WO2025001021A1 - 丝素蛋白水凝胶的制备方法 - Google Patents

丝素蛋白水凝胶的制备方法 Download PDF

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WO2025001021A1
WO2025001021A1 PCT/CN2023/142460 CN2023142460W WO2025001021A1 WO 2025001021 A1 WO2025001021 A1 WO 2025001021A1 CN 2023142460 W CN2023142460 W CN 2023142460W WO 2025001021 A1 WO2025001021 A1 WO 2025001021A1
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solution
preparation
freeze
silk
hydrogel
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张静
张曦昊
詹阳
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Shenzhen Institute of Advanced Technology of CAS
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2355/00—Characterised by the use of homopolymers or copolymers, obtained by polymerisation reactions only involving carbon-to-carbon unsaturated bonds, not provided for in groups C08J2323/00 - C08J2353/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K3/00—Use of inorganic substances as compounding ingredients
    • C08K3/02—Elements
    • C08K3/08—Metals
    • C08K2003/0806—Silver
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K2201/00—Specific properties of additives
    • C08K2201/011—Nanostructured additives

Definitions

  • the present application relates to the technical field of gel materials, and in particular to a method for preparing a silk fibroin hydrogel.
  • Silk fibroin has good biocompatibility, can promote the growth of human cells, and has certain biodegradability. Therefore, silk fibroin has received widespread attention in the fields of textiles, biomedicine, etc.
  • Gel is a physical state between solid and liquid with unique properties, especially hydrogel, which retains a large amount of water and can maintain a certain shape. It is currently widely used in artificial skin, tissue engineering materials, drug release, artificial muscle, biosensors and other aspects.
  • Silk fibroin hydrogel can be prepared from a silk fibroin solution, which will gradually turn into gel when left to stand.
  • Silk fibroin hydrogel can be used in the fields of wound repair, surgical suture, tissue repair, etc.
  • the existing silk fibroin hydrogel has the disadvantages of long gel time and single function (for example, no antibacterial property), which restricts the use of silk fibroin hydrogel.
  • the present application proposes a method for preparing a silk fibroin hydrogel, which has a short gel time and the prepared silk fibroin hydrogel has antibacterial properties.
  • An embodiment of the present application provides a method for preparing a silk fibroin hydrogel, comprising the following steps:
  • Degumming Add silk into sodium carbonate solution and heat to obtain degummed silk;
  • Dialysis dialyzing the reaction solution to obtain a supernatant
  • Freeze-drying freeze-drying the supernatant to obtain freeze-dried protein
  • Gelation mixing the antibacterial agent solution with the photoinitiator solution, then adding the freeze-dried protein to obtain a freeze-dried protein solution, and irradiating the freeze-dried protein solution with blue-violet light to obtain the silk fibroin hydrogel.
  • the antibacterial agent solution includes nano-silver solution, nano-copper solution or nano-zinc solution.
  • the photoinitiator solution is a phenyl (2,4,6-trimethylbenzoyl) lithium phosphate solution, and the mass volume concentration of the photoinitiator solution is 0.25% to 5%.
  • the wavelength of the blue-violet light is 365 nm to 405 nm.
  • the blue-violet light irradiation time is 10 s to 20 s.
  • the preparation method before the dissolving step, further comprises: drying the degummed silk.
  • the preparation method further comprises: centrifuging the reaction solution after dialysis to obtain the supernatant.
  • the molar ratio of the antibacterial agent solution to the photoinitiator solution is (1-2):1.
  • the concentration of the lithium bromide solution is 9.3 mol/L ⁇ 9.5 mol/L.
  • the concentration of the sodium carbonate solution is 0.02 mol/L ⁇ 0.05 mol/L.
  • the present invention uses glycidyl methacrylate to modify degummed silk (silk fibroin), adds an antibacterial agent and a photoinitiator in the gelling step, and uses blue-violet light to cure and crosslink the modified silk fibroin, thereby preparing a silk fibroin hydrogel with antibacterial properties, which can be widely used in the fields of biomedical materials, etc.
  • the preparation method of the present invention is simple and fast, and the gelling speed is fast.
  • FIG. 1 is a UV-visible spectrum of the silk fibroin hydrogels prepared in Example 1 and Comparative Example 1 of the present application.
  • FIG. 2 is the antibacterial ring test results of the silk fibroin hydrogels prepared in Example 1 and Comparative Example 1 of the present application.
  • FIG3 is an experimental result of the antibacterial rate of the silk fibroin hydrogels prepared in Example 1 and Comparative Example 1 of the present application.
  • the present application provides a method for preparing a silk fibroin hydrogel, comprising the steps of degumming, modification, dialysis, freeze-drying and gelation.
  • the main components of silk are sericin and fibroin (SF, a protein, also known as silk protein, silk), of which sericin accounts for about 20%-30% of the weight of silk, and fibroin accounts for about 70%-80% of the weight of silk.
  • the degumming step is to remove the sericin in the silk.
  • the degumming step is specifically: adding the silk to a sodium carbonate (Na 2 CO 3 ) solution, heating until no yellow colloid precipitate is produced (the yellow colloid precipitate is sericin), and obtaining degummed silk (i.e., fibroin).
  • the concentration of the Na 2 CO 3 solution can be, but is not limited to, 0.02 mol/L ⁇ 0.05 mol/L.
  • the concentration of the Na 2 CO 3 solution can be 0.02 mol/L, 0.03 mol/L, 0.04 mol/L, 0.05 mol/L, and the like.
  • the Na 2 CO 3 solution can be heated to boiling, and then the shredded silk (silk cocoon) of mulberry silk is added to the boiling Na 2 CO 3 solution, and the heating is continued to degummed the silk to obtain degummed silk.
  • the degummed silk can be washed with a large amount of deionized water to remove sericin and excess sodium carbonate.
  • the degummed silk may be dried.
  • the degummed silk may be placed in a vacuum drying oven to be dried, so that the degummed silk is completely dehydrated to obtain dry silk fibroin.
  • the modification step is specifically as follows: dissolving the dried degummed silk (dried silk fibroin) in a lithium bromide solution, and then adding glycidyl methacrylate (GMA) to react to obtain a reaction solution.
  • the reaction can be carried out under heating and stirring conditions, and the solid matter is completely dissolved and the solution turns yellow, indicating that the reaction is completed.
  • GMA can be added under light-proof conditions to prevent the raw materials from oxidative decomposition. Due to the special spatial structure of the silk fibroin molecule, it is very easy to form crystals and is difficult to dissolve in water before modification. By methacrylating the silk fibroin with GMA, double bonds can be introduced into the silk fibroin molecule.
  • the modified silk fibroin molecule (SF-GMA) is not easy to crystallize and can be dissolved in water, which allows SF-GMA to be photocured to form a hydrogel in the subsequent steps.
  • the application of GMA stabilizes the reaction, and its main mechanism is the ring opening of epoxides without acidic byproducts.
  • GMA can also promote the reaction with amino groups. In theory, two GMA molecules can react with one free amino group, so the use of GMA can maximize the number of vinyl groups on SF. GMA can also react with the hydroxyl and carboxyl groups in the SF molecule.
  • SF-GMA has a block structure that can load and encapsulate antibacterial agents, so that the formed silk fibroin hydrogel has antibacterial properties.
  • the concentration of the lithium bromide solution is 9.3 mol/L to 9.5 mol/L.
  • the concentration of the lithium bromide solution may be 9.3 mol/L, 9.4 mol/L, 9.5 mol/L, and the like.
  • the dialysis step is specifically as follows: the reaction solution is placed in a dialysis bag, dialyzed for three days, and the water is changed three times a day.
  • the dialysis can remove lithium bromide and impurities such as silk fibroin and GMA that have not reacted completely.
  • the dialyzed SF-GMA can also be centrifuged to take out the supernatant.
  • the speed of the centrifuge can be 5000 rpm, and the time can be 1 h. The speed and time of the centrifugation can be adjusted according to actual needs.
  • the freeze-drying step is specifically as follows: placing the supernatant in a -20°C refrigerator and freezing overnight, and then placing it in a freeze dryer and freeze-drying overnight to obtain a sponge-like (porous) freeze-dried protein.
  • the gelling step is specifically as follows: mixing the antibacterial agent solution with the photoinitiator solution, then adding the freeze-dried protein, stirring and ultrasonic treatment can be performed to promote the dissolution of the freeze-dried protein to obtain a freeze-dried protein solution, and irradiating the freeze-dried protein solution with blue-violet light to obtain the silk fibroin hydrogel with antibacterial properties.
  • the antimicrobial solution includes nano-silver solution, nano-copper solution or nano-zinc solution.
  • the photoinitiator solution is a phenyl (2,4,6-trimethylbenzoyl) lithium phosphate (LAP, CAS No.: 85073-19-4) solution, and the mass volume concentration (w/v) of the photoinitiator solution is 0.25% to 5%.
  • the mass volume concentration of the photoinitiator solution can be 0.25%, 0.30%, 0.40%, 0.50%, 1%, 2%, 3%, 4%, 5%, etc.
  • the molar ratio of the antimicrobial solution to the photoinitiator solution is (1-2): 1.
  • the antimicrobial solution is a nanosilver solution and the photoinitiator solution is a LAP solution
  • the nanosilver solution is added dropwise to the LAP solution, in the mixed solution of the two
  • the content of nanosilver is 0.1 mol
  • the content of LAP is at most 0.1 mol (at this time, the molar ratio of nanosilver to LAP is 1:1) and at least 0.05 mol (at this time, the molar ratio of nanosilver to LAP is 2:1).
  • the wavelength of the blue-violet light is 365 nm to 405 nm.
  • the wavelength of the blue-violet light is 365 nm, 370 nm, 375 nm, 380 nm, 390 nm, 400 nm, 405 nm, etc.
  • the photoinitiator LAP can cause the dissolved freeze-dried protein to undergo a cross-linking reaction under the irradiation of the blue-violet light with a wavelength of 365 nm to 405 nm to form a silk fibroin hydrogel.
  • the blue-violet light irradiation time is 10 s to 20 s.
  • (1) Degumming Add 3.18 g of solid sodium carbonate to 1.5 L of ultrapure water to prepare a sodium carbonate solution with a concentration of 0.02 M (mol/L), and heat the sodium carbonate solution until it boils; weigh 20 g of mulberry silk (silk cocoon), cut it into pieces, and then put the cut mulberry silk into the boiling sodium carbonate solution. Continue heating for about 1 h until no yellow colloid precipitate is produced, indicating that all the sericin has been removed. Stop heating, pour off the sodium carbonate solution, take out the degummed silk, and wash the degummed silk with a large amount of deionized water.
  • Dialysis Place the reaction solution in the beaker into a dialysis tape and dialyze for three days, changing the water three times a day. Then pour the dialyzed liquid into a centrifuge tube, centrifuge it at 5000 rpm for 1 hour, and remove the supernatant.
  • Freeze-drying Freeze the supernatant in a -20°C refrigerator overnight, and then freeze-dry it in a freeze dryer overnight to obtain a sponge-like (porous) freeze-dried protein.
  • the nanosilver solution was mixed with a 0.25% (w/v) LAP solution by a magnetic stirrer and stirred for 5 h to 6 h. In the resulting mixture, the molar ratio of nanosilver to LAP was 1:1.
  • the freeze-dried protein was added to the mixture of nanosilver and LAP, stirred and ultrasonically treated to promote the dissolution of the freeze-dried protein. After the freeze-dried protein was completely dissolved, the freeze-dried protein solution was irradiated with blue-violet light at a wavelength of 365 nm. The transition from liquid to hydrogel state was observed. After irradiation with blue-violet light for more than ten seconds (10 S to 20 S), the silk fibroin hydrogel AgNPs-GSF carrying nanosilver was generated.
  • Nanosilver is not easy to develop drug resistance, and has a strong inhibitory and killing effect on dozens of pathogenic microorganisms such as Escherichia coli, Staphylococcus aureus, Salmonella, Streptococcus pneumoniae, etc.
  • the silk fibroin hydrogel AgNPs-GSF loaded with nanosilver has excellent antibacterial effect. It can release nanosilver particles in the environment to inhibit the growth of bacteria in the environment, and due to the unique bactericidal mechanism of nanosilver, it can avoid making bacteria resistant.
  • Comparative Example 1 the degumming, drying, modification, dialysis, and freeze-drying steps are exactly the same as those in Example 1, and are not repeated here.
  • the difference between Comparative Example 1 and Example 1 is only the gelling step.
  • the gelling step of Comparative Example 1 is: adding the freeze-dried protein to the LAP solution, stirring and ultrasonic treatment to promote the dissolution of the freeze-dried protein. After the freeze-dried protein is completely dissolved, the freeze-dried protein solution is irradiated with blue-violet light with a wavelength of 365 nm to obtain the silk fibroin hydrogel GMA-SF.
  • the AgNPs-GSF aqueous solution before irradiation in the gelling step of Example 1 i.e., the solution after the lyophilized protein is completely dissolved but before light curing
  • the GMA-SF aqueous solution before irradiation in the gelling step of Comparative Example 1 i.e., the solution after the lyophilized protein is completely dissolved but before light curing
  • the nanosilver solution is added to the 96-well plate
  • the aqueous solution is irradiated with blue-violet light (365 nm) in the 96-well plate to cause photocrosslinking to form a hydrogel
  • the 96-well plate is scanned using a microplate reader in the range of 260 nm-700 nm to obtain the UV-visible spectrum shown in Figure 1.
  • the nanosilver solution showed a relatively obvious absorption peak at 415 nm, which was caused by the plasma resonance on its surface.
  • the silk fibroin hydrogel of Example 1 showed a relatively obvious absorption peak at 415 nm, indicating that the nanosilver was successfully loaded into the silk fibroin hydrogel (AgNPs-GSF was obtained) and the original particle size of the nanosilver was maintained.
  • the silk fibroin hydrogel (GMA-SF) of Comparative Example 1 did not show an absorption peak at 415 nm.
  • the antibacterial ring can be used to qualitatively determine whether the material has antibacterial properties. It is a relatively intuitive and convenient method to determine the antibacterial properties of materials. If bacteria can grow on the agar plate around the material, it means that the material has no killing and inhibitory effect on bacteria. If one or more sterile areas appear around the material, this sterile area is called an antibacterial ring. Generally speaking, the larger the antibacterial ring, the better the antibacterial effect of the material.
  • the GMA-SF hydrogel prepared in Comparative Example 1 did not produce an antibacterial ring on the plate inoculated with Staphylococcus aureus and Escherichia coli, indicating that the GMA-SF hydrogel has no antibacterial activity against these two bacteria.
  • the AgNPs-GSF hydrogel produced relatively clear antibacterial rings on the plates inoculated with Staphylococcus aureus and Escherichia coli, indicating that the AgNPs-GSF hydrogel prepared in Example 1 of the present application has a significant inhibitory and killing effect on Staphylococcus aureus and Escherichia coli.
  • Sample preparation The AgNPs-GSF aqueous solution before irradiation in the gelation step of Example 1 (i.e., the solution after the freeze-dried protein is completely dissolved but before light curing) and the GMA-SF aqueous solution before irradiation in the gelation step of Comparative Example 1 are placed in a 48-well plate, and irradiated with blue-violet light (365 nm) in the 48-well plate to solidify into a hydrogel at the bottom of the well plate.
  • blue-violet light 365 nm
  • test samples Add alcohol to the 48-well plate with solidified hydrogel to allow the alcohol to soak into the hydrogel. Then replace the alcohol with PBS (phosphate buffered saline). Repeat this process several times to remove the alcohol to prevent it from affecting the results of the antibacterial experiment. Place the sample under ultraviolet light for 30 min, dry it, and set aside.
  • PBS phosphate buffered saline
  • LB medium preparation Use ultrapure water, trypsin, yeast extract and NaCl to prepare a solution, and then place the solution in a steam sterilizer for high temperature and high pressure sterilization.
  • the culture medium cools to about 40-50°C, use an electric pipette to draw the culture medium into a sterile culture dish (plate), and cool it for use.
  • Co-culture + dilution coating counting test Dilute the bacterial solution (Escherichia coli, Staphylococcus aureus) to 10 6 CFU/mL with LB liquid culture medium, evenly add 400 ⁇ L of the bacterial solution to the samples to be tested in Example 1 and Comparative Example 1, and then place them in a 37°C constant temperature oscillator for oscillation culture for 12 h. After the oscillation culture is completed, dilute the bacterial solution with sterile PBS solution by 10 4 , 10 5 , and 10 6 times, respectively, and take 100 ⁇ L of the diluted bacterial solution and coat it on the culture medium of the plate. Place the inoculated plate in a constant temperature incubator for 18 h, take out the plate, take a picture of it, and count the number of colonies. Three parallel experiments can be performed for each material.
  • the oscillating co-culture-dilution plate method is a common method for testing the sensitivity of bacteria to antimicrobial substances.
  • the material and the bacterial solution are co-cultured and the bacterial solution after co-culture is used for coating. It can more objectively judge the antibacterial rate of the material, and can also quantitatively measure it and calculate the antibacterial rate.
  • the antibacterial rate is calculated according to the following formula: .
  • ⁇ represents the antibacterial rate of AgNPs-GSF prepared in Example 1
  • a represents the total bacterial colony count after oscillation co-culture of GMASF prepared in Comparative Example 1
  • A represents the total bacterial colony count after oscillation co-culture of AgNPs-GSF prepared in Example 1.
  • the colony counts of Staphylococcus aureus in the three culture media after oscillation co-culture of GMASF prepared in Comparative Example 1 were 30, 50 and 87, respectively.
  • the colony counts of Escherichia coli in the three culture media after oscillation co-culture of GMASF prepared in Comparative Example 1 were 56, 61 and 75, respectively.
  • the antibacterial rate of the AgNPs-GSF hydrogel prepared in Example 1 of the present application is 100%.
  • the present invention uses glycidyl methacrylate to modify degummed silk (silk fibroin), adds an antibacterial agent and a photoinitiator in the gelling step, and uses blue-violet light to cure and crosslink the modified silk fibroin, thereby preparing a silk fibroin hydrogel with antibacterial properties, which can be widely used in the fields of biomedical materials, etc.
  • the preparation method of the present invention is simple and fast, and the gelling speed is fast.

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Abstract

本申请提出一种丝素蛋白水凝胶的制备方法，包括如下步骤：将蚕丝加入碳酸钠溶液中，加热，得到脱胶蚕丝；将脱胶蚕丝溶于溴化锂溶液中，加入甲基丙烯酸缩水甘油酯进行反应，得到反应液；将反应液进行透析，得到上清液；将上清液冻干，得到冻干蛋白；将抗菌剂溶液与光引发剂溶液混合，加入冻干蛋白，用蓝紫光照射，得到丝素蛋白水凝胶。本申请利用甲基丙烯酸缩水甘油酯对脱胶蚕丝（丝素）进行改性，并在成胶步骤中加入抗菌剂和光引发剂，利用蓝紫光照射使改性后的丝素发生固化交联，从而制备出具有抗菌性能的丝素蛋白水凝胶，可广泛应用于生物医用材料等领域。本申请的制备方法简单快捷，成胶速度快。

Description

丝素蛋白水凝胶的制备方法 技术领域
本申请涉及凝胶材料技术领域，尤其涉及一种丝素蛋白水凝胶的制备方法。
 背景技术
丝素蛋白具有良好的生物相容性，能够促进人体细胞的生长，具有一定的生物可降解性，因此，丝素蛋白在纺织、生物医学等领域受到了广泛的关注。
凝胶是介于固体与液体之间的一种物理状态，具有独特的性质，尤其是水凝胶，在其中保持有大量的水分，能保持一定的形状，目前被广泛用于人工皮肤、组织工程材料、药物释放、人造肌肉、生物传感器等方面。
丝素蛋白水凝胶可由丝素蛋白溶液制得，丝素蛋白溶液在静置下会逐渐向凝胶化转变。丝素蛋白水凝胶可用于伤口修复、手术缝合、组织修复等领域，但现有的丝素蛋白水凝胶存在凝胶时间较长、功能单一（例如，不具备抗菌性）等缺点，制约了丝素蛋白水凝胶的使用。
发明内容
有鉴于此，本申请提出一种丝素蛋白水凝胶的制备方法，其凝胶时间短，且制得的丝素蛋白水凝胶具有抗菌性能。
本申请一实施方式提供一种丝素蛋白水凝胶的制备方法，包括如下步骤：
脱胶：将蚕丝加入碳酸钠溶液中，加热，得到脱胶蚕丝；
改性：将所述脱胶蚕丝溶于溴化锂溶液中，然后加入甲基丙烯酸缩水甘油酯进行反应，得到反应液；
透析：将所述反应液进行透析，得到上清液；
冻干：将所述上清液冻干，得到冻干蛋白；
成胶：将抗菌剂溶液与光引发剂溶液混合，然后加入所述冻干蛋白，得到冻干蛋白溶液，用蓝紫光照射所述冻干蛋白溶液，得到所述丝素蛋白水凝胶。
一种实施方式中，所述抗菌剂溶液包括纳米银溶液、纳米铜溶液或纳米锌溶液。
一种实施方式中，所述光引发剂溶液为苯基（2,4,6-三甲基苯甲酰基）磷酸锂盐溶液，所述光引发剂溶液的质量体积浓度为0.25%~5%。
一种实施方式中，所述蓝紫光的波长为365 nm~405 nm。
一种实施方式中，所述蓝紫光照射的时间为10 S~20 S。
一种实施方式中，在所述溶解步骤之前，所述制备方法还包括：将所述脱胶蚕丝烘干。
一种实施方式中，所述反应液完成透析后，所述制备方法还包括：对完成透析后的所述反应液进行离心，以得到所述上清液。
一种实施方式中，所述抗菌剂溶液与所述光引发剂溶液的摩尔比为（1~2）:1。
一种实施方式中，所述溴化锂溶液的浓度为9.3 mol/L~9.5 mol/L。
一种实施方式中，所述碳酸钠溶液的浓度为0.02 mol/L~0.05 mol/L。
本申请利用甲基丙烯酸缩水甘油酯对脱胶蚕丝（丝素）进行改性，并在成胶步骤中加入抗菌剂和光引发剂，利用蓝紫光照射使改性后的丝素发生固化交联，从而制备出具有抗菌性能的丝素蛋白水凝胶，可广泛应用于生物医用材料等领域。本申请的制备方法简单快捷，成胶速度快。
 附图说明
图1为本申请实施例1和对比例1制备的丝素蛋白水凝胶的紫外-可见光谱图。
图2为本申请实施例1和对比例1制备的丝素蛋白水凝胶的抑菌环实验结果。
图3为本申请实施例1和对比例1制备的丝素蛋白水凝胶的抗菌率实验结果。
如下具体实施方式将结合上述附图进一步说明本申请实施例。
具体实施方式
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请实施例的技术领域的技术人员通常理解的含义相同。本文中所使用的术语只是为了描述具体的实施方式的目的，不是旨在于限制本申请实施例。
本申请提出一种丝素蛋白水凝胶的制备方法，包括脱胶、改性、透析、冻干和成胶等步骤。
蚕丝的主要成分为丝胶和丝素（SF，一种蛋白质，又可称为丝朊、丝质），其中，丝胶约占蚕丝重量的20%-30%，丝素约占蚕丝重量的70%-80%。脱胶步骤便是将蚕丝中的丝胶去除。所述脱胶步骤具体为：将蚕丝加入碳酸钠（Na 2CO 3）溶液中，加热，直至无黄色胶质沉淀产生（黄色胶质沉淀即丝胶），得到脱胶蚕丝（即丝素）。所述Na 2CO 3溶液的浓度可为但不限于0.02 mol/L~0.05 mol/L。例如，Na 2CO 3溶液的浓度可为0.02 mol/L、0.03 mol/L、0.04 mol/L、0.05 mol/L，等等。Na 2CO 3溶液可先加热至沸腾，然后在沸腾的Na 2CO 3溶液中加入剪碎的桑蚕蚕丝（蚕茧），持续加热，使蚕丝脱胶，得到脱胶蚕丝。脱胶蚕丝可以用大量去离子水清洗，以去除丝胶和多余碳酸钠。
一些实施例中，在脱胶完成后，还可以对所述脱胶蚕丝进行烘干。例如，可将所述脱胶蚕丝置于真空干燥箱中干燥，使得所述脱胶蚕丝完全脱水，得到干燥的丝素。
所述改性步骤具体为：将所述干燥后的脱胶蚕丝（干燥后的丝素）溶于溴化锂溶液中，然后加入甲基丙烯酸缩水甘油酯（GMA）进行反应，得到反应液。反应可在加热并搅拌的条件下进行，固体物质完全溶解且溶液变黄，表明反应结束。GMA可以在避光条件下加入，以免原材料氧化分解。由于丝素分子特殊的空间结构，其在改性前极易形成结晶而难溶于水。通过GMA对丝素进行甲基丙烯酸化改性，可以在丝素分子上引入双键。由于引入额外的化学基团，改性后的丝素分子（SF-GMA）不易结晶，可在水中溶解，这使得SF-GMA可在后续的步骤中可光固化形成水凝胶。GMA的应用使反应稳定，其主要机理是环氧化物开环，没有酸性副产物。此外，GMA还可以促进与氨基的反应。理论上，两个GMA分子可以与一个游离氨基反应，因此，GMA的使用能使SF上的乙烯基数量最大化。GMA还能与SF分子中的羟基和羧基发生反应，这些官能团可以通过酯交换机制（作为次要机制）促进SF的进一步甲基丙烯酸化，增加甲基丙烯酸乙烯酯的量，从而使水凝胶的交联密度最大化，能大幅缩短水凝胶的成胶时间。并且，所述SF-GMA具有嵌段结构，能负载包裹抗菌剂，从而使得形成的丝素蛋白水凝胶具备抗菌性。
一些实施例中，所述溴化锂溶液的浓度为9.3 mol/L~9.5 mol/L。例如，溴化锂溶液的浓度可为9.3 mol/L、9.4 mol/L、9.5 mol/L，等等。
所述透析步骤具体为：将所述反应液装入透析袋中，透析三天，每天换水三次。所述透析能去除溴化锂以及未反应完全的丝素和GMA等杂质。当所述透析袋内的液体由澄清变得浑浊且透析袋膨胀后，表明透析完成。一些实施例中，还可以将透析完的SF-GMA进行离心，取出上清液。离心机的转速可为5000 rpm，时间可为1 h，离心的转速和时间可根据实际需求调整。
所述冻干步骤具体为：将所述上清液置于-20℃冰箱中冷冻过夜，然后再置于冻干机中冷冻干燥过夜，即可得到海绵状（多孔）的冻干蛋白。
所述成胶步骤具体为：将抗菌剂溶液与光引发剂溶液混合，然后加入所述冻干蛋白，可通过搅拌和超声处理以促进所述冻干蛋白的溶解，得到冻干蛋白溶液，用蓝紫光照射所述冻干蛋白溶液，得到所述具有抗菌性的丝素蛋白水凝胶。
一些实施例中，所述抗菌剂溶液包括纳米银溶液、纳米铜溶液或纳米锌溶液。
一些实施例中，所述光引发剂溶液为苯基（2,4,6-三甲基苯甲酰基）磷酸锂盐（LAP，CAS号：85073-19-4）溶液，所述光引发剂溶液的质量体积浓度（w/v）为0.25%~5%。例如，所述光引发剂溶液的质量体积浓度可为0.25%、0.30%、0.40%、0.50%、1%、2%、3%、4%、5%等等。
一些实施例中，所述抗菌剂溶液与所述光引发剂溶液的摩尔比为（1~2）:1。例如，所述抗菌剂溶液为纳米银溶液，所述光引发剂溶液为LAP溶液时，当将纳米银溶液滴加到LAP溶液中时，二者的混合液中，纳米银的含量为0.1 mol时，LAP的含量最高为0.1 mol（此时纳米银与LAP的摩尔比为1:1），最低为0.05 mol（此时纳米银与LAP的摩尔比为2:1）。
一些实施例中，所述蓝紫光的波长为365 nm~405 nm。例如，所述蓝紫光的波长为365 nm、370 nm、375 nm、380 nm、390 nm、400 nm、405 nm等等。光引发剂LAP可在波长为365 nm~405 nm的蓝紫光照射下，使溶解的冻干蛋白发生交联反应，形成丝素蛋白水凝胶。
一些实施例中，所述蓝紫光照射的时间为10 S~20 S。
以下将结合具体实施例对本申请作进一步说明。
实施例1
（1）脱胶：向1.5 L超纯水中加入3.18 g碳酸钠固体，配置成浓度为0.02 M（mol/L）的碳酸钠溶液，加热所述碳酸钠溶液直至其沸腾；称量20 g桑蚕蚕丝（蚕茧），将其剪碎，然后将剪碎的桑蚕蚕丝放入沸腾的碳酸钠溶液中，持续加热1 h左右，直至无黄色胶质沉淀产生，表明丝胶全部去除，停止加热，倒去碳酸钠溶液，取出脱胶蚕丝并用大量去离子水清洗脱胶蚕丝。
（2）烘干：将清洗后的脱胶蚕丝置于真空干燥箱中12 h，使其完全脱水。将脱水的脱胶蚕丝置于精密天平称量，得到15 g左右的干燥丝素。
（3）改性：配置40 ml浓度为9.3 M的溴化锂溶液，取4 g烘干的脱胶蚕丝（干燥丝素）溶于溴化锂溶液中，将盛有溴化锂和丝素溶液的烧杯置于加热搅拌器上，并向烧杯中加入GMA，将加热搅拌器设置为60℃，持续加热搅拌4h，直至固体物质完全溶解且溶液变黄，得到反应液，所述反应液的主要成分为改性后的丝素分子（SF-GMA）。
（4）透析：将烧杯中的反应液装入透析带中，透析三天，每天换水三次。然后将透析完的液体倒入离心管中，放入离心机中以5000 rpm的转速离心1h，取出上清液。
（5）冻干：将上清液置于-20℃冰箱中冷冻过夜，然后再置于冻干机中冷冻干燥过夜，即可得到海绵状（多孔）的冻干蛋白。
（6）成胶：将纳米银溶液与浓度为0.25%（w/v）的LAP溶液通过磁力搅拌器混合，磁力搅拌器搅拌5 h~6 h，得到的混合液中，纳米银与LAP的摩尔比为1:1。将冻干蛋白加入纳米银和LAP的混合液中，搅拌并超声处理以促进冻干蛋白的溶解。冻干蛋白完全溶解后，用波长为365 nm的蓝紫光照射冻干蛋白溶液，可观察到液态向水凝胶态转变，蓝紫光照射十余秒（10 S~20 S）后便生成了携带纳米银的丝素蛋白水凝胶AgNPs-GSF。
纳米银不易产生耐药性，对大肠杆菌、金黄色葡萄球菌、沙门氏菌、肺炎链球菌等数十种致病微生物都有强烈的抑制和杀灭作用。负载有纳米银的丝素蛋白水凝胶AgNPs-GSF具有优良的抑菌作用，它可以在环境中释放纳米银颗粒，抑制环境中细菌的生长，并且因纳米银独特的杀菌机理从而能避免使细菌产生耐药性。
对比例1
对比例1中，脱胶、烘干、改性、透析、冻干步骤与实施例1中的完全相同，此处不再赘述。对比例1与实施例1的区别仅在于成胶步骤不同，对比例1的成胶步骤为：将冻干蛋白加入LAP溶液中，搅拌并超声处理以促进冻干蛋白的溶解。冻干蛋白完全溶解后，用波长为365 nm的蓝紫光照射冻干蛋白溶液，得到丝素蛋白水凝胶GMA-SF。
测试例1：紫外-可见光谱
将实施例1成胶步骤中光照前的AgNPs-GSF水溶液（即冻干蛋白完全溶解后但未进行光照固化前的溶液）加入到96孔板中，将对比例1成胶步骤中光照前的GMA-SF水溶液（即冻干蛋白完全溶解后但未进行光照固化前的溶液）加入到96孔板中，将纳米银溶液加入到96孔板中，然后在96孔板中使用蓝紫光（365 nm）对水溶液进行照射使其发生光交联形成水凝胶，然后使用酶标仪在260 nm-700 nm的范围内对96孔板进行扫描，得到图1所示的紫外-可见光谱图。
如图1所示，纳米银溶液在415 nm处出现较为明显的吸收峰，这是由其表面的等离子体共振所引起的。实施例1的丝素蛋白水凝胶在415 nm处出现了较为明显的吸收峰，表明纳米银成功地负载到丝素蛋白水凝胶中（得到了AgNPs-GSF），并保持了纳米银原有的粒径。对比例1的丝素蛋白水凝胶（GMA-SF）在415 nm未出现吸收峰。
测试例2：抑菌环测试
（1）准备水凝胶样品：准备直径 10 mm的金属片若干，使用移液枪将实施例1成胶步骤中光照前的AgNPs-GSF水溶液（即冻干蛋白完全溶解后但未进行光照固化前的溶液）涂抹在金属片两面上，每面涂抹量为50 μL，涂抹后使用蓝紫光（365 nm）照射使其固化。对照组使用对比例1成胶步骤中光照前的GMA-SF水溶液（即冻干蛋白完全溶解后但未进行光照固化前的溶液）重复上述操作。每组取三个样品，并在固化之后用紫外照射灭菌封存备用。
（2）配置LB培养基：使用超纯水、胰蛋白胨、酵母提取物和NaCl配置培养基溶液，然后将溶液放入蒸汽灭菌锅中高温高压灭菌。待培养基溶液冷却至40-50℃左右，用电动移液器吸取培养基倒入无菌培养皿（平板）中，冷却待用。
（3）涂布细菌：使用移液枪取适量的菌液（大肠杆菌）接种于冷却后的固体培养基上，然后使用无菌涂布棒均匀地将菌液涂布在培养基表面，得到接种有大肠杆菌的个平板。按照相同步骤，得到接种有金黄色葡萄球菌的平板。
（4）放置材料：用镊子将上述涂有均匀水凝胶的金属片放置于平板正中间并轻压使其贴附，然后将平板倒置放入37℃恒温培养箱中。
（5）观察结果：从培养箱中培育12 h后取出，观察菌落的生长和抑菌环的生成情况并进行记录，结果如图2所示。
通过抑菌环可以定性地判断材料是否具有抑菌性能，是一种较为直观且方便的判断材料抑菌性能的方法。如果细菌可以在材料周围的琼脂平板上生长，说明材料对细菌没有杀灭和抑制的作用。如果材料周围出现一个或多个无菌区域，这个无菌区域被称为抑菌环，一般来说，抑菌环越大，说明材料的抗菌效果越好。
请参阅图2，对比例1制得的GMA-SF水凝胶在接种有金黄色葡萄球菌和大肠杆菌的平板上并没有产生抑菌环，说明GMA-SF水凝胶对这两种细菌没有抑菌性。而在实施例1中，AgNPs-GSF水凝胶在接种有金黄色葡萄球菌和大肠杆菌的平板上均出现了较为清晰的抑菌圈，这说明本申请实施例1制得的AgNPs-GSF水凝胶对金黄色葡萄球菌和大肠杆菌均有着明显的抑制和杀伤作用。
测试例3：抗菌率测试
（1）样品的制备：将实施例1成胶步骤中光照前的AgNPs-GSF水溶液（即冻干蛋白完全溶解后但未进行光照固化前的溶液）和对比例1成胶步骤中光照前的GMA-SF水溶液水溶液置于48孔板中，并在48孔板中对其进行蓝紫光（365 nm）照射使其在孔板底部固化成水凝胶。
（2）待测样品制备：向固化有水凝胶的48孔板中加入酒精，使酒精浸泡水凝胶，然后用PBS（磷酸缓冲液）置换酒精，重复多次，去除酒精，以免酒精对抗菌实验结果产生影响，并将样品置于紫外线下照射30 min后，晾干，备用。
（3）LB培养基配置：使用超纯水、胰蛋白胨、酵母提取物和NaCl配置溶液，然后将溶液放入蒸汽灭菌锅中高温高压灭菌。待培养基冷却至40-50℃左右，用电动移液器吸取培养基倒入无菌培养皿（平板）中，冷却待用。
（4）共培养+稀释涂布计数测试：用LB液体培养基将菌液（大肠杆菌、金黄色葡萄球菌）稀释至10 6CFU/mL，分别在实施例1和对比例1的待测样品中均匀滴加400 μL菌液，然后放于37℃恒温振荡器中振荡培养12 h。振荡培养完成后，用无菌PBS溶液将菌液分别稀释10 4、10 5、10 6倍数后，取100μL稀释后的菌液涂布于平板的培养基上。将接种后的平板置于恒温培养箱中培养18h，取出平板，对其进行拍照，并计算菌落数，每种材料可做三次平行实验。
振荡共培养-稀释涂布平板法是一种常见的用于测试细菌对抗菌物质的敏感性的方法，使材料和菌液共培养，并使用共培养之后的菌液进行涂布，能较为客观地评判材料的抗菌率，并可以对其进行定量的测量，计算出抗菌率。
抗菌率测试的实验结果如图3所示。由图3可知，即使是在最小的稀释倍数（10 4）的情况下，实施例1制得的AgNPs-GSF水凝胶共培养的实验组中，无论是对于大肠杆菌还是金黄色葡萄球菌，都没有菌落生成（细菌总菌落数为0）。而在对比例1制得的GMA-SF水凝胶共培养的对照组中，在10 4的稀释倍数下，两种菌的菌落几乎长满了平板，表明本申请实施例1制备的AgNPs-GSF水凝胶具有优异的抗菌性能。
抗菌率按照下列公式进行计算： 。其中，η表示实施例1制得的AgNPs-GSF的抗菌率，a表示对比例1制得的GMASF振荡共培养后的细菌总菌落数，A表示实施例1制得的AgNPs-GSF振荡共培养后的细菌总菌落数。在10 6的稀释倍数下，对比例1制得的GMASF振荡共培养后的三个培养基中，金黄色葡萄球菌的菌落数分别为30个、50个和87个。在10 6的稀释倍数下，对比例1制得的GMASF振荡共培养后的三个培养基中，大肠杆菌的菌落数分别为56个、61个和75个。本申请实施例1制备的AgNPs-GSF水凝胶，抗菌率为100%。
本申请利用甲基丙烯酸缩水甘油酯对脱胶蚕丝（丝素）进行改性，并在成胶步骤中加入抗菌剂和光引发剂，利用蓝紫光照射使改性后的丝素发生固化交联，从而制备出具有抗菌性能的丝素蛋白水凝胶，可广泛应用于生物医用材料等领域。本申请的制备方法简单快捷，成胶速度快。
以上说明是本申请一些具体实施方式，但在实际的应用过程中不能仅仅局限于这些实施方式。对本领域的普通技术人员来说，根据本申请的技术构思做出的其他变形和改变，都应该属于本申请的保护范围。

Claims (10)

  1. 一种丝素蛋白水凝胶的制备方法，其特征在于，所述制备方法包括如下步骤：
    脱胶：将蚕丝加入碳酸钠溶液中，加热，得到脱胶蚕丝；
    改性：将所述脱胶蚕丝溶于溴化锂溶液中，然后加入甲基丙烯酸缩水甘油酯进行反应，得到反应液；
    透析：将所述反应液进行透析，得到上清液；
    冻干：将所述上清液冻干，得到冻干蛋白；
    成胶：将抗菌剂溶液与光引发剂溶液混合，然后加入所述冻干蛋白，得到冻干蛋白溶液，用蓝紫光照射所述冻干蛋白溶液，得到所述丝素蛋白水凝胶。
  2. 如权利要求1所述的制备方法，其特征在于，所述抗菌剂溶液包括纳米银溶液、纳米铜溶液或纳米锌溶液。
  3. 如权利要求1所述的制备方法，其特征在于，所述光引发剂溶液为苯基（2,4,6-三甲基苯甲酰基）磷酸锂盐溶液，所述光引发剂溶液的质量体积浓度为0.25%~5%。
  4. 如权利要求1所述的制备方法，其特征在于，所述蓝紫光的波长为365 nm~405 nm。
  5. 如权利要求1所述的制备方法，其特征在于，所述蓝紫光照射的时间为10 S~20 S。
  6. 如权利要求1所述的制备方法，其特征在于，在所述溶解步骤之前，所述制备方法还包括：将所述脱胶蚕丝烘干。
  7. 如权利要求1所述的制备方法，其特征在于，所述反应液完成透析后，所述制备方法还包括：对完成透析后的所述反应液进行离心，以得到所述上清液。
  8. 如权利要求1所述的制备方法，其特征在于，所述抗菌剂溶液与所述光引发剂溶液的摩尔比为（1~2）:1。
  9. 如权利要求1所述的制备方法，其特征在于，所述溴化锂溶液的浓度为9.3 mol/L~9.5 mol/L。
  10. 如权利要求1所述的制备方法，其特征在于，所述碳酸钠溶液的浓度为0.02 mol/L~0.05 mol/L。
PCT/CN2023/142460 2023-06-29 2023-12-27 丝素蛋白水凝胶的制备方法 Ceased WO2025001021A1 (zh)

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