CN115845123B - Preparation method of in-situ formed short fiber hydrogel dressing - Google Patents
Preparation method of in-situ formed short fiber hydrogel dressing Download PDFInfo
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention relates to a preparation method of an in-situ formed short fiber hydrogel dressing, which comprises the steps of mixing electrospun short fibers, an aldehyde natural polymer, a methacryloyl natural polymer, a photoinitiator and a solvent to obtain a mixed solution, and carrying out ultraviolet irradiation forming. According to the invention, the electrospun short fibers and the hydrogel molecules are crosslinked through Schiff base reaction, so that the effects of mechanical enhancement and gelation acceleration of the hydrogel dressing are provided, and meanwhile, the interface effect between the short fibers and the hydrogel molecules is beneficial to uniform dispersion of the short fibers and the hydrogel molecules. The dynamic Schiff base bond between the fiber and the hydrogel molecule cooperates with the methacrylic acylated natural polymer ultraviolet light to initiate free radical polymerization to form a double network, so as to prepare the short fiber reinforced hydrogel with stable structure.
Description
Technical Field
The invention belongs to the field of functional hydrogels, and particularly relates to a preparation method of an in-situ formed short fiber hydrogel dressing.
Background
The hydrogel material can provide 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 to closely conform to irregular wounds. Meanwhile, the mechanical property of the hydrogel is poor, and the carried drug molecules are easy to be suddenly released or rapidly diffused from the polymer matrix.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of an in-situ formed drug-loaded short fiber hydrogel dressing.
The preparation method of the short fiber hydrogel dressing comprises the following steps:
(1) Mixing aliphatic polyester polymer materials with an organic solvent to prepare spinning solution, and preparing a fiber membrane through electrostatic spinning;
(2) Soaking a fiber membrane in a diamine solution, washing, then adding the fiber membrane into a PVA solution, homogenizing, and centrifugally washing to obtain short fibers;
(3) Mixing the short fiber, the aldehyde natural polymer, the methacrylic acylated natural polymer, the photoinitiator and the solvent, preparing a mixed solution, and irradiating with ultraviolet light for 2-30 min to obtain the drug-loaded short fiber hydrogel dressing.
The preferred mode of the preparation method is as follows:
the aliphatic polyester polymer material in the step (1) is one or more of polylactic acid-glycolic acid copolymer, polycaprolactone, polylactic acid, L-polylactic acid, poly L-lactide-caprolactone and racemized 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 pouring 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 substrate.
The diamine in the step (2) is one or more of 1, 6-hexamethylenediamine, 1, 2-ethylenediamine and Fmoc-polyethylene glycol-diamine; the concentration of the diamine solution is 0.1-10% (w/v); the PVA alcoholysis degree is 87.0-89.0 (mol/mol), and the concentration of the PVA solution is 0.1-2% (w/v).
The soaking treatment temperature in the step (2) is 37 ℃ and the soaking treatment time is 0.5-5 h; the technological parameters of the homogenizing treatment are as follows: the rotation 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; centrifugal washing is carried out for 2 to 3 times, wherein the centrifugal technological parameters are as follows: the rotating speed is 1000-6000 rpm, and the centrifugation time is 0.5-5 min.
The step (3) is to dissolve the natural polymer in a solvent, stir the mixture to be uniform under the dark condition, then add NaIO 4, react for 3-12 h at room temperature, add glycol solution to terminate the reaction, dialyze the sample, freeze-dry the sample, and obtain the aldehyde natural polymer.
The natural polymer is one of dextran, gelatin and hyaluronic acid; the solvent is one of deionized water and PBS. And (3) treating the mixed solution in the step (3) by using ultrasonic equipment for 5-30 min to uniformly disperse the short fibers in the solution.
The natural polymer in the methacryloylated 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 methacryloyl natural polymer is 5-20%, and the mass percentage concentration of the photoinitiator is 0.1-1%.
The invention relates to a drug-loaded short fiber hydrogel dressing, which comprises the short fiber hydrogel dressing prepared by the method and a drug. Based on the preparation method, the medicine is mixed with the spinning solution in the step (1) or the medicine is added into the mixed solution in the step (3).
The drug in the drug-loaded short fiber hydrogel dressing in the step (3) can be introduced by mixing the drug with the spinning solution in the step (1) or by blending the solution 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 ultraviolet light irradiation in the step (3) is 365nm.
The invention relates to application of the drug-loaded short fiber hydrogel dressing in a skin wound repair material.
The invention utilizes diamine solution to carry out surface modification and homogenization treatment on aliphatic polyester polymer materials, and then blends the aliphatic polyester polymer materials with aldehyde-based natural polymers, methacrylic-based natural polymers and photoinitiators. According to the preparation method, the short fibers and the hydrogel are crosslinked by utilizing the Schiff base reaction, so that the purposes of mechanical reinforcement and gelation acceleration of the hydrogel dressing are achieved, and meanwhile, the interface effect between the short fibers and the hydrogel is beneficial to uniform dispersion of the short fibers and the hydrogel, so that the short fiber reinforced hydrogel with a stable structure is prepared.
The patent is to adopt a method of combining electrostatic spinning short fibers and hydrogel to prepare the drug-loaded short fiber hydrogel composite stent, and the stent can realize in-situ molding under the ultraviolet light condition. The addition of the short fibers enhances the mechanical property of the hydrogel, effectively simulates the natural extracellular matrix structure, and simultaneously can promote the regeneration and repair of tissues by carrying the medicine in the fibers or the hydrogel matrix and realizing the slow release of the medicine.
The invention prepares the aliphatic polyester polymer fiber membrane by utilizing the electrostatic spinning technology, and then the fiber membrane is soaked in diamine solution to carry out amination of the fiber membrane, thereby achieving the purposes of improving hydrophilicity and functionalization. And then blending short fibers, an aldehyde-based natural polymer and a methacryloyl natural polymer, irradiating with ultraviolet, wherein the short fibers and the aldehyde-based natural polymer undergo Schiff base reaction, and the carbon-carbon double bonds of the methacryloyl natural polymer undergo free radical polymerization under the irradiation of ultraviolet, so that the hydrogel forms a stable double-crosslinked network in situ rapidly.
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 invention has industrial implementation prospect.
(2) According to the in-situ formed drug-loaded short fiber hydrogel dressing, the functional modified aliphatic polyester high-molecular short fiber is prepared through ammonolysis and homogenization treatment, schiff base reaction is generated between amino groups on the surface of the functional modified aliphatic polyester high-molecular short fiber and the hydrogel, so that the interfacial acting force between the polymer and the short fiber is favorably regulated, the functional modified aliphatic polyester high-molecular short fiber is uniformly dispersed in the hydrogel, and meanwhile, the stability and mechanical property of the fiber hydrogel can be improved through doping of the short fiber and chemical interaction between the short fiber and the polymer.
(3) The in-situ formed drug-loaded short fiber hydrogel dressing prepared by the invention can realize slow release of drugs.
(4) The invention prepares the in-situ formed drug-loaded short fiber hydrogel dressing.
Drawings
FIG. 1 is a schematic illustration of the preparation of an in situ formed drug-loaded staple fiber hydrogel dressing of the present invention;
FIG. 2 is a photograph of a short fiber scanning electron microscope obtained after the homogenization treatment in example 1;
FIG. 3 is a photograph of a short fiber hydrogel of example 1;
FIG. 4 is a photograph of the short fiber hydrogel of example 1 after injection and in situ molding;
FIG. 5 is a graph showing the compression mechanics of the short fiber hydrogel of example 1;
Fig. 6 is a graph showing the drug release profile of diclofenac sodium loaded staple hydrogels of example 3.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
1. Materials: polylactic acid-glycolic acid copolymer, ratio of lactic acid to glycolic acid 75:25, purchased from jinan Dai biomaterial limited; polylactic acid was purchased from atan-dai, biological materials limited; hexafluoroisopropanol was 99.5% gauge, available from micarin reagent limited; 1, 6-hexamethylenediamine was 99.0% gauge, commercially available from Shanghai Ala Ding Shiji, inc.; the alcoholysis degree of PVA is 87.0-89.0%, and is purchased from Shanghai Ala Ding Shiji Co., ltd; gelatin size was bovine Type a, molecular weight 120000, available from Shanghai Rong En reagent company, inc.; chitosan was purchased from Shanghai Ala Ding Shiji, inc.; methacrylic anhydride was 99.0% gauge, available from Shanghai Aba Ding Shiji Co., ltd; dextran molecular weight 70000, available from Shanghai Ara Ding Shiji, inc.; n, N-dimethylformamide has the specification AR,99.5% (GC) or more, and is available from Shanghai Taitan chemical company, inc.; the specification of methylene dichloride is AR which is more than or equal to 99.5 percent and is purchased from Shanghai Lingfeng chemical reagent Co., ltd; ethylene glycol was AR,98% in size, purchased from shanghai ji to biochemical technologies limited; sodium periodate has an AR specification of 99.5% and is available from wintergreen (Shanghai) chemical industry limited; photoinitiator I2959 was 98.0% specification, available from shanghai rohn reagent limited; the specification of diclofenac sodium is more than or equal to 99.5 percent, and the diclofenac sodium is purchased from Shanghai source leaf biotechnology Co Ltd; aspirin was 99.0% in size and was purchased from beijing enoKai technologies.
A process for the preparation of methacryloylated Gelatin (GM): dissolving gelatin in PBS (phosphate buffer solution) with the gelatin concentration of 5-15%, slowly dripping methacrylic anhydride, fully dissolving at 55 ℃ and the weight ratio of gelatin to methacrylic anhydride of 5:4-6, adding excessive PBS to terminate the reaction, dialyzing the sample, and freeze-drying to obtain the dry GM.
The preparation method of the methacryloyl chitosan comprises the following steps: dissolving chitosan in acetic acid solution, then adding a certain amount of ethanol solution for dilution, slowly dripping methacrylic anhydride, reacting for 12 hours at room temperature, dialyzing a sample, and freeze-drying to obtain the dried methacryloyl chitosan.
2. Test method
Mechanical property test: a HY-940FS microcomputer electronic universal tester is adopted to carry out compression test on cylindrical short fiber hydrogel samples (with the diameter of 10.5mm and the thickness of 10.0 mm), the compression rate is 0.5-5 mm min -1, and ten parallel samples are measured in each group.
In vitro release kinetics assay of drug: and (3) placing the drug-loaded short fiber hydrogel composite stent in 5mL of PBS, releasing the drug at 37 ℃ and 100rpm for -1 min, taking out 2mL of the liquid to be tested in a specific time, and supplementing 2mL of PBS in time for continuous experiments. And detecting the absorbance of the liquid 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 preparation method of the in-situ formed drug-loaded short fiber hydrogel dressing comprises the following steps:
(1) 2g PLGA is dissolved in 10mL hexafluoroisopropanol solution to prepare precursor spinning solution;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun by an electrostatic spinning device, and the fiber film was received through a receiving base material (glossy paper). Wherein, the electrostatic spinning technological parameters are as follows: the spinning voltage is 9kV, the receiving distance is 15cm, the pouring speed is 1mL/h, the temperature is 25+/-2 ℃, and the relative humidity is 50+/-5%;
(4) Immersing the fiber membrane in the step (3) in 2% (w/v) 1, 6-hexamethylenediamine solution at 37 ℃ for 60min, taking out and washing with deionized water for 3 times;
(5) Placing the fiber membrane in the step (4) into 200mL of PVA with the concentration of 0.5% (w/v), and homogenizing by using a homogenizer, wherein the homogenizing process parameters are as follows: the homogenized solution was centrifugally washed 3 times at 8000rpm for 10min to obtain an amino-modified PLGA electrospun staple fiber (APLGA) having an average fiber diameter of 2.4 μm and an average length of 22.2 μm as shown in FIG. 2;
(6) 5g of dextran was dissolved in 125mL of deionized water, stirred until completely dissolved, 5gNaIO 4 was added under dark conditions, stirred at room temperature for 3.5h, then 3mL of ethylene glycol was added dropwise with stirring, and left to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by using a dialysis bag with molecular weight cutoff of 8000-10000, changing water 1 time every 12h during dialysis, and freeze-drying for 2 days to obtain dry oxidized dextran (ODex);
(7) The staple fibers of (5), 0.05g of (6), 0.1g ODex g of GM, 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, then treated by ultrasonic equipment (working frequency is 50 kHz) for 10min to disperse short fibers, and then precursor liquid is irradiated by 365nm ultraviolet light for 10min, so that the in-situ formed drug-loaded short fiber hydrogel dressing is prepared, and 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 by a disposable medical syringe, and the hydrogel is formed in situ by ultraviolet irradiation.
The GM/ODex-APLGA drug loaded staple fiber hydrogel in this example had a compressive strength of 36.2kPa, which was 2.57 fold improved compared to GM/ODex hydrogel without added fiber (fig. 5).
Example 2
The preparation method of the in-situ formed drug-loaded short fiber hydrogel dressing comprises the following steps:
(1) 2g PLGA and 0.02g aspirin were dissolved in 10mL hexafluoroisopropanol solution to formulate a precursor dope;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun by an electrostatic spinning device, and the fiber film was received through a receiving base material (glossy paper). Wherein, the electrostatic spinning technological parameters are as follows: the spinning voltage is 9kV, the receiving distance is 15cm, the pouring speed is 1mL/h, the temperature is 25+/-2 ℃, and the relative humidity is 50+/-5%;
(4) Immersing the fiber membrane in the step (3) in 2% (w/v) 1, 6-hexamethylenediamine solution at 37 ℃ for 60min, taking out and washing with deionized water for 3 times;
(5) Placing the fiber membrane in the step (4) into 200mL of PVA with the concentration of 0.5% (w/v), and homogenizing by using a homogenizer, wherein the homogenizing process parameters are as follows: the rotation speed is 8000rpm, the time is 10min, the homogenized liquid is centrifugally washed for 3 times, and APLGA short fibers are obtained;
(6) 5g of dextran was dissolved in 125mL of deionized water, stirred until completely dissolved, 5gNaIO 4 was added under dark conditions, stirred at room temperature for 3.5h, then 3mL of ethylene glycol was added dropwise with stirring, and left to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by using a dialysis bag with molecular weight cutoff of 8000-10000, changing water 1 time every 12h during dialysis, and freeze-drying for 2 days to obtain dried ODex;
(7) Short fibers 0.05g in (5), 0.1g ODex g in (6), 0.5g of methacryloylated 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 by ultrasonic equipment (the working frequency is 50 kHz) for 10min to disperse short fibers, and then the precursor solution is irradiated by 365nm and ultraviolet light for 10min to prepare the in-situ formed drug-loaded short fiber hydrogel dressing.
Example 3
The preparation method of the in-situ formed drug-loaded short fiber hydrogel dressing comprises the following steps:
(1) 2g PLA was dissolved in 8mL methylene chloride and 2mL N, N-dimethylformamide solution to prepare a precursor dope;
(2) The spinning solution prepared in (1) was placed in a 10mL syringe, and spun by an electrostatic spinning device, and the fiber film was received through a receiving base material (glossy paper). Wherein, the electrostatic spinning technological parameters are as follows: the spinning voltage is 18kV, the receiving distance is 15cm, the pouring speed is 0.8mL/h, the temperature is 25+/-2 ℃, and the relative humidity is 50+/-5%;
(4) Immersing the fiber membrane in the step (3) in 2% (w/v) 1, 6-hexamethylenediamine solution at 37 ℃ for 60min, taking out and washing with deionized water for 3 times;
(5) Placing the fiber membrane in the step (4) into 200mL of PVA with the concentration of 0.5% (w/v), and homogenizing by using a homogenizer, wherein the homogenizing process parameters are as follows: the rotation speed is 8000rpm, the time is 10min, the homogenized liquid is centrifugally washed for 3 times, and APLA short fibers are obtained;
(6) 5g of dextran was dissolved in 250mL of deionized water, stirred until completely dissolved, 5gNaIO 4 was added under dark conditions, stirred at room temperature for 3.5h, then 3mL of ethylene glycol was added dropwise with stirring, and left to stand for half an hour to terminate the reaction. Dialyzing the obtained solution in deionized water for 3 days by using a dialysis bag with molecular weight cutoff of 8000-10000, changing water 1 time every 12h during dialysis, and freeze-drying for 2 days to obtain dried ODex;
(7) The staple fibers of (5), 0.05g of (6), 0.1g ODex g of GM, 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, then treated by ultrasonic equipment (the working frequency is 50 kHz) for 10min 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 GM/ODex-APLA drug-loaded short-fiber hydrogel in the example has a drug accumulated release amount of 64.04% at 36h, and has a good drug slow-release effect.
Claims (10)
1. A method of making a staple fiber hydrogel dressing comprising:
(1) Mixing aliphatic polyester polymer materials with an organic solvent to prepare spinning solution, and preparing a fiber membrane through electrostatic spinning;
(2) Soaking a fiber membrane in a diamine solution, washing, then adding the fiber membrane into a polyvinyl alcohol (PVA) solution, homogenizing, and centrifugally washing to obtain short fibers; wherein the technological parameters of the homogenizing treatment are as follows: the rotation speed is 5000-12000 rpm, and the homogenizing time is 10-60 min; the diamine is one or more of 1, 6-hexamethylenediamine, 1, 2-ethylenediamine and Fmoc-polyethylene glycol-diamine;
(3) And mixing the short fiber, the aldehyde natural polymer, the methacrylic acylated natural polymer, the photoinitiator and the solvent, preparing a mixed solution, and irradiating with ultraviolet light for 2-30 min to obtain the short fiber hydrogel dressing.
2. The preparation method of 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 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 pouring 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 substrate.
4. The method according to claim 1, wherein the diamine solution in the step (2) has a concentration of 0.1 to 10w/v%; the PVA alcoholysis degree is 87.0-89.0%, 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 temperature in the step (2) is 37 ℃ and the soaking treatment time is 0.5-5 h.
6. The preparation method of claim 1, wherein the step (3) is characterized in that the aldehyde-modified natural polymer is obtained by dissolving the natural polymer in a solvent, stirring the mixture under a dark condition until the mixture is uniform, adding sodium periodate (NaIO 4), reacting the mixture at room temperature for 3 to 12 hours, adding an ethylene glycol solution to terminate the reaction, dialyzing the sample, and freeze-drying the sample; the natural polymer is one of dextran, gelatin and hyaluronic acid; the solvent is one of deionized water and PBS.
7. The method according to claim 1, wherein the natural polymer of the methacryloylated 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; 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 methacryloyl 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, which is characterized in that the dressing contains 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 a drug is added to the mixed solution of step (3) based on the preparation method of claim 1;
The mass percentage concentration of the traditional Chinese medicine is 0.1-1%; the medicine is one or more of aspirin, diclofenac sodium and ibuprofen.
10. Use of the drug-loaded short fiber hydrogel dressing of claim 8 in the preparation of skin wound repair materials.
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