CN114736254B - Natural flavonoid derivative medicine and preparation method and application thereof - Google Patents
Natural flavonoid derivative medicine and preparation method and application thereof Download PDFInfo
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- CN114736254B CN114736254B CN202210323872.6A CN202210323872A CN114736254B CN 114736254 B CN114736254 B CN 114736254B CN 202210323872 A CN202210323872 A CN 202210323872A CN 114736254 B CN114736254 B CN 114736254B
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- naringin
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- 239000003814 drug Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000002214 flavonoid derivatives Chemical class 0.000 title claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 51
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 claims abstract description 40
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 claims abstract description 20
- 229930019673 naringin Natural products 0.000 claims abstract description 20
- 229940052490 naringin Drugs 0.000 claims abstract description 20
- 238000007639 printing Methods 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000839 emulsion Substances 0.000 claims abstract description 12
- 239000000843 powder Substances 0.000 claims abstract description 11
- 230000017423 tissue regeneration Effects 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 4
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000017 hydrogel Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 24
- 238000010146 3D printing Methods 0.000 claims description 16
- 108010010803 Gelatin Proteins 0.000 claims description 16
- 239000000499 gel Substances 0.000 claims description 16
- 239000008273 gelatin Substances 0.000 claims description 16
- 229920000159 gelatin Polymers 0.000 claims description 16
- 235000019322 gelatine Nutrition 0.000 claims description 16
- 235000011852 gelatine desserts Nutrition 0.000 claims description 16
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- 238000005286 illumination Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- KLGDRWGOXDJNPH-UHFFFAOYSA-N P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C Chemical compound P(=O)(O)(O)O.C1(=CC=CC=C1)C=1C(=C(C(=O)[Li])C(=CC1C)C)C KLGDRWGOXDJNPH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
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- 229930003935 flavonoid Natural products 0.000 abstract description 11
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- 235000017173 flavonoids Nutrition 0.000 abstract description 11
- 150000002215 flavonoids Chemical class 0.000 abstract description 4
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- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 235000001759 Citrus maxima Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 239000012620 biological material Substances 0.000 description 1
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- 150000001875 compounds Chemical class 0.000 description 1
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- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
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Classifications
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- 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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Abstract
The invention relates to a natural flavonoid derivative drug, a preparation method and application thereof, wherein naringin powder is dissolved in phosphate buffer solution PBS (phosphate buffer solution) at 75 ℃ to obtain naringin solution at pH 7.4; dispersing methacrylic anhydride MA in phosphate buffer solution PBS to obtain MA emulsion; dropwise adding the MA emulsion in the step 2 into the naringin solution in the step 1, adjusting the pH value to 8.0-9.0 by using a sodium hydroxide solution, and magnetically stirring the mixture at 75 ℃ in a dark place for reaction for 8 hours; terminating the reaction by adding hydrochloric acid solution to the reaction solution in step 3 to reach pH 7.0; dialyzing the reaction mixture in the step 4, and freeze-drying to obtain naringin derivative NARMA. The invention develops a novel medicine based on flavonoid glycoside compounds, improves the bioavailability of flavonoid naringin, can solve the problem of low fidelity of 3D biological printing, and can promote tissue regeneration.
Description
Technical Field
The invention relates to the technical fields of new medicine development, 3D printing biological ink and biological material development, in particular to a natural flavonoid derivative medicine, a preparation method and application thereof.
Background
The natural chemical micromolecules are mainly chemical substances generated by plants and microorganisms, have wide biological activity and stereochemistry, and are a promising medical resource. The 3D bioprinting technology is an emerging additive manufacturing technology, which accelerates the development of related fields of health science, such as tissue engineering, regenerative medicine and drug discovery and development. However, since the fidelity of 3D bio-printing is significantly affected by scattered light during printing, it is necessary to develop specific bio-ink to absorb the scattered light during bio-printing, thereby improving the fidelity of the printed product. The natural flavonoid compound contains at least one conjugated big pi bond and different numbers of conjugated double bonds, and absorbs light in a certain wavelength range. Therefore, the natural flavonoid micromolecules and the derivatives thereof are expected to absorb scattered light in the 3D biological printing process, and the shape fidelity of the printed product is improved. On the other hand, natural flavonoids have corresponding antioxidant, anti-inflammatory and anti-apoptotic properties, and have been used for the treatment of atherosclerosis, osteoporosis, rheumatic diseases and preclinical neurodegenerative diseases. But the natural flavonoid compounds have poor absorption capacity and low bioavailability, and limit the application of the natural flavonoid compounds in the fields of biomedicine and the like. Therefore, a natural flavonoid derivative drug is developed to improve 3D biological printing fidelity and medical applications such as tissue engineering and the like.
Compared with oral natural flavonoid compound tablets, the natural flavonoid small molecule derivatives not only can improve the shape fidelity of 3D biological printing products, but also can directly transfer the biological activity of the natural flavonoid compounds to adjacent cells through 3D biological printing, so that the natural flavonoid compounds are effectively utilized by the cells.
Disclosure of Invention
The invention designs a natural flavonoid derivative drug, a preparation method and application thereof, and solves the technical problems that the fidelity of 3D biological printing is obviously affected by scattered light in the printing process, and specific biological ink needs to be developed to absorb the scattered light in the biological printing process, so that the fidelity of a printed product is improved.
In order to solve the technical problems, the invention adopts the following scheme:
a preparation method of a natural flavonoid derivative drug comprises the following steps:
step 1, dissolving naringin powder in phosphate buffer PBS (phosphate buffer solution) with the temperature of 75-100 ℃ and the pH value of 7.0-8.0 to obtain naringin solution; step 2, dispersing methacrylic anhydride MA in phosphate buffer solution PBS to obtain MA emulsion with the volume ratio of 5-10%; step 3, dropwise adding the MA emulsion in the step 2 into the naringin solution in the step 1, adjusting the pH value to 8.0-9.0 by using a sodium hydroxide solution, and magnetically stirring the solution at 75-100 ℃ in a dark place for reaction for 6-12 hours; step 4, stopping the reaction by adding hydrochloric acid solution to the reaction solution in the step 3 to reach pH 7.0; and 5, dialyzing the reaction mixture in the step 4, and performing freeze drying treatment to obtain naringin derivative NARMA.
Preferably, the naringin solution in step 3 has a mass fraction of 0.5-2% w.t..
Preferably, the mole fraction of MA in step 3 is equal to or greater than the mole fraction of naringin.
A natural flavonoid derivative drug is characterized in that: including naringin derivatives NARMA as described above.
High-fidelity 3D printing hydrogel based on naringin derivative NARMAThe preparation method of the adhesive comprises the following steps: step 1, dissolving naringin derivative NARMA as claimed in claim 1 or 2 and methacryloylated gelatin GELMA or similar polymer macromolecule with photopolymerization capability in 0.1% w.t. -1% w.t. of phenyl-2, 4, 6-trimethylbenzoyl lithium phosphate LAP aqueous solution or phosphate buffer solution PBS, and obtaining a mixed solution with NARMA final concentration of 0.01% w.t. -4.0% w.t., GELMA or similar polymer macromolecule with photopolymerization capability final concentration of 8% w.t. -30% w.t.; step 2, adding the mixed solution in the step 1 into a trough of a 3D printing device based on 405nm wavelength light assisted printing, printing according to a preset digital model and program, wherein the illumination time is 6-20s/100 mu m, and the illumination intensity is 20-300mW/cm 2 Obtaining the NARMA-based high-fidelity 3D printing hydrogel.
Preferably, the synthesis procedure of the methacryloylated gelatin GELMA in step 1 is as follows: dissolving gelatin GEL powder in PBS at 55-65deg.C to obtain 5-10% w.t. GEL solution, wherein the GEL has number average molecular weight of 50000-100000; dropwise adding 2-10% of MA emulsion prepared in the method in the volume ratio of claim 1 into a GEL solution stirred by magnetic force, carrying out light-shielding reaction for 2-6 hours at 55-65 ℃, and regulating the pH value of the reaction solution to 8.0-9.0 by using a sodium hydroxide solution in the reaction process; terminating the reaction by adding a hydrochloric acid solution to the reaction solution to a pH of 7.0; dialyzing the reaction mixture, and freeze-drying to obtain the modified gelatin GELMA.
A high-fidelity 3D printing hydrogel, characterized in that: the preparation method is used for preparing the composite material.
A method for preparing a biological manufactured hydrogel for tissue repair based on NARMA, comprising the following steps: step 1, dissolving naringin derivative NARMA as claimed in claim 1 or 2 and methacryloylated gelatin GELMA or similar polymer macromolecule with photopolymerization capability in 0.1% w.t. -1% w.t. of phenyl-2, 4, 6-trimethylbenzoyl lithium phosphate LAP aqueous solution or phosphate buffer solution PBS, and obtaining a mixed solution with NARMA final concentration of 0.01% w.t. -4.0% w.t., GELMA or similar polymer macromolecule with photopolymerization capability final concentration of 8% w.t. -30% w.t.; step 2, adding 10 to the PBS-based mixed solution in the step 1 4 /ml-10 7 Living cells/ml, irradiating at 405nm for 0.5-5min with light intensity of 20-500mW/cm 2 Obtaining the NARMA-based tissue repair bio-fabricated hydrogel.
Preferably, the synthesis procedure of the methacryloylated gelatin GELMA in step 1 is as follows: dissolving gelatin GEL powder in PBS at 55-65deg.C to obtain 5-10% w.t. GEL solution, wherein the GEL has number average molecular weight of 50000-100000; dropwise adding 2-10% of MA emulsion prepared in the method in the volume ratio of claim 1 into a GEL solution stirred by magnetic force, carrying out light-shielding reaction for 2-6 hours at 55-65 ℃, and regulating the pH value of the reaction solution to 8.0-9.0 by using a sodium hydroxide solution in the reaction process; terminating the reaction by adding a hydrochloric acid solution to the reaction solution to a pH of 7.0; dialyzing the reaction mixture, and freeze-drying to obtain the modified gelatin GELMA.
A method for preparing the biological hydrogel for tissue repair based on NARMA.
The natural flavonoid derivative medicament, and the preparation method and application thereof have the following beneficial effects:
(1) The invention develops a novel medicine based on flavonoid glycoside compounds, improves the bioavailability of flavonoid naringin, can solve the problem of low fidelity of 3D biological printing, and can promote tissue regeneration.
(2) The biological manufactured hydrogel based on NARMA has good biocompatibility and high biological activity.
(3) The biological ink based on NARMA realizes high-fidelity 3D printing, and is expected to be used for repairing personalized customized tissue defects.
(4) When the medicine is used, the medicine is uniformly distributed and the content controllability of the medicine is high; avoiding inconvenience caused by frequent oral administration; the medicine can be directly delivered to the periphery of cells to exert the medicine effect; avoiding the unavoidable toxicity caused by taking large doses;
(5) The invention has simple process and is beneficial to large-scale production.
Drawings
FIG. 1 is an infrared spectrum of modified naringin powder prepared in example 1 of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of the modified naringin powder prepared in example 1 of the present invention.
FIG. 3 is an ultraviolet-visible spectrum of the modified naringin powder prepared in example 1 of the present invention.
Fig. 4 is a schematic macroscopic view of the 3D printing modified pomelo Pi Ganji hydrogel prepared in example 2 of the present invention.
FIG. 5 is a fluorescent staining chart of live cells after culturing rabbit articular chondrocytes in situ encapsulated by modified shaddock Pi Ganji hydrogel prepared in example 3 of the present invention for five days.
FIG. 6 is a graph of safranin O staining of a modified pomelo Pi Ganji hydrogel of the present invention after four weeks of culture of in situ encapsulated rabbit articular chondrocytes.
Detailed Description
The invention is further described with reference to fig. 1 to 6:
naringin is a flavonoid glycoside compound, has a reactive hydroxyl group, and can introduce carbon-carbon double bonds through esterification reaction, so that the molecular structure characteristics are changed, and the light absorption range and degree of the compound are regulated; in the use process, the polymer is mixed with GELMA or similar polymer macromolecules with photopolymerization capability, and under the irradiation of blue light, an initiator LAP reacts with carbon-carbon double bonds to generate free radicals, so that NARMA and GELMA or similar polymer macromolecules with photopolymerization capability are crosslinked to form hydrogel.
Example 1:
the preparation method of naringin derivative NARMA comprises the following steps:
step 1, 1g of naringin powder is dissolved in 100ml of PBS at 75 ℃ to obtain 1% w.t. naringin solution.
Step 2, dispersing 1ml of MA in 20ml of PBS to obtain MA emulsion.
And step 3, dropwise adding the MA emulsion in the step 2 into the naringin solution in the step 1, adjusting the pH value to 8.0-9.0 by using a sodium hydroxide solution, and magnetically stirring the mixture at 75 ℃ in a dark place for reaction for 8 hours.
And 4, adding hydrochloric acid solution into the reaction solution in the step 3 to reach pH7.0 so as to terminate the reaction.
And 5, dialyzing the reaction mixture in the step 4, and performing freeze drying treatment to obtain naringin derivative NARMA, and preserving the naringin derivative NARMA in a dark place at a low temperature.
The infrared spectrum of the modified naringin prepared in this example 1 is shown in FIG. 1. The nuclear magnetic hydrogen spectrum is shown in figure 2. The ultraviolet-visible spectrum is shown in figure 3, which proves that naringin modification is successful.
Example 2:
the preparation of the NARMA-based 3D printing hydrogel of the medicinal ink comprises the following steps of:
step 1, dissolving NARMA and GELMA in 0.5% w.t. LAP solution to obtain mixed solution with NARMA final concentration of 1% w.t., and GELMA final concentration of 10% w.t..
And 2, adding the mixed solution obtained in the step 1 into a trough of a 3D printing device for light assisted printing with the wavelength of 405nm, printing according to a preset digital model and a program, wherein the illumination time is 8s/100 mu m, and the illumination intensity is 20mW/cm < 2 >, so that the NARMA-based high-fidelity 3D printing hydrogel is obtained.
A macroscopic schematic of the 3D printing hydrogel prepared in this example is shown in fig. 4.
Example 3:
the invention relates to a preparation method of a tissue repair biological hydrogel based on NARMA, which comprises the following steps:
step 1, NARMA and GELMA are dissolved in 0.5% w.t. LAP/PBS solution, and the final concentration of NARMA in the obtained mixed solution is 1% w.t., and the final concentration of GELMA is 10% w.t..
Step 2, adding 10 into the mixed solution in the step 1 7 Per ml of live articular cartilage cells, uniformly mixing, transferring into polytetrafluoroethylene mould (phi 10 mm. Times.2 mm), irradiating at 405nm wavelength for 0.5min with irradiation light intensity of 300mW/cm 2 The biological manufactured hydrogel for tissue repair based on NARMA is obtained.
And 3, staining living cells in the hydrogel by adopting diacetic acid fluorescein, and observing the growth state of the chondrocytes in the hydrogel on the fifth day, as shown in fig. 5. The result shows that the chondrocytes are uniformly distributed in the three-dimensional structure of the hydrogel, are in a sphere shape and are partially aggregated to grow in a lump, and the growth state of the chondrocytes in the articular cartilage in the body is maintained.
And 4, continuously culturing the cell/hydrogel composite for four weeks and then performing histological staining, wherein the safranin O staining result shows that as shown in figure 6, cartilage cells in the hydrogel secrete a large amount of macromolecular glycosaminoglycans represented by a cartilage extracellular matrix, and a large amount of cartilage tissue specific pit structures are formed, so that the hydrogel based on the modified naringin has excellent cartilage regeneration and repair application potential.
The invention has been described above by way of example with reference to the accompanying drawings, it is clear that the implementation of the invention is not limited to the above-described manner, but it is within the scope of the invention to apply the inventive concept and technical solution to other situations as long as various improvements made by the inventive concept and technical solution are adopted or without any improvement.
Claims (10)
1. A preparation method of a natural flavonoid derivative drug comprises the following steps:
step 1, dissolving naringin powder in phosphate buffer PBS (phosphate buffer solution) with the temperature of 75-100 ℃ and the pH value of 7.0-8.0 to obtain naringin solution;
step 2, dispersing methacrylic anhydride MA in phosphate buffer solution PBS to obtain MA emulsion with the volume ratio of 5-10%;
step 3, dropwise adding the MA emulsion obtained in the step 2 into the naringin solution obtained in the step 1, adjusting the pH value to 8.0-9.0 by using a sodium hydroxide solution, and magnetically stirring the mixture at 75-100 ℃ in a dark place for reaction for 6-12 hours;
step 4, stopping the reaction by adding hydrochloric acid solution to the reaction solution in the step 3 to reach pH 7.0;
and 5, dialyzing the reaction mixture in the step 4, and performing freeze drying treatment to obtain naringin derivative NARMA.
2. The method for preparing a natural flavonoid derivative drug according to claim 1, wherein the method comprises the following steps: the mass fraction of naringin solution in step 3 is 0.5-2% w.t..
3. The method for preparing a natural flavonoid derivative drug according to claim 1, wherein the method comprises the following steps: the mole fraction of MA in step 3 is greater than the mole fraction of naringin.
4. A natural flavonoid derivative drug is characterized in that: naringin derivative NARMA as claimed in claim 1 or 2.
5. A preparation method of a high-fidelity 3D printing hydrogel based on naringin derivative NARMA comprises the following steps:
step 1, dissolving naringin derivative NARMA as claimed in claim 1 or 2 and methacryloylated gelatin GELMA in 0.1% w.t. -1% w.t. of phenyl-2, 4, 6-trimethylbenzoyl lithium phosphate LAP aqueous solution or phosphate buffer solution PBS, the final concentration of NARMA in the obtained mixture being 0.01% w.t. -4.0% w.t., the final concentration of GELMA being 8% w.t. -30% w.t.;
step 2, adding the mixed solution in the step 1 into a material tank of the 3D printing equipment, printing according to a preset digital model and a program, wherein the illumination time is 6-20s/100 mu m, and the illumination intensity is 20-300mW/cm 2 Obtaining the NARMA-based high-fidelity 3D printing hydrogel.
6. The method for preparing the high-fidelity 3D printing hydrogel based on naringin derivative NARMA as claimed in claim 5, which is characterized in that:
the synthesis procedure of the methacryloylated gelatin GELMA in step 1 is as follows:
dissolving gelatin GEL powder in PBS at 55-65deg.C to obtain 5-10% w.t. GEL solution, wherein the GEL has number average molecular weight of 50000-100000;
dropwise adding 2-10% of MA emulsion prepared in the method in the volume ratio of claim 1 into a GEL solution stirred by magnetic force, carrying out light-shielding reaction for 2-6 hours at 55-65 ℃, and regulating the pH value of the reaction solution to 8.0-9.0 by using a sodium hydroxide solution in the reaction process;
terminating the reaction by adding a hydrochloric acid solution to the reaction solution to a pH of 7.0;
dialyzing the reaction mixture, and freeze-drying to obtain the modified gelatin GELMA.
7. A high-fidelity 3D printing hydrogel, characterized in that: the method of claim 5 or 6.
8. A method for preparing a biological manufactured hydrogel for tissue repair based on NARMA, comprising the following steps:
step 1, dissolving naringin derivative NARMA as claimed in claim 1 or 2 and methacryloylated gelatin GELMA in 0.1% w.t. -1% w.t. of phenyl-2, 4, 6-trimethylbenzoyl lithium phosphate LAP aqueous solution or phosphate buffer solution PBS, the final concentration of NARMA in the obtained mixture being 0.01% w.t. -4.0% w.t., the final concentration of GELMA being 8% w.t. -30% w.t.;
step 2, adding 10 to the PBS-based mixed solution in the step 1 4 /ml-10 7 Living cells/ml, irradiating at 405nm for 0.5-5min with light intensity of 20-500mW/cm 2 Obtaining the NARMA-based tissue repair bio-fabricated hydrogel.
9. The method for preparing a NARMA-based tissue repair kit of claim 8, wherein:
the synthesis procedure of the methacryloylated gelatin GELMA in step 1 is as follows:
dissolving gelatin GEL powder in PBS at 55-65deg.C to obtain 5-10% w.t. GEL solution, wherein the GEL has number average molecular weight of 50000-100000;
dropwise adding 2-10% of MA emulsion prepared in the method in the volume ratio of claim 1 into a GEL solution stirred by magnetic force, carrying out light-shielding reaction for 2-6 hours at 55-65 ℃, and regulating the pH value of the reaction solution to 8.0-9.0 by using a sodium hydroxide solution in the reaction process;
terminating the reaction by adding a hydrochloric acid solution to the reaction solution to a pH of 7.0;
dialyzing the reaction mixture, and freeze-drying to obtain the modified gelatin GELMA.
10. A NARMA-based bio-fabricated hydrogel for tissue repair, characterized in that: a method of manufacture according to claim 8 or 9.
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