CN113150318B - Preparation method and application of injectable magnesium alloy composite multi-network hydrogel - Google Patents
Preparation method and application of injectable magnesium alloy composite multi-network hydrogel Download PDFInfo
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 79
- 229910000861 Mg alloy Inorganic materials 0.000 title claims abstract description 37
- 239000002131 composite material Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 59
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 59
- 239000000661 sodium alginate Substances 0.000 claims abstract description 59
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 37
- WWSOAUJHYNYLTM-UHFFFAOYSA-N C(C(=C)C)(=O)[Na] Chemical compound C(C(=C)C)(=O)[Na] WWSOAUJHYNYLTM-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000243 solution Substances 0.000 claims abstract description 21
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 18
- 102000008186 Collagen Human genes 0.000 claims abstract description 17
- 108010035532 Collagen Proteins 0.000 claims abstract description 17
- 229920001436 collagen Polymers 0.000 claims abstract description 17
- 230000007547 defect Effects 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000011259 mixed solution Substances 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 239000002245 particle Substances 0.000 claims abstract description 10
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000843 powder Substances 0.000 claims abstract description 9
- 230000007935 neutral effect Effects 0.000 claims abstract description 6
- 230000001376 precipitating effect Effects 0.000 claims abstract description 6
- 238000000502 dialysis Methods 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 15
- 229910001424 calcium ion Inorganic materials 0.000 claims description 13
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 7
- 229910001297 Zn alloy Inorganic materials 0.000 claims description 6
- 230000008439 repair process Effects 0.000 claims description 6
- PGTXKIZLOWULDJ-UHFFFAOYSA-N [Mg].[Zn] Chemical compound [Mg].[Zn] PGTXKIZLOWULDJ-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 210000002449 bone cell Anatomy 0.000 abstract description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 238000004132 cross linking Methods 0.000 abstract description 3
- 230000000638 stimulation Effects 0.000 abstract description 3
- 230000012010 growth Effects 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 5
- 239000008223 sterile water Substances 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 102000012422 Collagen Type I Human genes 0.000 description 3
- 108010022452 Collagen Type I Proteins 0.000 description 3
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910001425 magnesium ion Inorganic materials 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 241001474374 Blennius Species 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- LSWCMUBJZBXTDM-UHFFFAOYSA-M P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] Chemical compound P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] LSWCMUBJZBXTDM-UHFFFAOYSA-M 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- -1 methacrylic acid acylated sodium alginate Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
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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
- A61L27/50—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
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- 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
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
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Abstract
The application provides a preparation method of an injectable magnesium alloy composite multi-network hydrogel prepolymer, which comprises the following steps: dissolving sodium alginate in a sterile aqueous solution to obtain an aqueous sodium alginate solution; adding methacrylic anhydride into the sodium alginate aqueous solution for reaction; after the reaction is finished, precipitating and dissolving dialysis are carried out to obtain a dialysate; lyophilizing the dialysate to obtain methacryloylated sodium alginate powder; dissolving methacryloyl sodium alginate powder in a buffer; regulating the pH value of the collagen solution to be neutral; mixing the methacryloylated sodium alginate solution and the collagen solution to obtain a mixed solution; adding magnesium alloy particles into the mixed solution according to a proportion to obtain a hydrogel prepolymer, and photo-induced crosslinking the hydrogel prepolymer to form the multi-network hydrogel. The application utilizes the multi-network hydrogel to improve the mechanical property of the hydrogel, and promotes the growth of bone cells through the stimulation effect of magnesium metal on the bone cells, thereby achieving the purpose of repairing bone defects.
Description
Technical Field
The application belongs to the technical field of cell biology and biomedical material preparation, and particularly relates to a preparation method and application of a magnesium alloy composite multi-network hydrogel for repairing bone defects.
Background
Clinically, bone defects exceeding 3cm in diameter are difficult to heal naturally. Generally, bone grafting is one of the therapeutic techniques, and is classified into autologous bone grafting and allogeneic bone grafting, but both of these methods have certain drawbacks. Autografts suffer from the disadvantage that the materials available for implantation are limited and there may be a risk of infection and bone resorption. Allograft and xenograft have high failure rates, have immune rejection and a high risk of infection, and bone resorption may be more severe than autologous bone. These limitations have prompted efforts to study the use of scaffolds in combination with biochemical signals to promote bone repair.
In recent years, regenerative medicine has proposed repairing bone defects with biological hydrogels in combination with growth factors or materials that promote bone growth. The characteristics of the liquid before gel formation of the hydrogel can be utilized to directly repair bone defects by percutaneous injection. The natural biological hydrogel has excellent biocompatibility and is more similar to the extracellular matrix components of human bodies. The most commonly used biological macromolecules at present include natural polysaccharides, proteins and the like. The single-component hydrogel has the characteristics of poor biocompatibility and poor mechanical property, and is often required to chemically modify natural materials or to regulate parameters such as mechanical property, biocompatibility and the like by combining two or more substances to prepare the double-network hydrogel with specific functions, so that the environment condition of human tissues is simulated more truly.
Sodium alginate is a natural polysaccharide that forms hydrogels by cross-linking with calcium ions. However, in the prior art, in the research aspect of repairing bone loss, the elastic modulus of the seaweed polysaccharide gel of a single component of the sodium alginate is lower than that of bone tissues, and the sodium alginate is easy to degrade in vivo.
Therefore, there is a need to develop a new bone loss repair material.
Disclosure of Invention
The application aims to provide a magnesium alloy composite multi-network hydrogel which can be injected to form a structure with mechanical properties such as certain toughness and the like, thereby being used for repairing bone defects.
In order to solve the technical problems, the specific technical scheme of the application is as follows:
the preparation method of the injectable magnesium alloy composite multi-network hydrogel prepolymer is characterized by comprising the following steps of:
dissolving sodium alginate in a sterile aqueous solution to obtain an aqueous sodium alginate solution;
adding methacrylic anhydride into the sodium alginate aqueous solution for reaction;
after the reaction is finished, precipitating and dissolving dialysis are carried out to obtain dialysate;
lyophilizing the dialysate to obtain methacryloylated sodium alginate powder;
dissolving the methacryloyl sodium alginate powder in a buffer solution and mixing with a photoinitiator to obtain a first mixed solution of the methacryloyl sodium alginate and the photoinitiator;
regulating the pH value of the collagen solution to be neutral;
mixing the first mixed solution and the collagen solution to obtain a second mixed solution;
and adding magnesium alloy particles into the second mixed solution according to a proportion to obtain the hydrogel prepolymer.
Optionally, the mass concentration of the sodium alginate aqueous solution is 0.1% -10%.
Optionally, the photoinitiator comprises a lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate salt.
Alternatively, the magnesium alloy is a magnesium zinc alloy containing about 5% zinc by mass.
Optionally, the magnesium alloy is added according to the mass ratio of 0.05% -1%.
Optionally, the mass volume fraction of the methacryloylated sodium alginate buffer solution is 0.05% -1%.
Optionally, the volume ratio of the second mixed solution to the collagen solution is 1 (1-0.1).
The application also provides a preparation method of the injectable magnesium alloy composite multi-network hydrogel, which is prepared by using the method of the injectable magnesium alloy composite multi-network hydrogel prepolymer.
Optionally, the method further comprises the following steps:
culturing the hydrogel prepolymer in a culture medium containing calcium ions;
light is irradiated at a specific wavelength to form a multi-network hydrogel.
Alternatively, the medium has a calcium ion concentration of 0.1-5mM.
The application also provides a bone defect repair material prepared by the preparation method of the hydrogel or the hydrogel prepolymer.
The application can improve the mechanical property of the hydrogel by utilizing the multi-network hydrogel, provide a bracket channel, facilitate nutrient substance and nutrient transmission, improve degradation speed, promote bone cell growth by the stimulation of magnesium metal to bone cells, and achieve the aim of repairing bone defects. Meanwhile, the hydrogel for injection can fill the defect part more conveniently, and the pain of patients in multiple open surgeries is reduced.
Drawings
One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings, in which like references indicate similar elements, and in which the figures of the drawings are not to be taken in a limiting sense, unless otherwise indicated.
FIG. 1 is an SEM image of a hydrogel containing 1% methacryloylated sodium alginate according to one embodiment of the application;
FIG. 2 is an SEM image of a hydrogel containing 2% methacryloylated sodium alginate according to one embodiment of the application;
FIG. 3 is a graph showing the elastic modulus test of hydrogels according to example 1 and example 2 of the present application;
FIG. 4 is a schematic representation of cell morphology of MC3T3-E1 grown on a surface of a hydrogel containing 1% methacryloylated sodium alginate for 7 days according to one embodiment of the application;
FIG. 5 is a schematic representation of cell morphology of MC3T3-E1 grown on a surface of a hydrogel containing 2% methacryloylated sodium alginate for 7 days according to one embodiment of the application;
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the following detailed description of the embodiments of the present application will be given with reference to the accompanying drawings. However, those of ordinary skill in the art will understand that in various embodiments of the present application, numerous technical details have been set forth in order to provide a better understanding of the present application. However, the claimed application may be practiced without these specific details and with various changes and modifications based on the following embodiments. The following embodiments are divided for convenience of description, and should not be construed as limiting the specific implementation of the present application, and the embodiments can be mutually combined and referred to without contradiction.
The application relates to a preparation method of magnesium alloy composite multi-network hydrogel, which is used for repairing bone defects. The method is carried out as follows:
preparation of methacrylic acid acylated sodium alginate:
sodium alginate was dissolved in sterile water and stirred overnight to allow complete dissolution. So that the concentration of the sodium alginate aqueous solution is 0.1-10%, methacrylic anhydride is added dropwise under the condition of avoiding light, and 5-20ml of methacrylic anhydride is added into 1g of sodium alginate. Stirring thoroughly, reacting at room temperature in the absence of light for 24-72 hours, precipitating with acetone, dissolving and dialyzing, and lyophilizing at-80deg.C to obtain methacryloyl sodium alginate powder.
Preparation of magnesium alloy composite multi-network hydrogel prepolymer:
dissolving the methacryloyl sodium alginate in a buffer solution without calcium and magnesium ions, such as sodium hydrogen phosphate-sodium Dihydrogen Phosphate (DPBS), stirring overnight at room temperature to completely dissolve the sodium hydrogen phosphate-sodium dihydrogen phosphate, and mixing a photoinitiator with the methacryloyl sodium alginate to obtain the mass and volume fraction of the methacryloyl sodium alginate of 0.05-1%. The collagen was placed in an environment of 4deg.C and pH was adjusted to 6.5-8 with 0.06M acetic acid and 5M sodium hydroxide. The collagen is, for example, rat tail type I collagen. At low temperature (4-10 ℃), the methacryloylated sodium alginate solution and the neutral collagen solution are mixed uniformly according to a proportion (volume ratio is 1:1-0.1). Mixing with 0.05-1% of magnesium alloy particles, wherein the magnesium alloy is magnesium-zinc alloy, and the mass ratio of the magnesium alloy to the zinc alloy is 95% and 5%.
Using method of injectable magnesium alloy composite multi-network hydrogel
Injecting the hydrogel prepolymer into 37 ℃ culture medium containing 0.1-5mM calcium ion concentration, culturing at 37 ℃ for 30-60min, and irradiating with 600-700nm infrared for 30-60min to form multi-network hydrogel. The bone cells are inoculated on multi-network hydrogel, cultured for 7-21 days, the cell morphology is observed, and the cell activity and the corresponding index are detected.
Example 1:
1g of sodium alginate was dissolved in sterile water and stirred overnight to allow complete dissolution. So that the mass volume fraction (w/v) of the sodium alginate aqueous solution is 2.5%, methacrylic anhydride is added dropwise under the condition of avoiding light, and 12ml of methacrylic anhydride is added into 1g of sodium alginate. Fully stirring, carrying out light-shielding reaction for 48 hours at room temperature, adding 4 times of acetone into a reaction system, and precipitating and separating out the methacryloyl sodium alginate. Naturally air-drying the methacryloyl sodium alginate precipitate, dissolving in sterile water, and dialyzing in 10000Da dialysis bag for 7 days with water change every 4 hours. Freeze-drying at-80 ℃ to form the methacryloylated sodium alginate powder.
Dissolving the methacryloyl sodium alginate in sodium hydrogen phosphate-sodium Dihydrogen Phosphate Buffer (DPBS) without adding calcium and magnesium ions, stirring overnight at room temperature to completely dissolve the sodium hydrogen phosphate-sodium dihydrogen phosphate buffer, and mixing a photoinitiator with the dissolved methacryloyl sodium alginate to ensure that the mass volume fraction of the methacryloyl sodium alginate is 2.5%. Rat tail type I collagen was placed in an environment of 4deg.C, and pH of the collagen was adjusted to 7 with 0.06M acetic acid and 5M sodium hydroxide. At low temperature (4-10 ℃), uniformly mixing the methacryloyl sodium alginate solution and the neutral collagen solution according to a certain proportion, and then adding magnesium alloy particles for uniform mixing. So that the concentration (w/v) of each component of the final composite hydrogel prepolymer is as follows: 1% of methyl acrylated sodium alginate, 0.5% of photoinitiator, 2% of collagen and 1% of magnesium alloy particles. The hydrogel prepolymer solution was stored at 4 ℃.
The magnesium alloy in the present embodiment is a magnesium-zinc alloy, and the mass ratio is 95% of magnesium and 5% of zinc.
The hydrogel prepolymer is placed in a DMEM medium containing 2.5mM calcium ion concentration at 37 ℃ for 60min for culture, 600nm infrared irradiation is selected for about 45min, a multi-network hydrogel is formed, and the internal elastic modulus G' of the hydrogel is 15+/-2.01 KPa tested by a PIUMA nanoindentation instrument, as shown in figure 3. After freeze-drying the hydrogel, SEM scanning was performed to observe the pore size and magnesium particle distribution as shown in FIG. 1.
The hydrogel prepolymer was injected into a DMEM medium containing 2.5mM calcium ion concentration at 37℃and incubated at 37℃for 30min and irradiated with 600nm infrared radiation for 45min to form a multi-network hydrogel. MC3T3-E1 cells are inoculated on the multi-network hydrogel, cultured for 7 days, cell morphology is observed, bone cell activity and corresponding indexes are detected, the detection result is shown in figure 4, and through living and dead staining of the MC3T3-E1 cells, normal cell morphology, few dead cells and good biocompatibility of the magnesium alloy composite multi-network hydrogel can be observed.
Example 2:
1g of sodium alginate was dissolved in sterile water and stirred overnight to allow complete dissolution. So that the mass volume fraction (w/v) of the sodium alginate aqueous solution is 2.5%, methacrylic anhydride is added dropwise under the condition of avoiding light, and 12ml of methacrylic anhydride is added into 1g of sodium alginate. Fully stirring, carrying out light-shielding reaction for 48 hours at room temperature, adding 4 times of acetone into a reaction system, and precipitating and separating out the methacryloyl sodium alginate. Naturally air-drying the methacryloyl sodium alginate precipitate, dissolving in sterile water, and dialyzing in 10000Da dialysis bag for 7 days with water change every 4 hours. Freeze-drying at-80 ℃ to form the methacryloylated sodium alginate powder.
Dissolving the methacryloyl sodium alginate in sodium hydrogen phosphate-sodium Dihydrogen Phosphate Buffer (DPBS) without adding calcium and magnesium ions, stirring overnight at room temperature to completely dissolve the sodium hydrogen phosphate-sodium dihydrogen phosphate buffer, and mixing a photoinitiator with the dissolved methacryloyl sodium alginate to ensure that the mass volume fraction of the methacryloyl sodium alginate is 2.5%. Rat tail type I collagen was placed in an environment of 4deg.C, and pH of the collagen was adjusted to 7 with 0.06M acetic acid and 5M sodium hydroxide. At low temperature (4-10 ℃), uniformly mixing the methacryloyl sodium alginate solution and the neutral collagen solution according to a certain proportion, and then adding magnesium alloy particles for uniform mixing. So that the concentration (w/v) of each component of the final composite hydrogel prepolymer is as follows: 2% of methacryloyl sodium alginate, 0.5% of photoinitiator, 2% of collagen and 1% of magnesium alloy particles. The hydrogel prepolymer solution was stored at 4 ℃. The magnesium alloy in the present embodiment is a magnesium-zinc alloy, and the mass ratio is 95% of magnesium and 5% of zinc.
The hydrogel prepolymer is placed in a DMEM (medium with the concentration of 2.5mM calcium ions) at 37 ℃ for 60min, and is subjected to infrared irradiation for about 45min at 600nm to form a multi-network hydrogel, the internal elastic modulus G' of the hydrogel is 30.5+/-1.3 KPa tested by a PIUMA nanoindentation instrument, as shown in figure 3, and after the hydrogel is freeze-dried, the pore diameter and the distribution of magnesium alloy particles are observed by SEM scanning as shown in figure 2. The results show that compared with the first example, the concentration of the methacryloylated sodium alginate can change the crosslinking density of the hydrogel, change the pore size and obviously improve the mechanical properties of the multi-network hydrogel.
The hydrogel prepolymer was injected into a DMEM medium containing 2.5mM calcium ion concentration at 37℃and incubated at 37℃for 30min and irradiated with 600nm infrared radiation for about 45min to form a multi-network hydrogel. MC3T3-E1 cells were inoculated onto a multi-network hydrogel, cultured for 7 days, the cell morphology was observed, and the bone cell activity and the corresponding index were examined, as shown in FIG. 5. As can be seen from FIG. 2, the MC3T3-E1 cells are subjected to live-dead staining, so that the cells are normal in morphology, few in dead cells, and good in biocompatibility, compared with the example, the multi-network hydrogel with high elastic modulus is more beneficial to proliferation and growth of the MC3T3-E1 cells.
The application also provides a bone defect repair material prepared by the preparation method of the hydrogel or the hydrogel prepolymer.
The application can improve the mechanical property of the hydrogel by utilizing the multi-network hydrogel, provide a bracket channel, facilitate nutrient substance and nutrient transmission, improve degradation speed, promote bone cell growth by the stimulation of magnesium metal to bone cells, and achieve the aim of repairing bone defects. Meanwhile, the hydrogel for injection can fill the defect part more conveniently, and the pain of patients in multiple open surgeries is reduced.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples of carrying out the application and that various changes in form and details may be made therein without departing from the spirit and scope of the application.
Claims (9)
1. The preparation method of the injectable magnesium alloy composite multi-network hydrogel prepolymer is characterized by comprising the following steps of:
dissolving sodium alginate in a sterile aqueous solution to obtain an aqueous sodium alginate solution;
adding methacrylic anhydride into the sodium alginate aqueous solution for reaction;
after the reaction is finished, precipitating and dissolving dialysis are carried out to obtain dialysate;
lyophilizing the dialysate to obtain methacryloylated sodium alginate powder;
dissolving the methacryloyl sodium alginate powder in a buffer solution and mixing with a photoinitiator to obtain a first mixed solution of the methacryloyl sodium alginate and the photoinitiator;
adjusting the pH value of the collagen solution to be neutral;
mixing the first mixed solution and the collagen solution to obtain a second mixed solution;
and adding magnesium alloy particles into the second mixed solution according to a proportion to obtain the hydrogel prepolymer.
2. The method for preparing the injectable magnesium alloy composite multi-network hydrogel prepolymer according to claim 1, wherein the mass-volume ratio of the sodium alginate aqueous solution is 0.1% -10%.
3. The method for preparing an injectable magnesium alloy composite multi-network hydrogel prepolymer according to claim 1, wherein the magnesium alloy is a magnesium zinc alloy containing 5% zinc by mass.
4. The method for preparing an injectable magnesium alloy composite multi-network hydrogel prepolymer according to claim 1 or 3, wherein the magnesium alloy is added according to a mass ratio of 0.05% -1%.
5. The method for preparing an injectable magnesium alloy composite multi-network hydrogel prepolymer according to claim 1, wherein the volume ratio of the second mixed solution to the collagen solution is 1 (1-0.1).
6. The preparation method of the injectable magnesium alloy composite multi-network hydrogel is characterized by comprising the following steps of:
placing the hydrogel prepolymer in a culture medium containing calcium ions for culture;
illuminating with light of a specific wavelength to form a multi-network hydrogel; wherein,,
the hydrogel prepolymer prepared by the method of any one of claims 1-5.
7. The method for preparing an injectable magnesium alloy composite multi-network hydrogel according to claim 6, wherein the calcium ion concentration of the culture medium is 0.1-5mM.
8. The method for preparing the injectable magnesium alloy composite multi-network hydrogel according to claim 6, wherein the light with the specific wavelength is 600nm infrared light.
9. A bone defect repair material comprising a multi-network hydrogel prepolymer prepared according to the method of any one of claims 1-5 or a multi-network hydrogel prepared according to the method of any one of claims 6-8.
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