WO2022179255A1 - Antibacterial sodium alginate tissue engineering scaffold and preparation method therefor and use thereof - Google Patents

Antibacterial sodium alginate tissue engineering scaffold and preparation method therefor and use thereof Download PDF

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WO2022179255A1
WO2022179255A1 PCT/CN2021/137747 CN2021137747W WO2022179255A1 WO 2022179255 A1 WO2022179255 A1 WO 2022179255A1 CN 2021137747 W CN2021137747 W CN 2021137747W WO 2022179255 A1 WO2022179255 A1 WO 2022179255A1
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sodium alginate
tissue engineering
engineering scaffold
antibacterial
antibacterial sodium
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PCT/CN2021/137747
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Chinese (zh)
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阮长顺
胡成深
胡楠
唐澜
张欣洲
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中国科学院深圳先进技术研究院
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    • 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
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • 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
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/04—Alginic acid; Derivatives thereof

Definitions

  • the invention belongs to the technical field of biomedical materials, and in particular relates to an antibacterial sodium alginate tissue engineering scaffold and a preparation method and application thereof.
  • Sodium alginate is a linear polyanionic polysaccharide extracted from natural brown algae or bacteria. Its molecular chain is rich in hydroxyl and carboxyl groups. It is a polyanionic electrolyte with very good biocompatibility. It has been widely used in tissue project. The superior rheological properties of sodium alginate itself indicate that it is a very good potential 3D printing bioink precursor.
  • tissue engineering bioinks has the following problems: sodium alginate has poor mechanical properties and is easily soluble in water. In addition, sodium alginate does not have antibacterial properties, which limits its application in the field of tissue engineering. .
  • tissue engineering applications the threat posed by bacterial infection has always been a difficult problem to solve. Infectious diseases caused by tissue engineering scaffold transplantation threaten people's health. The antimicrobial properties of tissue engineering scaffolds are very important.
  • Some inventions use different chemical groups for grafting, for example CN 109851846 A discloses simultaneous grafting of hexamethyleneguanidine.
  • the method of directly mixing the mixed drug into the sodium alginate prevents the prepared sodium alginate stent from being released for a long time.
  • Simultaneous grafting of hexamethylene guanidine (patent number CN 109851846 A) to prepare antibacterial sodium alginate material has the following disadvantages: the reaction cannot be carried out at room temperature, and there are many steps, and the operation is cumbersome; this method crosslinks sodium alginate in one step Prepared into a sponge, there is no intermediate state with a certain viscosity that can be further processed by 3D printing, and it is difficult to apply to 3D printing processing; the stent cannot release drugs slowly to prevent systemic infection.
  • the purpose of the present invention is to provide an antibacterial sodium alginate tissue engineering scaffold and its preparation method and application.
  • aminoglycoside antibiotics rich in amino groups are used as cationic compounds, and sodium alginate is used as anionic compounds, and bio-ink is first prepared by a blending method. Under electrostatic complexation, the bio-ink can be processed and formed by 3D printing.
  • Antibacterial sodium alginate tissue engineering scaffold precursor After printing, the precursor of the antibacterial sodium alginate tissue engineering scaffold is immersed in the EDC/NHS solution for further cross-linking to obtain the antibacterial sodium alginate tissue engineering scaffold. The principle of this step is that the EDC/NHS solution activates the sodium alginate.
  • the carboxyl group on the aminoglycoside antibiotic makes it undergo an amidation reaction with the amino group rich in aminoglycoside antibiotics to form an amide bond, resulting in a cross-linking effect.
  • the antibacterial sodium alginate tissue engineering scaffold can release aminoglycoside antibiotics along with the degradation of amide bonds, so as to achieve the effect of slow-release antibiotics.
  • the present invention provides a preparation method of an antibacterial sodium alginate tissue engineering scaffold, comprising the following steps:
  • the bio-ink includes sodium alginate, aminoglycoside antibiotics, and solvent;
  • bio-ink is processed by 3D printing to obtain an antibacterial sodium alginate tissue engineering scaffold precursor
  • the preparation of the bio-ink is as follows: the bio-ink is prepared by blending the components of the bio-ink including sodium alginate, aminoglycoside antibiotics and a solvent.
  • aminoglycoside antibiotics include at least one of streptomycin, gentamicin, kanamycin, ribomycin, and amikacin.
  • the solvent is a solvent that does not chemically react with sodium alginate and aminoglycoside antibiotics; preferably, the solvent includes common solvents such as water and 1,4 dioxane.
  • the solvent is used to adjust the viscosity, and the content of the solvent can be adjusted freely according to printing needs, as long as it can be molded.
  • the reagent used to activate the carboxyl group on the sodium alginate in the antibacterial sodium alginate tissue engineering scaffold precursor is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDC) and N-hydroxysuccinimide (NHS). Further, the molar ratio of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to N-hydroxysuccinimide is 2:1 to 1:2.
  • step (3) is specifically as follows: immersing the antibacterial sodium alginate tissue engineering scaffold precursor in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) mixed solution for 15-45 minutes to obtain the antibacterial sodium alginate tissue engineering scaffold, the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • step (2) freeze-drying the precursor of the antibacterial sodium alginate tissue engineering scaffold is also included.
  • step (3) freeze-drying the antibacterial sodium alginate tissue engineering scaffold is also included.
  • the present invention provides an antibacterial sodium alginate tissue engineering scaffold prepared by any of the above-mentioned methods for preparing an antibacterial sodium alginate tissue engineering scaffold.
  • the present invention provides an application of the above-mentioned antibacterial sodium alginate tissue engineering scaffold in the field of tissue engineering.
  • the bioink of the present invention has certain viscosity and rheological properties before cross-linking, and can be prepared by 3D printing;
  • Cross-linking the cross-linked tissue engineering scaffold has the performance of long-term sustained release of antibacterial drugs, which can be well used in 3D printing tissue engineering.
  • the aminoglycoside antibiotics are used for electrostatic complexation with sodium alginate, and then the 3D printing antibacterial sodium alginate tissue engineering scaffold precursor is prepared.
  • the preparation of the antibacterial sodium alginate tissue engineering scaffold precursor was completed, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide were used (NHS) activates the carboxyl group on sodium alginate to chemically cross-link it with the amino group on aminoglycoside antibiotics to form an antibacterial sodium alginate tissue engineering scaffold.
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Fig. 1 is the actual example diagram of the antibacterial sodium alginate tissue engineering scaffold prepared in the embodiment of the present invention 1;
  • Fig. 2 is the result diagram of putting the bio-ink prepared in Example 1 of the present invention into a beaker and then inverting it;
  • Example 3 is a result diagram of the bioink prepared in Example 1 of the present invention after being soaked in EDC/NHS solution and then inverted;
  • Example 4 is a structural diagram of the bioink prepared in Example 1 of the present invention using a rheometer for rheological testing;
  • Example 5 is a graph showing the cumulative release curve of the antibacterial sodium alginate tissue engineering scaffold gentamicin sulfate prepared in Example 1 of the present invention.
  • a preparation method of an antibacterial sodium alginate tissue engineering scaffold comprising the following steps:
  • bio-ink is prepared by mixing sodium alginate, gentamicin sulfate, and water, and stirring for 10 minutes.
  • the solid content of the ink is 10%;
  • step 3 The bioink prepared in step 1) was tested by a rheometer, and the shear rate was changed from 0s -1 to 100s -1 . The results are shown in Figure 4. It can be seen from Figure 4 that step 1 ) The bioinks prepared have shear thinning properties.
  • the bioink of the present invention has certain viscosity and rheological properties before crosslinking, and can be prepared for 3D printing.
  • the antibacterial sodium alginate tissue engineering scaffold prepared in step 4) can sustainably The slow-release antibiotic, the aminoglycoside antibiotic (gentamicin sulfate), released only about 20% at day 20, indicating long-term drug release. That is, the antibacterial sodium alginate tissue engineering scaffold can gradually release gentamicin sulfate with the degradation of the cross-linked structure in an environment that simulates body fluids.

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Abstract

Disclosed are an antibacterial sodium alginate tissue engineering scaffold, a preparation method therefor and use thereof. The preparation method comprises the following steps: (1) preparing a biological ink comprising sodium alginate, amino glycoside antibiotics, and a solvent; (2) performing 3D printing processing molding on the biological ink to obtain an antibacterial sodium alginate tissue engineering scaffold precursor; and (3) activating the carboxyl group on sodium alginate in the antibacterial sodium alginate tissue engineering scaffold precursor, and amidating same with an amino group on amino glycoside antibiotics to generate a cross-link, so as to obtain the antibacterial sodium alginate tissue engineering scaffold. The antibacterial sodium alginate tissue engineering scaffold can slowly release amino glycoside antibiotics while being degraded, thereby achieving an antibacterial effect.

Description

一种抗菌海藻酸钠组织工程支架及其制备方法和应用A kind of antibacterial sodium alginate tissue engineering scaffold and preparation method and application thereof 技术领域technical field
本发明属于生物医用材料技术领域，具体涉及一种抗菌海藻酸钠组织工程支架及其制备方法和应用。The invention belongs to the technical field of biomedical materials, and in particular relates to an antibacterial sodium alginate tissue engineering scaffold and a preparation method and application thereof.
背景技术Background technique
海藻酸钠是一种线性聚阴离子多糖，从天然的褐藻或者细菌中提取，其分子链上具有丰富的羟基和羧基，是一种生物相容性非常好的聚阴离子电解质，已广泛用于组织工程。海藻酸钠自身优越的流变性能表明其是一种非常好的潜在的3D打印生物墨水前体。然而，将海藻酸钠用于组织工程生物墨水，存在以下问题：海藻酸钠力学性能较差，在水中易溶解，另外，海藻酸钠不具备抗菌性能，这限制了它在组织工程领域的应用。Sodium alginate is a linear polyanionic polysaccharide extracted from natural brown algae or bacteria. Its molecular chain is rich in hydroxyl and carboxyl groups. It is a polyanionic electrolyte with very good biocompatibility. It has been widely used in tissue project. The superior rheological properties of sodium alginate itself indicate that it is a very good potential 3D printing bioink precursor. However, the use of sodium alginate for tissue engineering bioinks has the following problems: sodium alginate has poor mechanical properties and is easily soluble in water. In addition, sodium alginate does not have antibacterial properties, which limits its application in the field of tissue engineering. .
现有技术方案中，为了解决海藻酸钠的力学性能较差，通常在将海藻酸钠3D打印成型后使用钙离子对其进行交联，交联后的海藻酸钠能够具有更好的力学性能。此外，聚阳离子如聚赖氨酸等也被用于两步交联海藻酸钠制备生物打印墨水。但是用钙离子交联制备的海藻酸钠支架以及用聚赖氨酸两步交联制备的海藻酸钠支架都无法令成型后的海藻酸钠支架具备抗菌性能。In the prior art solution, in order to solve the poor mechanical properties of sodium alginate, calcium ions are usually used to cross-link the sodium alginate after 3D printing, and the cross-linked sodium alginate can have better mechanical properties. . In addition, polycations such as polylysine have also been used for two-step cross-linking of sodium alginate to prepare bioprinting inks. However, the sodium alginate scaffold prepared by calcium ion cross-linking and the sodium alginate scaffold prepared by two-step cross-linking of polylysine could not make the formed sodium alginate scaffold have antibacterial properties.
组织工程应用中，由细菌感染带来的威胁一直是一个难以解决的问题。由组织工程支架移植带来的感染性疾病威胁着人们的健康。组织工程支架的抗菌性能非常重要。为了解决海藻酸钠的抗菌性能，许多人采用直接混合药物的方法。有些发明用不同的化学基团进行接枝，比如CN 109851846 A公开了同步接枝六亚甲基胍。但是直接将混合药物混入海藻酸钠的方法令制备完成的海藻酸钠支架无法长久释放。同步接枝六亚甲基胍（专利号CN 109851846 A）制备抗菌海藻酸钠材料存在以下缺点：该反应无法在室温下进行，且步骤较多，操作繁琐；该方法一步交联将海藻酸钠制备成海绵，不存在能够进行3D打印进一步加工的具有一定黏度的中间态，难以应用于3D打印加工成型；该支架无法缓释药物用于防止全身感染。In tissue engineering applications, the threat posed by bacterial infection has always been a difficult problem to solve. Infectious diseases caused by tissue engineering scaffold transplantation threaten people's health. The antimicrobial properties of tissue engineering scaffolds are very important. In order to solve the antibacterial properties of sodium alginate, many people adopt the method of directly mixing drugs. Some inventions use different chemical groups for grafting, for example CN 109851846 A discloses simultaneous grafting of hexamethyleneguanidine. However, the method of directly mixing the mixed drug into the sodium alginate prevents the prepared sodium alginate stent from being released for a long time. Simultaneous grafting of hexamethylene guanidine (patent number CN 109851846 A) to prepare antibacterial sodium alginate material has the following disadvantages: the reaction cannot be carried out at room temperature, and there are many steps, and the operation is cumbersome; this method crosslinks sodium alginate in one step Prepared into a sponge, there is no intermediate state with a certain viscosity that can be further processed by 3D printing, and it is difficult to apply to 3D printing processing; the stent cannot release drugs slowly to prevent systemic infection.
技术问题technical problem
为了解决上述背景技术中所提出的技术问题，本发明的目的在于提供一种抗菌海藻酸钠组织工程支架及其制备方法和应用。本发明以富含氨基的氨基糖苷类抗生素作为阳离子化合物，以海藻酸钠作为阴离子化合物，先采用共混的方法制备生物墨水，在静电络合作用下，该生物墨水能够通过3D打印加工成型得到抗菌海藻酸钠组织工程支架前体。打印成型后，将抗菌海藻酸钠组织工程支架前体浸入EDC/NHS溶液中进行进一步交联，得到所述抗菌海藻酸钠组织工程支架，该步骤的原理是由于EDC/NHS溶液活化海藻酸钠上的羧基，令其与氨基糖苷类抗生素上富含的氨基进行酰胺化反应生成酰胺键，产生交联的效果。所述抗菌海藻酸钠组织工程支架能随着酰胺键的降解释放出氨基糖苷类抗生素，达到缓释抗生素的效果。In order to solve the technical problems raised in the above background technology, the purpose of the present invention is to provide an antibacterial sodium alginate tissue engineering scaffold and its preparation method and application. In the present invention, aminoglycoside antibiotics rich in amino groups are used as cationic compounds, and sodium alginate is used as anionic compounds, and bio-ink is first prepared by a blending method. Under electrostatic complexation, the bio-ink can be processed and formed by 3D printing. Antibacterial sodium alginate tissue engineering scaffold precursor. After printing, the precursor of the antibacterial sodium alginate tissue engineering scaffold is immersed in the EDC/NHS solution for further cross-linking to obtain the antibacterial sodium alginate tissue engineering scaffold. The principle of this step is that the EDC/NHS solution activates the sodium alginate. The carboxyl group on the aminoglycoside antibiotic makes it undergo an amidation reaction with the amino group rich in aminoglycoside antibiotics to form an amide bond, resulting in a cross-linking effect. The antibacterial sodium alginate tissue engineering scaffold can release aminoglycoside antibiotics along with the degradation of amide bonds, so as to achieve the effect of slow-release antibiotics.
技术解决方案technical solutions
为了达到上述目的，本发明所采用的技术方案为：一方面，本发明提供了一种抗菌海藻酸钠组织工程支架的制备方法，包括以下步骤：In order to achieve the above purpose, the technical scheme adopted in the present invention is as follows: on the one hand, the present invention provides a preparation method of an antibacterial sodium alginate tissue engineering scaffold, comprising the following steps:
（1）生物墨水的制备：所述生物墨水包括海藻酸钠、氨基糖苷类抗生素、溶剂；(1) Preparation of bio-ink: the bio-ink includes sodium alginate, aminoglycoside antibiotics, and solvent;
（2）将生物墨水通过3D打印加工成型，得到抗菌海藻酸钠组织工程支架前体；(2) The bio-ink is processed by 3D printing to obtain an antibacterial sodium alginate tissue engineering scaffold precursor;
（3）活化所述抗菌海藻酸钠组织工程支架前体中海藻酸钠上的羧基，使其与氨基糖苷类抗生素上的氨基进行酰胺化反应产生交联，得到所述抗菌海藻酸钠组织工程支架。(3) activating the carboxyl group on the sodium alginate in the precursor of the antibacterial sodium alginate tissue engineering scaffold, so that it undergoes an amidation reaction with the amino group on the aminoglycoside antibiotic to generate cross-linking, so as to obtain the antibacterial sodium alginate tissue engineering bracket.
进一步地，所述生物墨水的制备具体为：将包括海藻酸钠、氨基糖苷类抗生素、溶剂的生物墨水的组份进行共混制备得到所述生物墨水。Further, the preparation of the bio-ink is as follows: the bio-ink is prepared by blending the components of the bio-ink including sodium alginate, aminoglycoside antibiotics and a solvent.
进一步地，所述氨基糖苷类抗生素包括链霉素、庆大霉素、卡那霉素、核糖霉素、阿米卡星中的至少一种。Further, the aminoglycoside antibiotics include at least one of streptomycin, gentamicin, kanamycin, ribomycin, and amikacin.
进一步地，所述溶剂为不与海藻酸钠和氨基糖苷类抗生素发生化学反应的溶剂；优选地，所述溶剂包括水、1，4二氧六环等常见溶剂。所述溶剂用于调节粘度，根据打印需要，自由调节溶剂含量，只要能成型即可。进一步地，所述海藻酸钠所含羧基与氨基糖苷类抗生素所含氨基的摩尔比为3:1～2:1；所述氨基包括-NH 2、-NH-、NH=C-中的至少一种； Further, the solvent is a solvent that does not chemically react with sodium alginate and aminoglycoside antibiotics; preferably, the solvent includes common solvents such as water and 1,4 dioxane. The solvent is used to adjust the viscosity, and the content of the solvent can be adjusted freely according to printing needs, as long as it can be molded. Further, the molar ratio of the carboxyl group contained in the sodium alginate to the amino group contained in the aminoglycoside antibiotic is 3:1 to 2:1; the amino group includes at least one of -NH 2 , -NH-, and NH=C- A sort of;
进一步地，活化所述抗菌海藻酸钠组织工程支架前体中海藻酸钠上的羧基所用的试剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS）的混合溶液。进一步地，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为2:1～1:2。Further, the reagent used to activate the carboxyl group on the sodium alginate in the antibacterial sodium alginate tissue engineering scaffold precursor is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDC) and N-hydroxysuccinimide (NHS). Further, the molar ratio of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to N-hydroxysuccinimide is 2:1 to 1:2.
进一步地，步骤（3）具体为：将所述抗菌海藻酸钠组织工程支架前体浸入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS）的混合溶液15～45分钟，得到所述抗菌海藻酸钠组织工程支架，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为2:1～1:2。Further, step (3) is specifically as follows: immersing the antibacterial sodium alginate tissue engineering scaffold precursor in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) mixed solution for 15-45 minutes to obtain the antibacterial sodium alginate tissue engineering scaffold, the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The molar ratio of amine hydrochloride and N-hydroxysuccinimide is 2:1 to 1:2.
进一步地，步骤（2）和步骤（3）之间还包括将抗菌海藻酸钠组织工程支架前体进行冷冻干燥。Further, between step (2) and step (3), freeze-drying the precursor of the antibacterial sodium alginate tissue engineering scaffold is also included.
进一步地，步骤（3）后还包括将抗菌海藻酸钠组织工程支架进行冷冻干燥。Further, after step (3), freeze-drying the antibacterial sodium alginate tissue engineering scaffold is also included.
另一方面，本发明提供了一种上述任一所述的抗菌海藻酸钠组织工程支架的制备方法制备得到的抗菌海藻酸钠组织工程支架。On the other hand, the present invention provides an antibacterial sodium alginate tissue engineering scaffold prepared by any of the above-mentioned methods for preparing an antibacterial sodium alginate tissue engineering scaffold.
再一方面，本发明提供了一种上述所述的抗菌海藻酸钠组织工程支架在组织工程领域中的应用。In another aspect, the present invention provides an application of the above-mentioned antibacterial sodium alginate tissue engineering scaffold in the field of tissue engineering.
有益效果beneficial effect
本发明的有益效果是：本发明生物墨水交联之前具有一定的粘度和流变特性，能够进行3D打印成型的制备；3D打印成型后能够在不破坏基本结构的情况下，用温和的方法进一步交联；交联后的组织工程支架具有长久缓释抗菌药物的性能，能够很好的应用于3D打印组织工程。The beneficial effects of the present invention are as follows: the bioink of the present invention has certain viscosity and rheological properties before cross-linking, and can be prepared by 3D printing; Cross-linking; the cross-linked tissue engineering scaffold has the performance of long-term sustained release of antibacterial drugs, which can be well used in 3D printing tissue engineering.
本发明采用氨基糖苷类抗生素与海藻酸钠进行静电力络合，随后进行3D打印抗菌海藻酸钠组织工程支架前体制备。当抗菌海藻酸钠组织工程支架前体制备完成后，再用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS）活化海藻酸钠上的羧基，令其与氨基糖苷类抗生素上的氨基进行化学交联，形成抗菌海藻酸钠组织工程支架。抗菌海藻酸钠组织工程支架在降解的同时能够缓释氨基糖苷类抗生素，达到抗菌的效果。In the present invention, the aminoglycoside antibiotics are used for electrostatic complexation with sodium alginate, and then the 3D printing antibacterial sodium alginate tissue engineering scaffold precursor is prepared. After the preparation of the antibacterial sodium alginate tissue engineering scaffold precursor was completed, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide were used (NHS) activates the carboxyl group on sodium alginate to chemically cross-link it with the amino group on aminoglycoside antibiotics to form an antibacterial sodium alginate tissue engineering scaffold. The antibacterial sodium alginate tissue engineering scaffold can slowly release aminoglycoside antibiotics while degrading to achieve antibacterial effect.
附图说明Description of drawings
图1为本发明实施例1中制备得到的抗菌海藻酸钠组织工程支架的实物示例图；Fig. 1 is the actual example diagram of the antibacterial sodium alginate tissue engineering scaffold prepared in the embodiment of the present invention 1;
图2为本发明实施例1中制备得到的生物墨水放入烧杯中然后倒置的结果图；Fig. 2 is the result diagram of putting the bio-ink prepared in Example 1 of the present invention into a beaker and then inverting it;
图3为本发明实施例1中制备得到的生物墨水浸泡EDC/NHS溶液后然后倒置的结果图；3 is a result diagram of the bioink prepared in Example 1 of the present invention after being soaked in EDC/NHS solution and then inverted;
图4为本发明实施例1中制备得到的生物墨水采用流变仪进行流变学测试的结构图；4 is a structural diagram of the bioink prepared in Example 1 of the present invention using a rheometer for rheological testing;
图5为本发明实施例1制备得到的抗菌海藻酸钠组织工程支架硫酸庆大霉素的累积释放曲线图。5 is a graph showing the cumulative release curve of the antibacterial sodium alginate tissue engineering scaffold gentamicin sulfate prepared in Example 1 of the present invention.
本发明的实施方式Embodiments of the present invention
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。In order to better understand the content of the present invention, the content of the present invention will be further described below in conjunction with specific implementation methods, but the protection content of the present invention is not limited to the following examples.
实施例1Example 1
一种生物墨水，包括海藻酸钠（购自西格玛奥德里奇的海藻酸钠，1摩尔的海藻酸钠含有1摩尔的羧基，由于海藻酸钠属于高分子，因此把其中一个重复单元称为1mol）、硫酸庆大霉素（购自麦克林的硫酸庆大霉素，1摩尔的硫酸庆大霉素含有5摩尔的氨基）、水；所述海藻酸钠与硫酸庆大霉素的摩尔比为15：1（羧基：氨基=3：1）。A bio-ink, including sodium alginate (sodium alginate purchased from Sigma-Aldrich, 1 mole of sodium alginate contains 1 mole of carboxyl group, since sodium alginate is a polymer, one of the repeating units is called 1mol ), gentamicin sulfate (gentamicin sulfate purchased from McLean, 1 mole of gentamicin sulfate contains 5 moles of amino groups), water; the molar ratio of the sodium alginate to gentamicin sulfate It is 15:1 (carboxyl:amino=3:1).
一种抗菌海藻酸钠组织工程支架的制备方法，包括以下步骤：A preparation method of an antibacterial sodium alginate tissue engineering scaffold, comprising the following steps:
1）生物墨水的制备：将海藻酸钠、硫酸庆大霉素、水进行混合后搅拌10min制备得到生物墨水，墨水固含量为10%；1) Preparation of bio-ink: The bio-ink is prepared by mixing sodium alginate, gentamicin sulfate, and water, and stirring for 10 minutes. The solid content of the ink is 10%;
2）用3D打印机将生物墨水进行3D打印加工成型，得到抗菌海藻酸钠组织工程支架前体；喷嘴压力为60Kpa，喷嘴移动速度为10mm/s，打印支架的参数为10mm*10mm*35mm；2) 3D printing the bioink with a 3D printer to obtain an antibacterial sodium alginate tissue engineering scaffold precursor; the nozzle pressure is 60Kpa, the nozzle moving speed is 10mm/s, and the parameters of the printing scaffold are 10mm*10mm*35mm;
3）将抗菌海藻酸钠组织工程支架前体进行冷冻干燥；3) freeze-dry the precursor of the antibacterial sodium alginate tissue engineering scaffold;
4）将冷冻干燥后的抗菌海藻酸钠组织工程支架前体浸入EDC/NHS的混合溶液（EDC的浓度为1.0M，NHS的浓度为0.5M）30分钟，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为2：1，取出洗涤后冷冻干燥得到所述抗菌海藻酸钠组织工程支架，如图1所示。4) Immerse the freeze-dried antibacterial sodium alginate tissue engineering scaffold precursor in a mixed solution of EDC/NHS (the concentration of EDC is 1.0M, and the concentration of NHS is 0.5M) for 30 minutes. The molar ratio of aminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 2:1, and the antibacterial sodium alginate tissue engineering scaffold is obtained by freeze drying after taking out and washing, as shown in the figure 1 shown.
性能测试：Performance Testing:
1、将步骤1）制备得到的生物墨水放入烧杯中然后倒置，结果如图2所示，从图2可以看出，生物墨水具有流动性能够进行打印。1. Put the bioink prepared in step 1) into a beaker and turn it upside down. The result is shown in Figure 2. It can be seen from Figure 2 that the bioink has fluidity and can be printed.
2、将EDC/NHS的混合溶液（EDC的浓度为1.0M，NHS的浓度为0.5M，所述EDC和NHS的摩尔比为2：1）倒入步骤1）制备得到的生物墨水中，没过上表面，浸泡30min后然后进行倒置，结果如图3所示，从图3可以看出，生物墨水交联成凝胶，流动性丧失，颜色变深。2. Pour the mixed solution of EDC/NHS (the concentration of EDC is 1.0M, the concentration of NHS is 0.5M, and the molar ratio of EDC and NHS is 2:1) into the bioink prepared in step 1). Passing over the upper surface, soaking for 30 min and then inverting, the results are shown in Figure 3. It can be seen from Figure 3 that the bioink is cross-linked into a gel, the fluidity is lost, and the color becomes darker.
3、将步骤1）制备得到的生物墨水采用流变仪进行流变学测试，剪切速率由0s -1变化至100s -1，结果如图4所示，从图4可以看出，步骤1）制备得到的生物墨水具有剪切变稀性能。本发明生物墨水交联之前具有一定的粘度和流变特性，能够进行3D打印成型的制备。 3. The bioink prepared in step 1) was tested by a rheometer, and the shear rate was changed from 0s -1 to 100s -1 . The results are shown in Figure 4. It can be seen from Figure 4 that step 1 ) The bioinks prepared have shear thinning properties. The bioink of the present invention has certain viscosity and rheological properties before crosslinking, and can be prepared for 3D printing.
4、测试步骤4）中制备得到的抗菌海藻酸钠组织工程支架中硫酸庆大霉素的长期缓释效果。具体为将步骤4）中制备得到的抗菌海藻酸钠组织工程支架浸入模拟体液中，用酶标仪测量每日测试溶液中硫酸庆大霉素的浓度，计算得到硫酸庆大霉素的释放含量，并与硫酸庆大霉素的总含量进行比较，绘制出累积释放曲线，结果如图5所示，从图5可以看出，步骤4）中制备得到的抗菌海藻酸钠组织工程支架能够持续缓慢释放抗菌药物氨基糖苷类抗生素（硫酸庆大霉素），在第20天时仅释放了约20%，表明能够进行长期释放药物。即抗菌海藻酸钠组织工程支架在模拟体液的环境下，能够随着交联结构的降解，逐步释放硫酸庆大霉素。4. Test the long-term sustained-release effect of gentamicin sulfate in the antibacterial sodium alginate tissue engineering scaffold prepared in step 4). Specifically, the antibacterial sodium alginate tissue engineering scaffold prepared in step 4) is immersed in the simulated body fluid, and the concentration of gentamicin sulfate in the daily test solution is measured with a microplate reader, and the release content of gentamicin sulfate is calculated. , and compared with the total content of gentamicin sulfate to draw a cumulative release curve, the results are shown in Figure 5, it can be seen from Figure 5 that the antibacterial sodium alginate tissue engineering scaffold prepared in step 4) can sustainably The slow-release antibiotic, the aminoglycoside antibiotic (gentamicin sulfate), released only about 20% at day 20, indicating long-term drug release. That is, the antibacterial sodium alginate tissue engineering scaffold can gradually release gentamicin sulfate with the degradation of the cross-linked structure in an environment that simulates body fluids.
以上所述仅为本发明的具体实施方式，不是全部的实施方式，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。The above descriptions are only specific embodiments of the present invention, not all of the embodiments. Any equivalent transformations to the technical solutions of the present invention that are taken by those of ordinary skill in the art by reading the description of the present invention are covered by the claims of the present invention. .

Claims (10)

  1. 一种抗菌海藻酸钠组织工程支架的制备方法，其特征在于，包括以下步骤：A method for preparing an antibacterial sodium alginate tissue engineering scaffold, comprising the following steps:
    （1）生物墨水的制备：所述生物墨水包括海藻酸钠、氨基糖苷类抗生素、溶剂；(1) Preparation of bio-ink: the bio-ink includes sodium alginate, aminoglycoside antibiotics, and solvent;
    （2）将生物墨水通过3D打印加工成型，得到抗菌海藻酸钠组织工程支架前体；(2) The bio-ink is processed by 3D printing to obtain an antibacterial sodium alginate tissue engineering scaffold precursor;
    （3）活化所述抗菌海藻酸钠组织工程支架前体中海藻酸钠上的羧基，使其与氨基糖苷类抗生素上的氨基进行酰胺化反应产生交联，得到所述抗菌海藻酸钠组织工程支架。(3) activating the carboxyl group on the sodium alginate in the precursor of the antibacterial sodium alginate tissue engineering scaffold, so that it undergoes an amidation reaction with the amino group on the aminoglycoside antibiotic to generate cross-linking, so as to obtain the antibacterial sodium alginate tissue engineering bracket.
  2. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，所述生物墨水的制备具体为：将包括海藻酸钠、氨基糖苷类抗生素、溶剂的生物墨水的组份进行共混制备得到所述生物墨水。The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein the preparation of the bio-ink is as follows: the components of the bio-ink comprising sodium alginate, aminoglycoside antibiotics, and a solvent are prepared The bioink is prepared by blending.
  3. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，所述氨基糖苷类抗生素包括链霉素、庆大霉素、卡那霉素、核糖霉素、阿米卡星中的至少一种。The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein the aminoglycoside antibiotics include streptomycin, gentamicin, kanamycin, ribomycin, amica at least one of the stars.
  4. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，所述溶剂为不与海藻酸钠和氨基糖苷类抗生素发生化学反应的溶剂；优选地，所述溶剂包括水、1，4二氧六环。The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein the solvent is a solvent that does not chemically react with sodium alginate and aminoglycoside antibiotics; preferably, the solvent comprises water , 1,4 dioxane.
  5. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，所述海藻酸钠所含羧基与氨基糖苷类抗生素所含氨基的摩尔比为3:1～2:1；所述氨基包括-NH 2、-NH-、NH=C-中的至少一种。 The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein the molar ratio of the carboxyl group contained in the sodium alginate to the amino group contained in the aminoglycoside antibiotic is 3:1 to 2:1; The amino group includes at least one of -NH 2 , -NH-, and NH=C-.
  6. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，活化所述抗菌海藻酸钠组织工程支架前体中海藻酸钠上的羧基所用的试剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS）的混合溶液。The preparation method of the antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein the reagent used for activating the carboxyl group on the sodium alginate in the antibacterial sodium alginate tissue engineering scaffold precursor is 1-(3- A mixed solution of dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS).
  7. 根据权利要求6所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为2:1～1:2。The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 6, wherein the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N- The molar ratio of hydroxysuccinimide is 2:1 to 1:2.
  8. 根据权利要求1所述的抗菌海藻酸钠组织工程支架的制备方法，其特征在于，步骤（3）具体为：将所述抗菌海藻酸钠组织工程支架前体浸入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS）的混合溶液15～45分钟，得到所述抗菌海藻酸钠组织工程支架，所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为2:1～1:2。The method for preparing an antibacterial sodium alginate tissue engineering scaffold according to claim 1, wherein step (3) is specifically: immersing the antibacterial sodium alginate tissue engineering scaffold precursor in 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) mixed solution for 15 to 45 minutes to obtain the antibacterial sodium alginate tissue engineering scaffold, the The molar ratio of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide is 2:1-1:2.
  9. 权利要求1-8任一项所述的抗菌海藻酸钠组织工程支架的制备方法制备得到的抗菌海藻酸钠组织工程支架。The antibacterial sodium alginate tissue engineering scaffold prepared by the method for preparing an antibacterial sodium alginate tissue engineering scaffold according to any one of claims 1-8.
  10. 权利要求9所述的抗菌海藻酸钠组织工程支架在组织工程领域中的应用。Application of the antibacterial sodium alginate tissue engineering scaffold of claim 9 in the field of tissue engineering.
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