pores are connected.
  • the gas adsorption method was used to test the samples obtained in each example.
  • the results of the gas adsorption method showed that while the material formed macropores, the macroporous material skeleton had a mesoporous structure.
  • the mesoporous pore diameter and porosity of each example are shown in Table 1. :
  • Scheme 1 respectively take the solid samples obtained in Examples 1-4 and add water to prepare a mixture with a mass fraction of 5%, soak the solid samples (stand) for 2 hours, and then filter to determine the pH value of the filtrate;
  • Scheme 2 Take three sets of solid samples, prepare the mixed solution according to the method in Scheme 1, soak them for different times (1d, 3d, 7d), and then filter to determine the pH value of the filtrate;
  • Scheme 3 prepare the solution according to the method in Scheme 1, and filter after soaking for 24 hours. After washing and drying the filter residue, measure the PH value again according to the method of Scheme 1.
  • the regenerative medicine material of the present invention can adjust the pH value according to demand; the pH value of a single sample is stable during the action; the pH value of the material does not change after soaking and washing, indicating that the material has a continuous release of ions Ability.
  • Specific implementation method use glass conical flask or polyethylene plastic flask as reaction vessel. Place the material in the reaction vessel, measure 200.0mL SBF simulated body fluid per 0.3g powder, and place the vessel in a 37°C water bath shaker after mixing, and shake the reaction vessel at a shaking speed of 175r/min. Chemical experiments. After the sample is soaked for a certain period of time (maximum 28d), the soaked mineralized sample is separated, rinsed with deionized water and acetone solution, and dried at room temperature; the sample is subjected to X-ray diffraction (XRD) test, Scanning electron microscope test.
  • XRD X-ray diffraction
  • the immersion mineralization time is 4h
  • the test results of the sample after mineralization The X-ray diffraction pattern is shown in attached figure 2 of the specification, in which obvious characteristic peaks of carbonate hydroxyapatite are formed; the scanning electron microscope test (SEM) is shown in figure 3
  • SEM scanning electron microscope test
  • TRIS buffer solution Use tris(hydroxymethyl)aminomethane and hydrochloric acid solution to prepare a TRIS buffer solution with a pH of 7.4 ⁇ 0.1 (Preparation of TRIS buffer solution: Put 800ML of deionized water in a 2000ML beaker and place it on a magnetic stirrer Stir, then add 35ML of 1mol/L hydrochloric acid solution, add tris(hydroxymethyl)aminomethane under stirring, adjust the PH value to 7.25, and finally transfer the solution to a 1000ML volumetric flask to make the volume constant, configure to obtain the TRIS buffer solution) ; Then immerse the material in it and shake for 120 ⁇ 1h, then take out the insoluble matter, rinse, dry, and weigh to calculate the weight change before and after the test to obtain the degradation rate.
  • Test Example 7 Animal experiment to verify the efficacy of regenerative medicine materials
  • Subject female Guizhou miniature pigs, age: 6-10 months, weight: 20-25Kg;
  • Defect 1 Use the regenerative medicine material described in Example 2 of the present invention (denoted as group a)
  • Defect 2 Use 45S5 bioactive glass as a control group (denoted as group b)
  • the regenerative medicine material synthesized in each embodiment of the present invention uses a material with a mesoporous structure as the skeleton to form a porous material with uniform pore size and interconnected pores with large specific surface area, high biological activity, and degradation rate. It is controllable, can increase the healing rate during the tissue repair process, and promote the orderly growth of tissues, and achieve tissue regeneration in situ. It is a new type of regenerative medicine material.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Transplantation (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)

Abstract

一种促进组织原位再生的可降解再生医学材料及其制备方法。可降解再生医学材料具有Si、P、O和包含钙的金属元素通过化学键合形成的具有纳米级介孔结构的材料为骨架的规则三维网状结构，规则三维网状结构中均匀分布有孔与孔相通的微米级大孔。可降解再生医学材料的制备方法包括混合溶胶、发泡固化和煅烧步骤。可降解再生医学材料具有巨大的比表面积、强大的生物活性和高的生物安全性，能够促进细胞增殖，诱导损伤组织自身细胞迅速再生，实现组织原位修复。

Description

一种促进组织原位再生的可降解再生医学材料及其制备方法 技术领域
本发明涉及生物医用材料技术领域，特别涉及一种可促进组织原位再生的可降解再生医学材料及其制备方法。
背景技术
再生医学是综合应用生命科学、材料科学和临床医学等学科的原理和方法，研究和开发用于替代、修复、重建或再生人体各种组织和器官的理论技术的前沿交叉学科，已经广泛用于治疗先天性遗传缺陷疾病和各种组织器官损伤，是人类医学发展的一次飞跃；其已成为医学生物学领域的一个新的前沿领域，对医学生物学发展具有极其重要的理论、应用的意义和价值；再生医学的发展对生物医用材料提出了更高的要求。
生物材料，指的是本着医疗目的，通过诊断、修复、治疗或者更换人体组织器官帮助病人实现康复治愈或增强病人体质功能的材料。传统的生物材料主要是生物惰性材料，与人体有良好的生物相容性，异物反应低，使得体内植入生物材料的病患在五到二十五年内生活质量有了明显的提高。
随着再生医学的发展，老年化速度的不断加快，传统的生物惰性材料已经不能满足于患者多重的临床治疗需要，医学的研究重心也从原来的生物相容性研究转变到生物活性、生物修复和再生研究中，要求生物材料可以被降解，以至于完全被人体的新生组织替代，使得生物材料与人体本身的组织不再有明显的区别。再生医学材料要具有与人体组织或器官相似的成分和结构,有良好的生物相容性和诱导性，植入人体内后能引发机体的自我修复机制。
目前，在临床应用的再生医学材料主要有两大类，一类是组织工程材料；将组织工程再生医学材料植入到人体组织器官病损部位中，使得生物材料被人体吸收，同时不断激发身体的某些细胞再生，形成新的组织，取代病损部位的细胞组 织，帮助人体实现修复和重建。组织工程材料产品已经应用于部分临床治疗，例如皮肤科、关节软骨、血管系统的修复等等。另一种是原位组织再生材料。所谓原位组织再生，即在人体内引入一些粉末、溶液或者微粒形式的生物材料，以离子形式释放出一些生长因子，诱导损伤组织自身细胞迅速再生，实现原组织的原位修复功能。例如将再生医学生物材料注入到受损伤的机体中，将会让原骨结构重新建立新骨组织。
无机类再生医学生物材料，由于类似于人体硬组织中无机矿物的组成和结构特性，使其具有良好的生物相容性、生物应答特性、基因激活特性和促进新生组织形成的功能，受到生物材料学界和临床界的高度重视，在人体组织修复方面有着重要的应用。但是，无机再生医学生物材料的组成稳定性，使得材料在体内生物活性低、降解缓慢，难以满足再生医学的要求；针对这一问题，科研工作者做了大量的研究，包括在材料成型过程中增加造孔剂，及利用无机再生医学生物材料与医用高分子结合组成多孔支架材料等，以增加材料与体液的接触面而提高活性、促进降解等；上述措施虽然在一定程度上提升了材料的性能，但通过添加造孔剂的方法造孔过程中孔径及成孔均匀性不可控，且对性能的提升有限；与高分子材料复合的方法未能从基本上改变材料基本单元的结构，而且与高分子材料复合部分阻断了材料与体液的接触。
再生医学材料产业由于行业壁垒高，介入层次高，容易形成护城河效应，长期以来被发达国家垄断。目前，我国医疗市场再生医学材料需求巨大，而临床治疗所采用的高端再生医学材料大都需要进口，消耗了大量外汇储备。据统计，我国每年需要再生医学组织修复和治疗的患者约1亿人次，随着老龄化社会的到来，临床治疗使用的再生医学医疗器械需求更为突出。仅2016年，我国再生医学使用的医疗器械年销售额约为1200亿美元，年增长率大于25％，其中绝大部分需要直接进口或者进口再生医学材料后制备而成，发达国家的再生医学材料行业已逐渐形成垄断局面；一方面是我国巨大的再生医学医疗器械需求的持续增长；另外一方面，由于制造医疗器械的核心材料被国外独家垄断造成的大量进口产品价格居高不下，大量中低收入患病群体无法使用上优质的再生医学医疗器械，从而形成巨大的矛盾。
鉴于现有无机类再生医学生物材料的问题，发明人基于从事生物医用材料的多年设计制造经验，提出一种具有三维网络结构、促进组织原位再生的可降解再 生医学材料及其制备方法。
发明内容
针对现有技术的局限性，本发明的主要目的在于提供一种促进组织原位再生的可降解再生医学材料及其制备方法，该方法通过在无机再生医学生物材料凝胶化成型过程中实现发泡并同步固化，形成微观泡沫体，然后将泡沫体高温煅烧除去溶剂，形成具有微观三维网络结构的无机再生医学生物材料，其发泡倍率高、孔径均匀、比表面积大，能够实现活性基团与体液充分接触，从而实现高的生物活性、提升降解速率。
为了实现上述目的，本发明采用了以下技术方案：
在由硅酸酯、磷酸酯及可溶性金属盐组成的富含金属、磷、硅元素的混合溶胶中加入增稠剂、泡沫稳定剂、发泡剂、泡沫固定剂等助剂混合均匀后，经过加热、起泡、固泡后进行烘干、煅烧形成具有生物活性的微观多孔材料。
一种促进组织原位再生的可降解再生医学材料，所述可降解再生医学材料是以Si、P、O和包含钙的金属元素通过化学键合的作用形成的，是以具有纳米级介孔结构的材料作为骨架形成的规则三维网状结构，所述规则三维网状结构中均匀分布有孔与孔相通的微米级大孔。
在上述促进组织原位再生的可降解再生医学材料中，作为一种优选实施方式，按摩尔份数计，制备所述可降解再生医学材料的原料包括：
Figure PCTCN2019106736-appb-000001
Figure PCTCN2019106736-appb-000002
在本发明中，硅酸酯类作为硅源，用量要适当，过多则形成材料体系降解缓慢，过少不能满足作为载体成分的需求。
磷酸酯类作为材料体系磷源提供者，控制形成材料的降解速率，过多或过少不利于降解调控；
可溶性金属盐加入过多则材料pH值偏高，过少则影响金属和磷之间比例进而影响羟基磷灰石的形成速率。
在上述可降解再生医学材料中，作为一种优选实施方式，所述硅酸酯类为正硅酸甲酯、正硅酸乙酯、正硅酸丙酯中的至少一种；
在上述可降解再生医学材料中，作为一种优选实施方式，所述磷酸酯类为磷酸一酯、磷酸二酯、磷酸三酯、甘油磷酸酯和肌醇六磷酸酯中的至少一种；
在上述可降解再生医学材料中，作为一种优选实施方式，所述可溶性金属盐为钙、锶、铜和锌的无机盐和醇盐中的至少一种；在上述可降解再生医学材料中，作为一种优选实施方式，所述水为去离子水；
在上述可降解再生医学材料中，作为一种优选实施方式，所述催化剂为酸或碱；其中，所述酸为无机酸或有机酸，所述无机酸优选为硝酸、盐酸或硫酸，所述有机酸优选为乙酸、乙二酸、马来酸和柠檬酸中的至少一种；所述碱为无机碱或有机胺，其中，所述无机碱优选为氢氧化钠、氨水和碳酸氢钠中的至少一种，优选地，所述有机胺优选为乙二胺和正丙胺中的至少一种。
在上述可降解再生医学材料中，作为一种优选实施方式，所述醇溶剂为甲醇、乙醇、乙二醇、二甘醇和丙三醇中的至少一种；优选地，所述醇溶剂为甲醇、乙醇、乙二醇和二甘醇中的至少一种与丙三醇的混合物。
在上述可降解再生医学材料中，作为一种优选实施方式，所述增稠剂为水溶性聚乙烯醇、羟甲基纤维素和聚乙二醇6000中的至少一种；
在上述可降解再生医学材料中，作为一种优选实施方式，所述泡沫稳定剂为硅碳型表面活性剂、十二烷基磺酸钠、脂肪酸聚氧乙烯醚、硬脂酸甘油酯、PEG- 75硬脂酸酯、鲸蜡醇醚-20、鲸蜡硬脂醇聚醚-6、鲸蜡硬酯醇聚醚-25、PEG-100硬脂酸酯、鲸蜡硬脂醇葡糖苷和C20-22醇磷酸酯钠中的至少一种；
在上述可降解再生医学材料中，作为一种优选实施方式，所述泡沫固定剂为玉米蛋白粉、乳清蛋白粉、淀粉和甲基纤维素中的至少一种；
在上述可降解再生医学材料中，作为一种优选实施方式，所述发泡剂为物理发泡剂，优选地，所述发泡剂为戊烷、己烷、庚烷、石油醚、氯氟甲烷、二氯二氟甲烷和二氯四氟乙烷的一种或多种混合物。
在上述可降解再生医学材料中，作为一种优选实施方式，所述可降解再生医学材料具有3-10nm的介孔结构和20-100μm(形成三维网络结构孔的孔径)孔孔相连的规则三维网络结构。
在上述可降解再生医学材料中，作为一种优选实施方式，所述可降解再生医学材料的比表面积为740-1500m 2/g。
在上述可降解再生医学材料中，作为一种优选实施方式，所述可降解再生医学材料具有Si、P、O、金属元素通过化学键形成的三维网状结构，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，所述可降解再生医学材料中：SiO 2含量为46.4-75.4％、P 2O 5含量为3.4-9.4％、金属氧化物含量为21.2-44.2％。
一种上述促进组织原位再生的可降解再生医学材料的制备方法，包括：
混合溶胶制备步骤：在水中加入催化剂搅拌均匀，之后加入硅酸酯类、磷酸酯类进行预水解反应，水解至混合液变透明后加入可溶性金属盐，搅拌至完全溶解，得到混合溶胶；
发泡固化步骤：将增稠剂用醇溶剂分散后加入所述混合溶胶中，搅拌至完全溶胀溶解后，再加入泡沫稳定剂及泡沫固定剂搅拌均匀，之后陈化，然后加入发泡剂搅拌均匀，得到混合料，然后将所述混合料进行加热发泡固化,之后对固化成型的泡沫进行干燥，得到泡沫体；其中，增稠剂既可起到增稠作用，又可在发泡过程中有助于成膜。
煅烧步骤：将所述泡沫体煅烧至完全除去有机物，即得到具有三维网络结构、促进组织原位再生的可降解再生医学材料。
在所述混合溶胶制备步骤中，所述预水解反应的机理为：配方中的硅酸酯类、磷酸酯类在溶剂体系中，在催化剂作用下进行酯类水解生成硅醇及羟基磷单体， 然后水解生成的单体相互之间缩水聚合成硅、氧、磷以共价键结合的网络结构，金属离子穿插于网络中以离子键结合，从而实现各元素分子级混合，形成材料组成的主体结构。
在上述可降解再生医学材料的制备方法中，作为一种优选实施方式，在所述发泡固化步骤中，所述陈化为常温陈化，优选地，所述陈化是指陈化至粘度达到6000-20000cp(如7000、8000、9000、10000、11000、12000、13000、14000、15000、16000、17000、18000、19000cp)，粘度过低在发泡过程中容易破泡，造成低沸点物理发泡剂逃逸；粘度过高则发泡困难造成发泡倍率过小；之后降温至25℃以下(因为发泡剂为低沸点物质，所以加入发泡剂时保证体系温度在25℃以下，可防止发泡剂直接汽化)；优选地，加入发泡剂后搅拌速度为120-300r/min(如130、150、170、200、220、150、270、290r/min)；优选地，所述加热发泡固化的温度为60-100℃(65、70、75℃、80℃、85℃、90℃、95℃)，时间为0.5-1h(由于所述发泡剂沸点为36-50℃，加热发泡固化的温度过低发泡剂不能汽化发泡，温度过高则发泡剂急速膨胀破坏泡孔结构；固化时间过短会发泡不完全，固化时间过长则发泡剂聚集造成泡孔过大)；优选地，所述加热发泡固化为在体积大于所述混合料体积五倍的容器中进行；优选地，所述干燥的温度为100-200℃，且干燥至体系水分不大于5％。
在上述可降解再生医学材料的制备方法中，作为一种优选实施方式，在所述煅烧步骤中，所述煅烧的温度为500-1000℃(如520、540、560、580、600、620、640、660、680、700、720、740、760、800、850、900、960℃)，时间为1-3h(如1.5、2.0、2.5h)，煅烧温度过大会导致材料部分熔融，影响微观结构，煅烧温度过低不能完全除去有机物造成杂质残留；煅烧时间过短会造成煅烧不完全，时间过长没有意义(浪费时间及能源)。
本发明与现有技术相比具有如下积极效果：
一、本发明简单可行，在溶胶凝胶形成过程中通过加入发泡助剂、稳泡助剂等实现发泡、固泡及均匀造孔，且形成的材料具有3-10nm的介孔结构及由发泡形成的20-100μm孔孔相连的规则三维网络结构，有利于细胞有序攀爬。
二、本发明的再生医学材料具有巨大的比表面积，材料具有强大的生物活性，能够在4h以内形成碳酸羟基磷灰石。
三、本发明再生医学材料的pH稳定、可控，材料的pH可控制在7.4-10.0之间，生物安全性高，具有促进细胞增殖的效果。
四、本发明的再生医学材料具有可控降解的性能，能够实现材料降解与细胞增殖同步，5天材料降解率可达到30％左右，能够诱导损伤组织自身细胞迅速再生，实现组织原位修复功能。
附图说明
图1为实施例2样品的表面形貌图。
图2为实施例1-4样品在SBF模拟体液中矿化前后的对比图。
图3为实施例2样品矿化后形成碳酸羟基磷灰石的形貌图。
图4为本发明实施例2样品功效验证动物实验模型及过程记录图。
图5为本发明实施例2样品功效验证动物实验病理切片分析图。
具体实施方式
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施方式，对本发明作进一步详细的说明。以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
实施例1
一种具有三维网络结构、促进组织原位再生的可降解再生医学材料，按照摩尔份数，原料包括：
Figure PCTCN2019106736-appb-000003
Figure PCTCN2019106736-appb-000004
本实施例具有三维网络结构、促进组织原位再生的可降解再生医学材料的制备方法如下：
首先制备混合溶胶：在反应器中加入110份水，将0.2份催化剂加入后搅拌均匀，之后加入78份硅酸酯类及7份磷酸酯类进行预水解反应，水解至混合液变透明清澈后加入22份可溶性金属盐，搅拌至完全溶解，得到混合溶胶；
然后，将0.5份增稠剂用2份的醇溶剂分散后加入混合溶胶中，搅拌至完全溶胀溶解后，再加入1份泡沫稳定剂及5份泡沫固定剂，搅拌均匀后常温陈化；
持续陈化至体系粘度达到10000cp后降温至25℃以下，然后加入4份发泡剂高速搅拌均匀，然后将所得混合料倒入体积大于混合料体积五倍的容器中，然后置于70℃烘箱中加热发泡固化0.5h；
然后，将固化成型的泡沫体移至120℃的烘箱中继续干燥至体系水分挥发至不大于5％；
将干燥完成的泡沫体置于马弗炉中，在800℃煅烧1h至完全除去有机物，所得的材料即为最终产物。
所述硅酸酯类为正硅酸乙酯；
所述磷酸酯类为甘油磷酸酯；
所述可溶性金属盐为氯化钙、乳酸锌、氯化锶按100:5:2的摩尔比混合物，锶、锌等微量元素对创伤修复及成骨细胞增值具有促进作用，加入锶、锌等微量元素可提升材料性能；
所述催化剂为质量分数为36％的盐酸；
所述醇溶剂为乙二醇与甘油按质量比1：1的混合物；可根据各自(乙二醇与甘油)结构的不同增加体系中各材料的相容性；
所述增稠剂为水溶性聚乙烯醇PVA1788；
所述泡沫稳定剂为H‐203聚硅氧烷型表面活性剂(中山东骏化工)；
所述泡沫固定剂为玉米蛋白粉与淀粉按质量比1:1的混合物；
所述发泡剂为正戊烷与己烷按质量比1:1的混合物。
本实施例所合成的材料为成分组成为Si、P、O、金属元素的各元素通过化学键合的作用形成的复合结构，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，材料组成分别为75.4％SiO 2、3.4％P 2O 5、21.2％钙、锌、锶的金属氧化物；最终材料结构中有3-20nm介孔及40-100μm微米级大孔。
实施例2
一种具有三维网络结构、促进组织原位再生的可降解再生医学材料，按照摩尔份数，包括：
Figure PCTCN2019106736-appb-000005
本实施例具有三维网络结构、促进组织原位再生的可降解再生医学材料的制备方法如下：
首先制备混合溶胶：在反应器中加入150份水，将0.4份催化剂加入后搅拌均匀，之后加入60份硅酸酯类及15份磷酸酯类进行预水解反应，水解至混合液变透明清澈后加入30份可溶性金属盐，搅拌至完全溶解，得到混合溶胶；
然后，将1.5份增稠剂用3.5份的醇分散后加入混合溶胶中，搅拌至完全溶胀溶解后，再加入2份泡沫稳定剂及7.5份泡沫固定剂，搅拌均匀后常温陈化；
持续陈化至体系粘度达到12000cp后降温至25℃以下，然后加入5份发泡剂高速搅拌均匀，然后将所得混合料倒入体积大于料体体积五倍的容器中，然后置于60℃烘箱中加热发泡固化1h；
然后，将固化成型的泡沫体移至120℃的烘箱中继续干燥至体系水分挥发至不大于5％；
将干燥完成的泡沫体置于马弗炉中，在700℃煅烧1.5h至完全除去有机物，所得的材料即为最终产物。
所述硅酸酯类为正硅酸乙酯；
所述磷酸酯类为甘油磷酸酯；
所述可溶性金属盐为乙酸钙、乳酸锌、硝酸锶按摩尔比100:5:2混合物；
所述催化剂为质量分数为50％的硝酸；
所述醇溶剂为乙二醇与甘油按质量比1：1的混合物；
所述增稠剂为水溶性聚乙烯醇PVA1788；
所述泡沫稳定剂为PEG-75硬脂酸酯与H-203聚硅氧烷型表面活性剂按质量比1:1的混合物；
所述泡沫固定剂为乳清蛋白粉与甲基纤维素按质量比1:1的混合物；
所述发泡剂为正戊烷与己烷按质量1:1的混合物。
本实施例所合成的材料为成分组成为Si、P、O、金属元素各元素通过化学键和的作用形成的复合结构，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，材料组成分别为61.5％SiO 2、7.7％P 2O 5、30.8％钙、锌、锶的金属氧化物；最终材料结构中有3-7nm介孔及30-100μm微米级大孔。
实施例3
一种具有三维网络结构、促进组织原位再生的可降解再生医学材料，按照摩尔份数，包括：
Figure PCTCN2019106736-appb-000006
本实施例具有三维网络结构、促进组织原位再生的可降解再生医学材料的制备方法如下：
首先制备混合溶胶：在反应器中加入150份水，将0.4份催化剂加入后搅拌均匀，之后加入60份硅酸酯及15份磷酸酯类进行预水解反应，水解至混合液变透明清澈后加入30份可溶性金属盐，搅拌至完全溶解，得到混合溶胶；
然后，将2.5份增稠剂用5份的醇分散后加入混合溶胶中，搅拌至完全溶胀溶解后，再加入3份泡沫稳定剂及10份泡沫固定剂，搅拌均匀后常温陈化；
持续陈化至体系粘度达到14000cp后降温至25℃以下，然后加入6份发泡剂高速搅拌均匀，然后将所得混合料倒入体积大于料体体积五倍的容器中，然后置于70℃烘箱中加热发泡固化45min；
然后，将固化成型的泡沫体移至120℃的烘箱中继续干燥至体系水分挥发至不大于5％；
将干燥完成的泡沫体置于马弗炉中，在700℃煅烧1.5h至完全除去有机物，所得的材料即为最终产物。
所述硅酸酯类为正硅酸乙酯；
所述磷酸酯类为甘油磷酸酯；
所述可溶性金属盐为硝酸钙、硝酸锌、乙酸锶按摩尔比100:5:2的混合物；
所述催化剂为质量分数为50％的硝酸；
所述醇溶剂为乙二醇与甘油按质量比1：1的混合物；
所述增稠剂为水溶性聚乙烯醇PVA1788；
所述泡沫稳定剂为PEG-75硬脂酸酯与H-203聚硅氧烷型表面活性剂按质量比1:1的混合物；
所述泡沫固定剂为乳清蛋白粉与淀粉按质量比1:1的混合物；
所述发泡剂为正戊烷与己烷按质量比1:1的混合物。
本实施例按所合成的材料为成分组成为Si、P、O、金属元素各元素通过化学键合的作用形成的复合结构，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，材料组成分别为61.5％SiO 2、7.7％P 2O 5、30.8％钙、锌、锶的金属氧化物；最终材料结构中有3-7nm介孔及20-80μm微米级大孔。
实施例4
一种具有三维网络结构、促进组织原位再生的可降解再生医学材料，按照摩尔份数，包括：
Figure PCTCN2019106736-appb-000007
本实施例具有三维网络结构、促进组织原位再生的可降解再生医学材料的制备方法如下：
首先制备混合溶胶：在反应器中加入200份水，将0.6份催化剂加入后搅拌均匀，之后加入42份硅酸酯类及17份磷酸酯类进行预水解反应，水解至混合液变透明清澈后加入40份可溶性金属盐，搅拌至完全溶解得到混合溶胶；
然后，将2.5份增稠剂用5份的醇分散后加入混合溶胶中，搅拌至完全溶胀溶解后，再加入3份泡沫稳定剂及10份泡沫固定剂搅拌均匀后常温陈化；
持续陈化至体系粘度达到10000cp后降温至25℃以下，然后加入6份发泡剂高速搅拌均匀，然后将所得混合料倒入体积大于料体体积五倍的容器中，然后置于65℃烘箱中加热发泡固化45min；
然后，将固化成型的泡沫体移至120℃的烘箱中继续干燥至体系水分挥发至不大于5％；
将干燥完成的泡沫体置于马弗炉中，在600℃煅烧2h至完全除去有机物，所得的材料即为最终产物。
所述硅酸酯类为正硅酸乙酯；
所述磷酸酯类为磷酸二甲酯；
所述可溶性金属盐为硝酸钙、乙酸锌、硝酸锶按摩尔质量比100:5:1混合物；
所述催化剂为质量分数为50％的柠檬酸水溶液；
所述醇溶剂为乙二醇与甘油按质量比1：1的混合物；
所述增稠剂为水溶性聚乙烯醇PVA1788；
所述泡沫稳定剂为硬脂酸甘油三酯与十二烷基磺酸钠按质量比1:1的混合物；
所述泡沫固定剂为玉米蛋白粉与淀粉按质量比1:1的混合物；
所述发泡剂为正戊烷与己烷按质量比1:1的混合物。
本实施例所合成的材料为成分组成为Si、P、O、金属元素各元素通过化学键和的作用形成的复合结构，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，材料组成分别为46.4％SiO 2、9.4％P 2O 5、44.2％钙、锌、锶的金属氧化物；最终材料结构中有3-7nm介孔及30-100μm微米级大孔。
性能研究：
再生医学材料检测：为验证本发明是否达到预期效果，对本发明各实施例样品的三维网络结构、介孔及大孔结构、比表面积、生物活性、降解性能等进行检测分析，具体如下：
测试例1再生医学材料的三维网络结构测试
对实施例1-4所得样品进行SEM测试，结果表明，各实施例所得样品均形成了规则的三维网状结构，孔径均匀，孔与孔相通。其中，实施例2所得样品的SEM测试结果如附图1，从图1可见，实施例2所得样品形成了规则的三维网状结构，孔径均匀，且孔与孔相通。
测试例2再生医学材料的介孔结构及孔隙度分析
采用气体吸附法对各实施例所得样品进行测试，气体吸附法检测结果显示材料在形成大孔的同时，搭建大孔的材料骨架具有介孔结构，各实施例介孔孔径及孔隙度如下表1：
表1.样品孔径、孔隙度检测结果
Figure PCTCN2019106736-appb-000008
测试例3再生医学材料的比表面积检测
采用氮气吸附法对实施例1-4所得样品进行比表面积测试，结果如下表2；
表2.样品比表面积检测结果
样品编号 检测结果(m 2/g)
实施例1 1282
实施例2 932
实施例3 1104
实施例4 742
测试例4再生医学材料pH值及其稳定性测试：
检测方法：方案一，分别取实施例1‐4所得的固体样品加水配制成质量分数为5％的混合液，固体样品浸泡(静置)2h，之后分别过滤测定滤液的pH值；方案二，取三组固体样品，按方案一中方法配制混合液，分别浸泡不同时间(1d、3d、7d)然后过滤，测定滤液的PH值；方案三，按方案一中方法配制溶液浸泡24h后过滤、洗涤、干燥滤渣后重新按方案一方法测定PH值。
检测结果如下表3：
表3.实施例1‐4所得样品pH值测定结果
Figure PCTCN2019106736-appb-000009
由表3结果可看出：本发明所述再生医学材料，可根据需求调整pH值；单一样品在作用过程中pH值稳定；材料经过浸泡、洗涤后pH值不变，说明材料具有持续释放离子的能力。
测试例5再生医学材料的生物活性测试
依据YY/T 0964‐2014《沉积羟基磷灰石的测试方法》进行体外矿化实验，验证再生医学材料的生物活性；
具体实施方法：以玻璃锥形瓶或聚乙烯塑料瓶为反应容器。将材料置于反应容器中，按每0.3g粉体、量取200.0mL SBF模拟体液，混合后将容器置于37℃的水浴摇床中，以175r/min的振荡速度振荡反应容器，进行矿化实验。样品浸泡若干时间后(最长不超过28d)，分离出浸泡矿化的样品，并分别用去离子水和丙酮溶液淋洗、于室温下晾干；将样品进行X射线衍射(XRD)测试、扫描电镜测试。
本实验中浸泡矿化时间为4h，矿化后样品检测结果：X射线衍射图见说明书附图2，其中形成了明显的碳酸羟基磷灰石特征峰；扫描电镜测试(SEM)见附图3，在实施例2材料大孔的内壁基表面，形成了大量的针状及团簇状碳酸羟基磷灰石搭成的三维网状结构；能快速矿化及在材料表面形成羟基磷灰石相，说明该材料生物活性高，达到了本发明的目的。
测试例6再生医学材料的降解性能测试
依据GB/T 16886.14《医疗器械生物学评价：第14部分》，利用植入物模拟溶液测试法测试再生医学材料的降解性能；
具体实施方法：利用三(羟甲基)氨基甲烷及盐酸溶液配制pH为7.4±0.1的TRIS缓冲溶液(TRIS缓冲溶液的配制：在2000ML的烧杯内盛800ML的去离子水，置于磁力搅拌上搅拌，然后加入35ML的1mol/L盐酸溶液，在搅拌情况下加入三(羟甲基)氨基甲烷，调节PH值为7.25，最后将溶液移至1000ML容量瓶中定容，配置得到TRIS缓冲溶液)；然后将材料浸泡其中振荡120±1h，然后将不溶物取出冲洗、烘干、称重计算试验前及试验后重量变化，得出降解率。
检测结果如下表4：
表4.再生医学材料的降解率
样品编号 实验时间 降解百分率(％)
实施例1 120h 19.7
实施例2 120h 21.6
实施例3 120h 25.2
实施例4 120h 30.1
由表4结果可看出本发明再生医学材料中磷含量越高材料的降解速率越快；组成相同时比表面积越大材料的降解速率越快。
测试例7再生医学材料功效验证动物实验
实验对象：雌性贵州小型猪，年龄：6‐10个月，体重：20‐25Kg；
实验周期：7+21天(其中7天为动物适应期，21天为试验期)
实验方法：于同一头贵州猪脊柱右侧做三个缺损(缺损尺寸：5*5cm，去皮，去脂肪，至肌肉层，深3‐6cm)，加修复材料后，每个缺损进行传统打包技术，遮盖创口，定期换药、更换纱布。
缺损1：使用本发明实施例2所述再生医学材料(记为a组)
缺损2：使用45S5生物活性玻璃作为对照组(记为b组)
缺损3：不使用产品作为空白对照组(记为c组)
实验模型及过程见说明书附图4；
实验结果病理切片分析见说明书附图5。
实验结果：由实验修复过程(附图4)可看出使用本发明所述再生医学材料的实验组在组织缺损修复过程中愈合速率明显高于对照组及空白对照组；由实验病理切片分析(图5)可看出，使用本发明所述再生医学材料的实验组实现了组织有序生长，促进毛细血管生长，促进成纤维细胞、胶原组织等有序增殖，新生组织结构完整，并伴有毛囊生成。
由上述测试结果可见，本发明各实施例合成的再生医学材料由具有介孔结构的材料作为骨架形成了孔径均匀，且孔与孔相通的多孔材料，具有比表面积大、生物活性高、降解速率可控，在组织修复过程中能够提高愈合速率，并且促进组织有序生长，实现组织原位再生，是一类新型再生医学材料。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (10)

  1. 一种促进组织原位再生的可降解再生医学材料，其特征在于，所述可降解再生医学材料是以Si、P、O和包含钙的金属元素通过化学键合的作用形成的，是以具有纳米级介孔结构的材料作为骨架形成的规则三维网状结构，所述规则三维网状结构中均匀分布有孔与孔相通的微米级大孔。
  2. 根据权利要求1所述的可降解再生医学材料，其特征在于，按摩尔份数计，制备所述可降解再生医学材料的原料包括：
    Figure PCTCN2019106736-appb-100001
  3. 根据权利要求1所述的可降解再生医学材料，其特征在于，所述硅酸酯类为正硅酸甲酯、正硅酸乙酯和正硅酸丙酯中的至少一种；优选地，所述磷酸酯类为磷酸一酯、磷酸二酯、磷酸三酯、甘油磷酸酯和肌醇六磷酸酯中的至少一种；优选地，所述可溶性金属盐为钙、锶、铜和锌的无机盐和醇盐中的至少一种；优选地，所述水为去离子水。
  4. 根据权利要求1所述的可降解再生医学材料，其特征在于，所述催化剂为酸或碱；其中，所述酸为无机酸或有机酸，所述无机酸优选为硝酸、盐酸或硫酸，所述有机酸优选为乙酸、乙二酸、马来酸和柠檬酸中的至少一种；所述碱为无机碱或有机胺，其中，所述无机碱优选为氢氧化钠、氨水和碳酸氢钠中的至少一种，所述有机胺优选为乙二胺和正丙胺中的至少一种。
  5. 根据权利要求1所述的可降解再生医学材料，其特征在于，所述醇溶剂为甲醇、乙醇、乙二醇、二甘醇和丙三醇中的至少一种；优选地，所述醇溶剂为甲醇、乙醇、乙二醇和二甘醇中的至少一种与丙三醇的混合物；优选地，所述增稠剂为水溶性聚乙烯醇、羟甲基纤维素和聚乙二醇6000中的至少一种。
  6. 根据权利要求1所述的可降解再生医学材料，其特征在于，所述泡沫稳定剂为硅碳型表面活性剂、十二烷基磺酸钠、脂肪酸聚氧乙烯醚、硬脂酸甘油酯、PEG-75硬脂酸酯、鲸蜡醇聚醚-20、鲸蜡硬脂醇聚醚-6、鲸蜡硬酯醇聚醚-25、PEG-100硬脂酸酯、鲸蜡硬脂醇葡糖苷和C20-22醇磷酸酯钠中的至少一种；优选地，所述泡沫固定剂为玉米蛋白粉、乳清蛋白粉、淀粉和甲基纤维素中的至少一种；优选地，所述发泡剂为物理发泡剂，更优选地，所述发泡剂为戊烷、己烷、庚烷、石油醚、氯氟甲烷、二氯二氟甲烷和二氯四氟乙烷的一种或多种。
  7. 根据权利要求1所述的可降解再生医学材料，其特征在于，所述介孔孔径为3-10nm，所述微米级大孔孔径为20-100μm；
    优选地，所述可降解再生医学材料的比表面积为740-1500m 2/g；优选地，用SiO 2、P 2O 5、金属氧化物的摩尔含量来表示，所述可降解再生医学材料中：SiO 2含量为46.4-75.4％、P 2O 5含量为3.4-9.4％、金属氧化物含量为21.2-44.2％。
  8. 一种权利要求1-7中任一项所述的促进组织原位再生的可降解再生医学材料的制备方法，其特征在于，包括：
    混合溶胶制备步骤：在水中加入催化剂搅拌均匀，之后加入硅酸酯类、磷酸酯类进行预水解反应，水解至混合液变透明后加入可溶性金属盐，搅拌至完全溶解，得到混合溶胶；
    发泡固化步骤：将增稠剂用醇溶剂分散后加入所述混合溶胶中，搅拌至完全溶胀溶解后，再加入泡沫稳定剂及泡沫固定剂搅拌均匀，之后陈化，然后加入发泡剂搅拌均匀，得到混合料，然后将所述混合料进行加热发泡固化,之后对固化成型的泡沫进行干燥，得到泡沫体；
    煅烧步骤：将所述泡沫体煅烧至完全除去有机物，即得到具有三维网络结构、 促进组织原位再生的可降解再生医学材料。
  9. 权利要求8所述的可降解再生医学材料的制备方法，其特征在于，在所述发泡固化步骤中，所述陈化为常温陈化，优选地，所述陈化是指陈化至粘度达到6000-20000cp，之后降温至25℃以下；优选地，加入发泡剂后搅拌速度为120-300r/min；
    可选地，在所述发泡固化步骤中，所述加热发泡固化的温度为60-100℃，时间为0.5-1h；优选地，所述加热发泡固化为在体积大于所述混合料体积五倍的容器中进行；优选地，所述干燥的温度为100-200℃，且干燥至体系水分不大于5％。
  10. 权利要求8所述的可降解再生医学材料的制备方法，其特征在于，在所述煅烧步骤中，所述煅烧的温度为500-1000℃，时间为1-3h。
PCT/CN2019/106736 2019-06-20 2019-09-19 一种促进组织原位再生的可降解再生医学材料及其制备方法 WO2020252957A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US17/596,627 US20220296785A1 (en) 2019-06-20 2019-09-19 Degradable regenerative medical material for promoting tissue in-situ regeneration and preparation method therefor
EP19934179.3A EP3988136A4 (en) 2019-06-20 2019-09-19 DEGRADABLE REGENERATIVE MEDICAL MATERIAL TO PROMOTE IN SITU TISSUE REGENERATION AND METHODS OF PRODUCTION THEREOF

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910538684.3A CN110101904B (zh) 2019-06-20 2019-06-20 一种促进组织原位再生的可降解再生医学材料及其制备方法
CN201910538684.3 2019-06-20

Publications (1)

Publication Number Publication Date
WO2020252957A1 true WO2020252957A1 (zh) 2020-12-24

Family

ID=67495577

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/106736 WO2020252957A1 (zh) 2019-06-20 2019-09-19 一种促进组织原位再生的可降解再生医学材料及其制备方法

Country Status (4)

Country Link
US (1) US20220296785A1 (zh)
EP (1) EP3988136A4 (zh)
CN (1) CN110101904B (zh)
WO (1) WO2020252957A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114409696A (zh) * 2022-02-21 2022-04-29 山东星达新材料有限公司 再生料加工用稳定剂以及包括该稳定剂的pc再生料

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110101904B (zh) * 2019-06-20 2020-07-28 北京幸福益生再生医学科技有限公司 一种促进组织原位再生的可降解再生医学材料及其制备方法
CN110885071B (zh) * 2019-12-17 2021-07-09 衢州学院 一种微米级超长钙基蠕虫状胶束模板及羟基钙磷灰石晶须
CN112972776B (zh) * 2021-02-23 2022-01-28 四川大学 具有光热效应的多级孔骨修复生物支架材料及制备方法
CN115246989B (zh) * 2021-11-18 2023-07-18 浙江理工大学 一种多孔分级结构泡沫材料及其制备方法
CN116077724B (zh) * 2023-01-13 2023-09-15 北京幸福益生再生医学科技有限公司 负载微量元素的多孔磷硅酸盐材料及其制备方法和应用
CN117357694B (zh) * 2023-10-10 2024-03-19 北京幸福益生再生医学科技有限公司 一种硅基再生医学材料及其制备方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1087279A (zh) * 1992-11-27 1994-06-01 中国科学院光电技术研究所 生物活性玻璃陶瓷人工骨及其制法
EP1987850A1 (en) * 2000-12-21 2008-11-05 Ethicon, Incorporated Reinforced tissue implants and methods of manufacture and use
CN103721292A (zh) * 2012-10-10 2014-04-16 中国科学院上海硅酸盐研究所 一种新型的多功能介孔生物活性玻璃支架及其制备方法和用途
CN104117090A (zh) * 2013-04-24 2014-10-29 上海交通大学医学院附属第九人民医院 放射性同位素标记的介孔生物玻璃多孔支架及其制备方法
CN106902393A (zh) * 2017-02-17 2017-06-30 天津大学 一种介孔生物活性玻璃纳米管支架的制备方法
IN201621003266A (zh) * 2016-01-29 2017-10-20
CN107823718A (zh) * 2017-11-22 2018-03-23 广州光鼎科技有限公司 一种含铷多级介孔生物活性玻璃及其制备方法和应用
CN110101904A (zh) * 2019-06-20 2019-08-09 北京幸福益生再生医学科技有限公司 一种促进组织原位再生的可降解再生医学材料及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1253391C (zh) * 2003-12-22 2006-04-26 复旦大学 纳米介孔以及介孔－大孔复合生物玻璃及其制备方法
GB0516157D0 (en) * 2005-08-05 2005-09-14 Imp College Innovations Ltd Process for preparing bioglass scaffolds
CN101091805A (zh) * 2006-06-20 2007-12-26 华东理工大学 双孔块状生物支架材料及其制备方法
ES2378044B2 (es) * 2010-03-17 2012-11-21 Universidad Complutense De Madrid Fabricación de andamios tridimensionales con vidrios mesoporosos bioactivos mediante prototipado rápido.
KR101271721B1 (ko) * 2010-08-18 2013-06-04 한국기계연구원 다공성생체활성유리를 포함하며 하이드록시아파타이트 및/또는 콜라겐이 코팅된 경조직 재생용 지지체 및 이의 제조방법

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1087279A (zh) * 1992-11-27 1994-06-01 中国科学院光电技术研究所 生物活性玻璃陶瓷人工骨及其制法
EP1987850A1 (en) * 2000-12-21 2008-11-05 Ethicon, Incorporated Reinforced tissue implants and methods of manufacture and use
CN103721292A (zh) * 2012-10-10 2014-04-16 中国科学院上海硅酸盐研究所 一种新型的多功能介孔生物活性玻璃支架及其制备方法和用途
CN104117090A (zh) * 2013-04-24 2014-10-29 上海交通大学医学院附属第九人民医院 放射性同位素标记的介孔生物玻璃多孔支架及其制备方法
IN201621003266A (zh) * 2016-01-29 2017-10-20
CN106902393A (zh) * 2017-02-17 2017-06-30 天津大学 一种介孔生物活性玻璃纳米管支架的制备方法
CN107823718A (zh) * 2017-11-22 2018-03-23 广州光鼎科技有限公司 一种含铷多级介孔生物活性玻璃及其制备方法和应用
CN110101904A (zh) * 2019-06-20 2019-08-09 北京幸福益生再生医学科技有限公司 一种促进组织原位再生的可降解再生医学材料及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3988136A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114409696A (zh) * 2022-02-21 2022-04-29 山东星达新材料有限公司 再生料加工用稳定剂以及包括该稳定剂的pc再生料
CN114409696B (zh) * 2022-02-21 2024-02-02 山东星达新材料有限公司 再生料加工用稳定剂以及包括该稳定剂的pc再生料

Also Published As

Publication number Publication date
CN110101904B (zh) 2020-07-28
EP3988136A1 (en) 2022-04-27
CN110101904A (zh) 2019-08-09
US20220296785A1 (en) 2022-09-22
EP3988136A4 (en) 2023-07-05

Similar Documents

Publication Publication Date Title
WO2020252957A1 (zh) 一种促进组织原位再生的可降解再生医学材料及其制备方法
Xin et al. Inorganic strengthened hydrogel membrane as regenerative periosteum
Zhao et al. Magnetic bioinspired micro/nanostructured composite scaffold for bone regeneration
Baino et al. Bioceramics and scaffolds: a winning combination for tissue engineering
CN109432505B (zh) 一种3d打印构建的多孔级复合医用凝胶支架及其制备方法
CN110665063A (zh) 3d生物打印墨水及其制备方法、组织工程支架及其制备方法
CN102558599A (zh) 一种表层含介孔硅胶的硅酸/海藻酸钙杂化材料的制备方法
CN109260508A (zh) 一种具有促进皮肤成纤维细胞增殖功能性的聚乙烯醇/海藻酸钠水凝胶的制备方法
CN110302432B (zh) 一种具有梯度孔结构的全层皮肤组织工程支架的制备方法
CN106267357A (zh) 一种修复骨软骨组织的双层复合水凝胶、制备方法及应用
Wang et al. The spatial arrangement of cells in a 3D-printed biomimetic spinal cord promotes directional differentiation and repairs the motor function after spinal cord injury
CN105381505A (zh) 一种骨缺损修复支架的3d打印制备方法
CN108686265A (zh) 一种3d打印的磁共振显影水凝胶及其制备方法和应用
CN113082286A (zh) 一种基于3d打印技术的三层仿生皮肤支架及其制备方法
Bashiri et al. 3D-printed placental-derived bioinks for skin tissue regeneration with improved angiogenesis and wound healing properties
CN107032775A (zh) 一种纳米羟基磷灰石、硅酸二钙复合生物陶瓷及其制备方法和应用
CN106620840A (zh) 一种丝素蛋白改性的骨水泥多孔支架及制备和应用
CN111214702A (zh) 一种可注射型颞下颌关节盘缺损的仿生修复材料及其制备方法和应用
CN107625996A (zh) 一种具有生物活性的仿生软骨材料及其制备方法
CN110420356B (zh) 一种用于骨肉瘤临床治疗的双功能一体化骨-软骨复合组织工程支架
JP5935181B2 (ja) 創傷治癒用の生体材料およびその調製
CN112978741B (zh) 一种可免疫调节血管化的硅酸锰空心纳米球及其制备方法和应用
CN112028620B (zh) 一种多孔性羟基磷灰石生物活性材料及其制备方法和应用
Gong et al. Preparation and characterization of a self‐crosslinking sodium alginate‐bioactive glass sponge
WO2022120902A1 (zh) 骨修复支架及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19934179

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2019934179

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2019934179

Country of ref document: EP

Effective date: 20220120