CN113476654A - Preparation method of bone regeneration hydrogel - Google Patents

Preparation method of bone regeneration hydrogel Download PDF

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Publication number
CN113476654A
CN113476654A CN202110790380.3A CN202110790380A CN113476654A CN 113476654 A CN113476654 A CN 113476654A CN 202110790380 A CN202110790380 A CN 202110790380A CN 113476654 A CN113476654 A CN 113476654A
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hydrogel
bone regeneration
solution
bone
propylene groups
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施雪涛
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Peking University Shenzhen Graduate School
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Peking University Shenzhen Graduate School
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
    • A—HUMAN NECESSITIES
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    • 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
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3821—Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A61L27/3843—Connective tissue
    • A61L27/3847—Bones
    • 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
    • A61L27/52—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
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
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    • 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
    • A—HUMAN NECESSITIES
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    • 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
    • A61L2300/43—Hormones, e.g. dexamethasone
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    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

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Abstract

The invention provides a preparation method of a bone regeneration hydrogel, which comprises the following steps: (1) mixing Ag nano particles with N, N-di (acryloyl) cystamine with disulfide bonds in water, and carrying out ultrasonic treatment for 10 minutes to enable the N, N-di (acryloyl) cystamine to be combined to the surfaces of the Ag nano particles through the disulfide bonds to form the Ag nano particle-based cross-linking agent with a plurality of propylene groups on the surfaces; (2) adding GelMA into a solution of a crosslinking agent based on Ag nano particles, the surface of which contains a plurality of propylene groups, fully and uniformly stirring, and then adding a photoinitiator to prepare a hydrogel precursor solution; (3) seed cells or/and water-soluble drugs for assisting bone regeneration and repair are/is added into the hydrogel precursor solution to form the bone regeneration hydrogel. Also provides the bone regeneration hydrogel prepared by the method. The method has simple process, and the prepared bone regeneration hydrogel has good biocompatibility, excellent mechanical property and good forming capability, and is suitable for the application of bone joint and bone tissue repair.

Description

Preparation method of bone regeneration hydrogel
Technical Field
The invention relates to the technical field of biological hydrogel preparation, in particular to a preparation method of bone regeneration hydrogel.
Background
The current biomaterials for the repair of human bone tissue include: inorganic scaffold materials, synthetic polymer materials (degradable and non-degradable) and biological hydrogel materials. The biological hydrogel material has excellent biocompatibility and biodegradability, can entrap cells or load water-soluble drugs to introduce and retain the cells to the defect part of bone tissue, accelerates bone regeneration, and has certain advantages. However, most biological hydrogel materials are fragile, easily crack and have weak mechanical strength, especially tensile strength, due to the lack of mechanical dissipative matrix, which limits the application and development of biological hydrogel in bone tissue repair and is difficult to be clinically applied.
Disclosure of Invention
The invention aims to provide a preparation method of bone regeneration hydrogel with simple process, and also provides the bone regeneration hydrogel prepared by the method, which has good biocompatibility, excellent mechanical property and good forming capability, and is suitable for application of bone joint and bone tissue repair.
The invention is realized by the following scheme:
a preparation method of the bone regeneration hydrogel comprises the following steps:
(1) mixing Ag nanoparticles (the particle size is 10-50 nm) with N, N-di (acryloyl) cystamine with disulfide bonds in water, and carrying out ultrasonic treatment for 10 minutes to enable the N, N-di (acryloyl) cystamine to be combined on the surfaces of the Ag nanoparticles through the disulfide bonds to form the Ag nanoparticle-based cross-linking agent with a plurality of propylene groups on the surfaces;
(2) adding GelMA (methacrylic acid hydrogel) into a solution of a crosslinking agent based on Ag nano particles with a plurality of propylene groups on the surface, fully and uniformly stirring, and then adding a photoinitiator (generally selected I2959) to prepare a hydrogel precursor solution;
(3) seed cells or/and water-soluble drugs for assisting bone regeneration and repair are/is added into the hydrogel precursor solution to form the bone regeneration hydrogel.
Further, in the step (1), the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface is controlled to be 10 to 30 mg/mL, the concentration of N, N-di (acryloyl) cystamine is different, the grafting ratio of the nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface is different, and the concentration of N, N-di (acryloyl) cystamine can be selected according to specific needs.
Further, in the step (2), the amount of GelMA is 8 to 15% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of acryl groups on the surface, and the amount of the photoinitiator is 0.25 to 0.5% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of acryl groups on the surface.
Further, in the step (3), the seed cells for assisting bone regeneration and repair are bone marrow mesenchymal stem cells, adipose mesenchymal stem cells or osteoblasts, and the water-soluble drug is flavonoid, dexamethasone or bisphosphonate.
A bone regeneration hydrogel, which is prepared by the preparation method of the bone regeneration hydrogel.
The preparation method of the bone regeneration hydrogel is simple in process, and the prepared bone regeneration hydrogel is good in biocompatibility, excellent in mechanical property and good in forming capability, and is suitable for application in bone joint and bone tissue repair. Injecting the prepared bone regeneration hydrogel into the bone defect part at 10 mW/cm2The bone defect part is filled up by in-situ crosslinking under the UV illumination condition, thereby achieving the regeneration and repair effect of the bone.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to the description of the examples.
Example 1
A preparation method of the bone regeneration hydrogel comprises the following steps:
(1) preparation of GelMA (methacrylated hydrogel):
first, 7.95 g of Na2CO3And 14.65 g NaHCO3Dissolving in 1L deionized water to obtain carbonate buffer solution, adding 15 g of type A gelatin from pig skin into 150 mL of carbonate buffer solution, stirring at 50 deg.C to dissolve completely, adjusting pH to 9.3, and adding into the mixed solutionSlowly dropwise adding 1.5 mL of methacrylic anhydride, stirring at 50 ℃ by adopting a stirring speed of 500 rpm to perform acylation reaction for 3 h, then adjusting the pH of the reaction solution to 7.4 again, filtering the solution by using standard filter paper, pouring the obtained product solution into a dialysis bag (with the molecular weight cutoff of 12-14 KDa) and dialyzing in deionized water at 40 ℃ for one week, removing unreacted reagents, finally performing freeze drying to obtain GelMA, and storing the GelMA in an environment at 4 ℃ for later use.
(2) Preparing Ag nano particles:
adding 30ml of sodium borohydride into a conical flask, magnetically stirring the mixture in an ice bath, adding 2ml of silver nitrate into the conical flask at the speed of 1 drop per second, stopping stirring the mixture after all the silver nitrate is dropped to form a colloidal suspension, adding a drop of polyvinylpyrrolidone (PVP) with the mass concentration of 0.3% into the colloidal suspension to prevent the colloidal suspension from polymerizing, and then adding a sodium chloride solution and enough solid polyvinyl alcohol (PVA) to obtain an Ag nano particle solution with the mass concentration of 4%.
(3) Preparation of N, N-cysteamine (acryloyl):
adding 5.8 g cysteamine dihydrochloride hydrochloride into 60 mL NaOH aqueous solution, dropwise adding 5mL dichloromethane solution containing 4.7g acryloyl chloride while stirring at 0 deg.C, stirring at room temperature for 3 hr, filtering to obtain solid product, extracting the liquid phase with dichloromethane, and extracting the organic extract with anhydrous Na2SO4The mixture was dried overnight and the solvent was removed under reduced pressure to give the final product, N-di (acryloyl) cystamine with disulfide bonds as a white solid.
(4) Preparing a crosslinking agent based on Ag nanoparticles, the surface of which contains a plurality of propylene groups:
0.1g of N, N-di (acryloyl) cystamine having a disulfide bond was added to a 5mL of the nanoparticle solution and mixed under sonication for 10 minutes, ensuring that the N, N-di (acryloyl) cystamine was bound to the surface of the Ag nanoparticles via a disulfide bond, forming an Ag nanoparticle-based crosslinking agent having a plurality of propylene groups on the surface, and the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based crosslinking agent having a plurality of propylene groups on the surface was controlled to 20 mg/mL.
(5) Preparing bone regeneration hydrogel:
GelMA (methacrylated hydrogel) is added into a solution of a crosslinking agent based on Ag nanoparticles, the surface of which contains a plurality of propylene groups, and the GelMA is added in an amount of 10% of the volume of the solution of the crosslinking agent based on Ag nanoparticles, the surface of which contains a plurality of propylene groups, and then a photoinitiator (selection I2959) is added to prepare a hydrogel precursor solution, the amount of the photoinitiator is 0.5% of the volume of the solution of the crosslinking agent based on Ag nanoparticles, the surface of which contains a plurality of propylene groups, and seed cells for assisting bone regeneration and repair are added into the hydrogel precursor solution to form a bone regeneration hydrogel, wherein the seed cells for assisting bone regeneration and repair in the embodiment 1 are mesenchymal stem cells.
Example 2
A method for preparing a bone regeneration hydrogel, which comprises substantially the same steps as those of the method for preparing a bone regeneration hydrogel of example 1, except that: the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface thereof was controlled to be 10 mg/mL, the amount of GelMA was 15% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface thereof, the amount of photoinitiator was 0.25% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface thereof, and the seed cells for assisting bone regeneration repair in this example 2 were adipose mesenchymal stem cells.
Example 3
A method for preparing a bone regeneration hydrogel, which comprises substantially the same steps as those of the method for preparing a bone regeneration hydrogel of example 1, except that: the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface was controlled to 30 mg/mL, the amount of GelMA was 8% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface, the amount of photoinitiator was 0.35% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface, and a water-soluble drug, which was a flavonoid in example 3, was added to the hydrogel precursor solution.
Example 4
A method for preparing a bone regeneration hydrogel, which comprises substantially the same steps as those of the method for preparing a bone regeneration hydrogel of example 1, except that: the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface was controlled to 25 mg/mL, the amount of GelMA was 12% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface, the amount of photoinitiator was 0.4% by volume of the solution of the Ag nanoparticle-based cross-linking agent having a plurality of propylene groups on the surface, and a water-soluble drug, which was a bisphosphonate in example 3, was added to the hydrogel precursor solution.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. A preparation method of the bone regeneration hydrogel is characterized by comprising the following steps: the method comprises the following steps:
(1) mixing Ag nano particles with N, N-di (acryloyl) cystamine with disulfide bonds in water, and carrying out ultrasonic treatment for 10 minutes to enable the N, N-di (acryloyl) cystamine to be combined to the surfaces of the Ag nano particles through the disulfide bonds to form the Ag nano particle-based cross-linking agent with a plurality of propylene groups on the surfaces;
(2) adding GelMA into a solution of a crosslinking agent based on Ag nano particles, the surface of which contains a plurality of propylene groups, fully and uniformly stirring, and then adding a photoinitiator to prepare a hydrogel precursor solution;
(3) seed cells or/and water-soluble drugs for assisting bone regeneration and repair are/is added into the hydrogel precursor solution to form the bone regeneration hydrogel.
2. The method of preparing a bone regeneration hydrogel according to claim 1, wherein: in the step (1), the concentration of N, N-di (acryloyl) cystamine in the Ag nanoparticle-based cross-linking agent with a plurality of propylene groups on the surface is controlled to be 10-30 mg/mL.
3. The method of preparing a bone regeneration hydrogel according to claim 1, wherein: in the step (2), the dosage of GelMA is 8-15% of the volume of the solution of the crosslinking agent based on Ag nano particles with a plurality of propylene groups on the surface, and the dosage of the photoinitiator is 0.25-0.5% of the volume of the solution of the crosslinking agent based on Ag nano particles with a plurality of propylene groups on the surface.
4. A method for preparing a hydrogel for bone regeneration according to any one of claims 1 to 3, wherein: in the step (3), the seed cells for assisting bone regeneration and repair are bone marrow mesenchymal stem cells, adipose mesenchymal stem cells or osteoblasts, and the water-soluble medicine is flavonoid, dexamethasone or bisphosphonate.
5. A bone regeneration hydrogel, comprising: the bone regeneration hydrogel prepared by the method for preparing the bone regeneration hydrogel as claimed in any one of claims 1 to 4.
CN202110790380.3A 2021-07-13 2021-07-13 Preparation method of bone regeneration hydrogel Pending CN113476654A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024023688A1 (en) * 2022-07-25 2024-02-01 Dawn Elizabeth Coates Nanocomposite hydrogel

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024023688A1 (en) * 2022-07-25 2024-02-01 Dawn Elizabeth Coates Nanocomposite hydrogel

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