CN115845123A - Preparation method of in-situ forming short fiber hydrogel dressing - Google Patents
Preparation method of in-situ forming short fiber hydrogel dressing Download PDFInfo
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Images
Abstract
The invention relates to a preparation method of in-situ formed short fiber hydrogel dressing, which comprises the steps of mixing electrospun short fibers, aldehyde natural polymer, methacrylation natural polymer, photoinitiator and solvent to obtain mixed solution, and irradiating and forming by ultraviolet light. According to the invention, the electrospun short fibers and hydrogel molecules are crosslinked through Schiff base reaction, so that the hydrogel dressing has the functions of mechanical enhancement and gelation acceleration, and the interface action between the short fibers and the hydrogel molecules is favorable for uniform dispersion. Dynamic Schiff base bonds between the fibers and hydrogel molecules cooperate with methacrylic acylated natural polymers to initiate ultraviolet light to polymerize free radicals to form a double network, so that the short fiber reinforced hydrogel with a stable structure is prepared.
Description
Technical Field
The invention belongs to the field of functional hydrogel, and particularly relates to a preparation method of an in-situ forming short fiber hydrogel dressing.
Background
The hydrogel material can provide the characteristics similar to tissues, has high water retention, biocompatibility and biodegradability, and is a good drug carrier material. However, most hydrogels are preformed and do not meet the need for close fitting irregular wounds. Meanwhile, the mechanical property of the hydrogel is poor, and the loaded drug molecules are easily released suddenly or diffused quickly from the polymer matrix.
Disclosure of Invention
Aiming at the defects of the prior art, the technical problem to be solved by the invention is to provide a preparation method of a drug-loaded short fiber hydrogel dressing formed in situ.
The preparation method of the short fiber hydrogel dressing comprises the following steps:
(1) Mixing an aliphatic polyester polymer material with an organic solvent to prepare a spinning solution, and preparing a fiber membrane through electrostatic spinning;
(2) Soaking a fiber membrane in a diamine solution, washing, adding the fiber membrane into a PVA solution, homogenizing, and centrifugally washing to obtain short fibers;
(3) Mixing short fibers, an aldehyde natural polymer, a methacrylic acylated natural polymer, a photoinitiator and a solvent to prepare a mixed solution, and irradiating the mixed solution by ultraviolet light for 2 to 30min to obtain the drug-loaded short fiber hydrogel dressing.
The preferred mode of the above preparation method is as follows:
in the step (1), the aliphatic polyester polymer material is one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, levorotatory polylactic acid, poly L-lactide-caprolactone and racemic polylactic acid; the organic solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, hexafluoroisopropanol and dichloromethane;
the mass percentage concentration of the aliphatic polyester polymer material in the spinning solution in the step (1) is 5-30%.
The electrostatic spinning process parameters in the step (1) are as follows: the spinning voltage is 5-25 kV, the receiving distance is 5-30 cm, the perfusion speed is 0.1-2 mL/h, the temperature is 20-50 ℃, the relative humidity is 20-70%, and the fiber is received on the base material.
In the step (2), diamine is one or more of 1, 6-hexamethylene diamine, 1, 2-ethylene diamine and Fmoc-polyethylene glycol-diamine; the concentration of the diamine solution is 0.1-10% (w/v); the alcoholysis degree of the PVA is 87.0-89.0 (mol/mol), and the concentration of the PVA solution is 0.1-2% (w/v).
The soaking treatment in the step (2) is carried out at the temperature of 37 ℃ for 0.5-5 h; the technological parameters of the homogenization treatment are as follows: the rotating speed is 5000-12000 rpm, and the homogenizing time is 10-60 min.
The washing in the step (2) is deionized water washing for 2-3 times; centrifuging and washing for 2-3 times, wherein the centrifugation technological parameters are as follows: the rotating speed is 1000-6000 rpm, and the centrifugation time is 0.5-5 min.
The aldehyde-based natural polymer in the step (3) is prepared by dissolving the natural polymer in a solvent, stirring the mixture evenly in the dark, and adding NaIO 4 Reacting at room temperature for 3-12 h, adding glycol solution to terminate the reaction, dialyzing the sample, and freeze-drying to obtain the aldehyde natural polymer.
The natural polymer is one of glucan, gelatin and hyaluronic acid; the solvent is one of deionized water and PBS. And (4) treating the mixed solution in the step (3) for 5-30 min by using ultrasonic equipment to uniformly disperse the short fibers in the solution.
The natural polymer in the methacrylated natural polymer in the step (3) is one of gelatin, chitosan and hyaluronic acid; the photoinitiator is at least one of LAP and I2959; the solvent is PBS solution; the mass percentage concentration of the short fiber in the mixed solution is 1-5%, the mass percentage concentration of the aldehyde natural polymer is 1-20%, the mass percentage concentration of the methacrylated natural polymer is 5-20%, and the mass percentage concentration of the photoinitiator is 0.1-1%.
The invention relates to a drug-loading short fiber hydrogel dressing, which contains the short fiber hydrogel dressing prepared by the method and a drug. Mixing a drug with the spinning solution of the step (1) or adding a drug to the mixed solution of the step (3) based on the preparation method.
The medicament in the medicament-carrying short fiber hydrogel dressing in the step (3) can be introduced by mixing with the spinning solution in the step (1) or solution blending in the step (3);
the mass percentage concentration of the medicine is 0.1-1%, and the medicine is one or more of aspirin, diclofenac sodium, ibuprofen and the like.
The wavelength of the ultraviolet light irradiation in the step (3) is 365nm.
The invention discloses application of a drug-loaded short fiber hydrogel dressing in a skin wound repair material.
The invention uses diamine solution to modify the surface of aliphatic polyester polymer material and homogenize, and then blends the aliphatic polyester polymer material with aldehydic natural polymer, methacrylation natural polymer and photoinitiator. The invention utilizes Schiff base reaction to crosslink the short fibers and the hydrogel, thereby achieving the purposes of mechanical enhancement and gelation acceleration of the hydrogel dressing, and simultaneously the interface action between the short fibers and the hydrogel is beneficial to uniform dispersion of the short fibers and the hydrogel, so as to prepare the short fiber reinforced hydrogel with a stable structure.
The patent aims to prepare the drug-loaded short fiber hydrogel composite stent by combining the electrostatic spinning short fibers and the hydrogel, and the stent can realize in-situ forming under the ultraviolet condition. The addition of the short fibers enhances the mechanical property of the hydrogel, effectively simulates the structure of the natural extracellular matrix, and can realize the slow release of the drug by loading the drug in the fiber or hydrogel matrix, thereby promoting the regeneration and repair of tissues.
The invention utilizes the electrostatic spinning technology to prepare the aliphatic polyester polymer fiber membrane, and then the fiber membrane is soaked in the diamine solution to carry out amination on the fiber membrane, thereby achieving the purposes of improving the hydrophilicity and functionalization. And then blending the short fiber, the aldehydic natural polymer and the methacrylation natural polymer and carrying out ultraviolet irradiation, wherein the short fiber and the aldehydic natural polymer are subjected to Schiff base reaction, carbon-carbon double bonds of the methacrylation natural polymer are subjected to free radical polymerization under the ultraviolet irradiation condition, and finally the hydrogel rapidly forms a stable double cross-linking network in situ.
Advantageous effects
(1) The main materials used in the invention are natural polymers and electrostatic spinning short fibers, the materials are easy to obtain, the processing technology is simple and convenient, and the method has an industrial implementation prospect.
(2) According to the in-situ formed drug-loaded short fiber hydrogel dressing, the functional modified aliphatic polyester type high polymer short fibers are prepared through ammonolysis and homogenization treatment, schiff base reaction is generated between amino groups carried on the surfaces of the short fibers and hydrogel, so that the adjustment of the interfacial force between polymers and the short fibers is facilitated, the uniform dispersion in the hydrogel is realized, and meanwhile, the stability and the mechanical property of the fiber hydrogel can be improved through the doping of the short fibers and the chemical interaction between the short fibers and the polymers.
(3) The in-situ formed drug-loaded short fiber hydrogel dressing can realize the slow release of drugs.
(4) The in-situ formed drug-loaded short fiber hydrogel dressing is prepared by the invention.
Drawings
FIG. 1 is a schematic diagram of the preparation of an in-situ forming drug-loaded short fiber hydrogel dressing according to the present invention;
FIG. 2 is a scanning electron micrograph of a short fiber obtained after the homogenization treatment in example 1;
FIG. 3 is a photograph of a hydrogel of staple fibers of example 1;
FIG. 4 is a photograph of the hydrogel of staple fibers of example 1 after injection and in situ formation;
FIG. 5 is a compression mechanical curve of a hydrogel of staple fibers of example 1;
fig. 6 is a drug release profile of the diclofenac sodium loaded staple hydrogel of example 3.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
1. Materials: polylactic acid-glycolic acid copolymer, lactic acid to glycolic acid ratio of 75, purchased from the handle bio materials ltd, gorgeon; polylactic acid was purchased from the bio-material ltd, handlei, gorge, denham; hexafluoroisopropanol, 99.5% standard, available from mclin reagents, inc; 1, 6-hexanediamine, 99.0% by weight, available from Shanghai Allantin reagents, inc.; the alcoholysis degree of PVA is 87.0-89.0%, and the PVA is purchased from Shanghai Aladdin reagent Co., ltd; gelatin is bovine Type A, has a molecular weight of 120000, and is available from Shanghai Rongen reagent, inc.; chitosan was purchased from shanghai alading reagent limited; methacrylic anhydride, 99.0% by weight, available from Shanghai Aladdin reagents, inc.; dextran molecular weight is 70000 available from Shanghai Aladdin reagent, inc.; the specification of N, N-dimethylformamide is AR, is more than or equal to 99.5 percent (GC), and is purchased from Shanghai Tantan chemical Co., ltd; the specification of the dichloromethane is AR which is not less than 99.5 percent and is purchased from Shanghai Lingfeng chemical reagent company Limited; ethylene glycol specification AR,98%, available from shanghai ji to biochemistry technologies limited; the specification of the sodium periodate is AR,99.5 percent, and the sodium periodate is purchased from Shanghai chemical industry Co., ltd; photoinitiator I2959, 98.0% standard, available from shanghai rahn reagents ltd; the specification of the diclofenac sodium is more than or equal to 99.5 percent, and the diclofenac sodium is purchased from Shanghai-sourced leaf Biotechnology GmbH; aspirin has a specification of 99.0% and is available from Beijing YinuoKai science and technology Co.
Preparation of methacrylated Gelatin (GM): dissolving gelatin in PBS (5-15% of gelatin concentration), slowly dropwise adding methacrylic anhydride, fully dissolving at 55 ℃, adding excessive PBS to stop reaction, dialyzing a sample, and freeze-drying to obtain the dried GM, wherein the weight ratio of the gelatin to the methacrylic anhydride is 5-6.
The preparation method of the methacrylated chitosan comprises the following steps: dissolving chitosan in acetic acid solution, adding a certain amount of ethanol solution for dilution, slowly dripping methacrylic anhydride, reacting at room temperature for 12 hours, dialyzing a sample, and freeze-drying to obtain dried methacryloylated chitosan.
2. Test method
And (3) testing mechanical properties: adopting HY-940FS microcomputer electronic universal tester to make compression test on cylindrical short fibre hydrogel sample (diameter is 10.5mm, thickness is 10.0 mm) at compression rate of 0.5-5 mm min -1 Ten parallel samples were measured for each group.
Determination of in vitro release kinetics of drugs: placing the drug-loaded short fiber hydrogel composite stent in 5mL PBS (PBS) at 37 ℃ for 100rpm min -1 Then, the drug is released, 2mL of the solution to be tested is taken out within a specific time, and 2mL of PBS is timely supplemented to continue the experiment. And detecting the absorbance of the solution to be detected by adopting an ultraviolet spectrophotometer under the specified wavelength, calculating according to a standard curve to obtain the corresponding concentration, and finally obtaining a drug release curve.
Example 1
The in-situ formed drug-loaded short fiber hydrogel dressing and the preparation method thereof comprise the following steps:
(1) Dissolving 2g of PLGA in 10mL of hexafluoroisopropanol solution to prepare a precursor spinning solution;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun using an electrospinning device, and the fiber membrane was received by a receiving base material (glossy paper). Wherein the electrostatic spinning process parameters are as follows: the spinning voltage is 9kV, the receiving distance is 15cm, the perfusion speed is 1mL/h, the temperature is 25 +/-2 ℃, and the relative humidity is 50 +/-5%;
(4) Soaking the fiber membrane in the step (3) in a 2% (w/v) 1, 6-hexamethylene diamine solution at 37 ℃ for 60min, and then taking out and washing the fiber membrane for 3 times by using deionized water;
(5) And (5) placing the fiber membrane in the step (4) into 200mL of PVA, wherein the concentration is 0.5% (w/v), and carrying out homogenization treatment by using a homogenizer, wherein the homogenization process parameters are as follows: rotating at 8000rpm for 10min, centrifuging and washing the homogeneous solution for 3 times to obtain amino-modified PLGA electrostatic spinning short fiber (APLGA), as shown in FIG. 2, with average fiber diameter of 2.4 μm and average length of 22.2 μm;
(6) Dissolving 5g dextran in 125mL deionized water, stirring to dissolve completely, adding 5g NaIO under dark condition 4 After stirring at room temperature for 3.5 hours, 3mL of ethylene glycol was added dropwise with stirring, and the mixture was allowed to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by adopting a dialysis bag with the molecular weight cutoff of 8000-10000 specification, changing water for 1 time every 12h during dialysis, and freeze-drying for 2 days to obtain dried oxidized dextran (ODex);
(7) 0.05g of the short and medium fibers (5), 0.1g of ODex (6), 0.5g of GM (6), 0.02g of diclofenac sodium and 0.025g of photoinitiator I2959 were dissolved in 5mL of PBS (pH = 7.4). The mixed solution is stirred uniformly and then treated for 10min by an ultrasonic device (the working frequency is 50 kHz) to disperse short fibers, and then the precursor solution is irradiated by 365nm ultraviolet light for 10min to prepare the in-situ formed drug-loaded short fiber hydrogel dressing, wherein a short fiber hydrogel photo is shown in figure 3. As shown in fig. 4, the drug-loaded short fiber hydrogel can be uniformly poured into a mold through a disposable medical syringe, and the hydrogel is formed in situ by ultraviolet irradiation.
The compressive strength of the GM/ODex-APLGA drug loaded staple hydrogel in this example was 36.2kPa, which is a 2.57-fold increase over the GM/ODex hydrogel without added fiber (FIG. 5).
Example 2
The in-situ formed drug-loaded short fiber hydrogel dressing and the preparation method thereof comprise the following steps:
(1) Dissolving 2g of PLGA and 0.02g of aspirin in 10mL of hexafluoroisopropanol solution to prepare a precursor spinning solution;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun using an electrospinning device, and the fiber membrane was received by a receiving base material (glossy paper). Wherein the electrostatic spinning process parameters are as follows: the spinning voltage is 9kV, the receiving distance is 15cm, the perfusion speed is 1mL/h, the temperature is 25 +/-2 ℃, and the relative humidity is 50 +/-5%;
(4) Soaking the fiber membrane in the step (3) in 2% (w/v) 1, 6-hexamethylene diamine solution at 37 ℃ for 60min, and then taking out and washing the fiber membrane for 3 times by using deionized water;
(5) And (3) placing the fiber membrane in the step (4) in 200mL of PVA, wherein the concentration is 0.5% (w/v), and carrying out homogenization treatment by using a homogenizer, wherein the homogenization process parameters are as follows: rotating at 8000rpm for 10min, centrifuging and washing the homogenized solution for 3 times to obtain APLGA short fiber;
(6) Dissolving 5g dextran in 125mL deionized water, stirring to dissolve completely, adding 5g NaIO under dark condition 4 After stirring at room temperature for 3.5 hours, 3mL of ethylene glycol was added dropwise with stirring, and the mixture was allowed to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by adopting a dialysis bag with the molecular weight cutoff of 8000-10000 specification, changing water for 1 time every 12 hours during dialysis, and freeze-drying for 2 days to obtain dried ODex;
(7) 0.05g of the short fiber in (5), 0.1g of ODex in (6), 0.5g of methacrylated chitosan and 0.025g of photoinitiator I2959 were dissolved in 5mL of PBS (pH = 7.4). The mixed solution is stirred uniformly and then treated for 10min by ultrasonic equipment (the working frequency is 50 kHz) to disperse short fibers, and then the precursor solution is irradiated by 365nm ultraviolet light for 10min to prepare the in-situ formed drug-loaded short fiber hydrogel dressing.
Example 3
The in-situ formed drug-loaded short fiber hydrogel dressing and the preparation method thereof comprise the following steps:
(1) Dissolving 2g of PLA in 8mL of dichloromethane and 2mL of N, N-dimethylformamide solution to prepare a precursor spinning solution;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun using an electrospinning device, and the fiber membrane was received by a receiving base material (glossy paper). Wherein the electrostatic spinning process parameters are as follows: the spinning voltage is 18kV, the receiving distance is 15cm, the perfusion speed is 0.8mL/h, the temperature is 25 +/-2 ℃, and the relative humidity is 50 +/-5%;
(4) Soaking the fiber membrane in the step (3) in 2% (w/v) 1, 6-hexamethylene diamine solution at 37 ℃ for 60min, and then taking out and washing the fiber membrane for 3 times by using deionized water;
(5) And (3) placing the fiber membrane in the step (4) in 200mL of PVA, wherein the concentration is 0.5% (w/v), and carrying out homogenization treatment by using a homogenizer, wherein the homogenization process parameters are as follows: rotating at 8000rpm for 10min, centrifuging and washing the homogenized solution for 3 times to obtain APLA short fiber;
(6) Dissolving 5g of dextran in 250mL of deionized water, stirring until the dextran is completely dissolved, and adding 5g of NaIO under the condition of keeping out of the light 4 After stirring at room temperature for 3.5 hours, 3mL of ethylene glycol was added dropwise with stirring, and the mixture was allowed to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by adopting a dialysis bag with the molecular weight cutoff of 8000-10000 specification, changing water for 1 time every 12 hours during dialysis, and freeze-drying for 2 days to obtain dried ODex;
(7) 0.05g of the short fibers in (5), 0.1g of ODex in (6), 0.5g of GM in (6), 0.02g of diclofenac sodium and 0.025g of photoinitiator I2959 were dissolved in 5mL of PBS (pH = 7.4). The mixed solution is stirred uniformly and then treated for 10min by ultrasonic equipment (the working frequency is 50 kHz) to disperse short fibers, and then the precursor solution is irradiated by 365nm ultraviolet light for 10min to prepare the in-situ formed drug-loaded short fiber hydrogel dressing.
As shown in FIG. 6, the cumulative release amount of the drug in 36h of the GM/ODex-APLA drug-loaded short fiber hydrogel in this example is 64.04%, which has a good drug release effect.
Claims (10)
1. A method of making a staple fiber hydrogel dressing, comprising:
(1) Mixing an aliphatic polyester polymer material and an organic solvent to prepare a spinning solution, and preparing a fiber membrane through electrostatic spinning;
(2) Soaking a fiber membrane in a diamine solution, washing, adding the fiber membrane into a polyvinyl alcohol (PVA) solution, homogenizing, and centrifugally washing to obtain short fibers;
(3) Mixing short fibers, an aldehyde natural polymer, a methacrylic acylated natural polymer, a photoinitiator and a solvent, preparing a mixed solution, and irradiating by ultraviolet light for 2-30 min to obtain the short fiber hydrogel dressing.
2. The preparation method according to claim 1, wherein the aliphatic polyester-based polymer material in the step (1) is one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, levorotatory polylactic acid, dextrorotatory polylactic acid, poly L-lactide-caprolactone and racemic polylactic acid; the organic solvent is one or more of N, N-dimethylformamide, tetrahydrofuran, hexafluoroisopropanol and dichloromethane;
the mass percentage concentration of the aliphatic polyester polymer material in the spinning solution in the step (1) is 5-30%.
3. The preparation method according to claim 1, wherein the electrostatic spinning process parameters in the step (1) are as follows: the spinning voltage is 5-25 kV, the receiving distance is 5-30 cm, the perfusion speed is 0.1-2 mL/h, the temperature is 20-50 ℃, the relative humidity is 20-70%, and the fiber is received on the base material.
4. The preparation method according to claim 1, wherein the diamine in the step (2) is one or more of 1, 6-hexamethylenediamine, 1, 2-ethylenediamine, fmoc-polyethylene glycol-diamine; the concentration of the diamine solution is 0.1-10% (w/v);
the alcoholysis degree of the PVA is 87.0-89.0 (mol/mol), and the concentration of the PVA solution is 0.1-2% (w/v).
5. The preparation method according to claim 1, wherein the soaking treatment in the step (2) is carried out at 37 ℃ for 0.5-5 h; the technological parameters of the homogenization treatment are as follows: the rotating speed is 5000-12000 rpm, and the homogenizing time is 10-30 min.
6. The preparation method according to claim 1, wherein the aldehydized natural polymer in step (3) is prepared by dissolving the natural polymer in a solvent, stirring the solution to be uniform in the dark, and adding sodium periodate (NaIO) 4 ) Reacting at room temperature for 3-12 h, adding ethylene glycol solution to terminate the reaction, dialyzing the sample, and freeze-drying to obtain the aldehyde natural polymer; the natural polymer is one of glucan, gelatin and hyaluronic acid; the solvent is one of deionized water and PBS.
7. The method according to claim 1, wherein the natural polymer in the methacrylated natural polymer in the step (3) is one of gelatin, chitosan, hyaluronic acid; the photoinitiator is at least one of LAP and I2959; the solvent is PBS; the mass percentage concentration of the short fibers in the mixed solution is 1-5%, the mass percentage concentration of the aldehyde natural polymer is 1-20%, the mass percentage concentration of the methylacryloylation natural polymer is 5-20%, and the mass percentage concentration of the photoinitiator is 0.1-1%.
8. A drug-loaded short fiber hydrogel dressing comprising the short fiber hydrogel dressing prepared by the method of claim 1 and a drug.
9. The drug-loaded short fiber hydrogel dressing according to claim 8, wherein a drug is mixed with the spinning solution of step (1) of claim 1 or added to the mixed solution of step (3) based on the preparation method of claim 1;
wherein the mass percentage concentration of the medicine is 0.1-1%; the medicine is one or more of aspirin, diclofenac sodium, ibuprofen, etc.
10. The use of the drug-loaded short-fiber hydrogel dressing of claim 8 in a skin wound repair material.
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| CN102417734A (en) * | 2011-11-21 | 2012-04-18 | 东华大学 | Oxidized sodium alginate/gelatin degradable hydrogel and preparation method thereof |
| CN106075568A (en) * | 2016-06-13 | 2016-11-09 | 广州迈普再生医学科技有限公司 | A kind of tissue repair degradable nano short fiber material and its preparation method and application |
| CN112300420A (en) * | 2020-11-20 | 2021-02-02 | 福州大学 | Injectable antibacterial interpenetrating double-network hydrogel and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102417734A (en) * | 2011-11-21 | 2012-04-18 | 东华大学 | Oxidized sodium alginate/gelatin degradable hydrogel and preparation method thereof |
| CN106075568A (en) * | 2016-06-13 | 2016-11-09 | 广州迈普再生医学科技有限公司 | A kind of tissue repair degradable nano short fiber material and its preparation method and application |
| CN112300420A (en) * | 2020-11-20 | 2021-02-02 | 福州大学 | Injectable antibacterial interpenetrating double-network hydrogel and preparation method and application thereof |
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