技术领域technical field
本发明涉及一种水凝胶制备方法，特别是可注射型水凝胶制备方法，应用于再生医学、组织工程、药物控释等技术领域。The invention relates to a preparation method of hydrogel, in particular to a preparation method of injectable hydrogel, which is applied in the technical fields of regenerative medicine, tissue engineering, drug controlled release and the like.
背景技术Background technique
水凝胶是亲水的聚合物网络，它能够吸收大量的水分，但由于聚合物链间的物理交联和化学交联作用而不会溶解于水中，只能溶涨且保持一定的形状。水凝胶具有良好的生物相容性、水渗透性，通过人工合成可得到不同微观结构和性能的水凝胶材料，这些性质使水凝胶在生物医学领域获得了广泛的应用。在再生医学领域，可注射水凝胶的研究尤其引人注目。可注射水凝胶可用于生物活性分子控释、细胞的包埋以及用作组织支架材料等方面。水凝胶在体内原位形成，这样就可避免外科手术过程中的高度创伤性，加速愈合、减少病人痛苦、降低医疗费用。特别当用于修复复杂形状的组织时，可注射水凝胶具有自适应性，可体温固化，这是一般水凝胶不可比拟的。可以说，可注射水凝胶是未来生物医用材料应用发展的重要方向之一。Hydrogel is a hydrophilic polymer network, which can absorb a large amount of water, but will not dissolve in water due to the physical cross-linking and chemical cross-linking between polymer chains, and can only swell and maintain a certain shape. Hydrogels have good biocompatibility and water permeability, and hydrogel materials with different microstructures and properties can be obtained through artificial synthesis. These properties make hydrogels widely used in the field of biomedicine. In the field of regenerative medicine, research into injectable hydrogels has been particularly compelling. Injectable hydrogels can be used for controlled release of bioactive molecules, embedding of cells, and as tissue scaffolding materials. Hydrogels are formed in situ in the body, which can avoid highly traumatic surgical procedures, accelerate healing, reduce patient pain, and reduce medical costs. Especially when used to repair complex-shaped tissues, injectable hydrogels are self-adaptive and can be cured at body temperature, which is unmatched by general hydrogels. It can be said that injectable hydrogel is one of the important directions for the application and development of biomedical materials in the future.
可注射水凝胶按形成机理可分为物理交联水凝胶和化学交联水凝胶。物理交联水凝胶的分子链通过非共价键连接，如范德华作用、离子作用、氢键作用和疏水作用等一些次价力作用所形成的交联网状结构，而这些水凝胶一般都可以由溶胶-凝胶状态之间相互转变。但是物理交联作用力较弱，容易在pH值、离子强度等外界条件发生变化时遭到破坏，机械性能较差，故在实际应用上受到一定的限制。化学交联水凝胶则通过交联剂使分子链由共价键作用形成三维交联的网络结构，性能较物理交联水凝胶稳定，具有较高的交联密度和较好的机械性能，并且能够通过调节交联剂的用量来控制凝胶的交联度和溶胀度。但化学交联水凝胶使用有一定毒副作用的低分子交联剂或者改性剂，不可避免地带来生物相容性问题。Injectable hydrogels can be divided into physical cross-linked hydrogels and chemical cross-linked hydrogels according to the formation mechanism. The molecular chains of physically cross-linked hydrogels are connected by non-covalent bonds, such as cross-linked structures formed by secondary valence forces such as van der Waals interactions, ionic interactions, hydrogen bonds, and hydrophobic interactions. These hydrogels are generally Interchange between sol-gel states is possible. However, the physical cross-linking force is weak, it is easy to be destroyed when the external conditions such as pH value and ionic strength change, and the mechanical properties are poor, so it is limited in practical application. The chemically cross-linked hydrogel uses a cross-linking agent to make the molecular chains form a three-dimensional cross-linked network structure through covalent bonds. The performance is more stable than that of the physical cross-linked hydrogel, with higher cross-linking density and better mechanical properties. , and the degree of cross-linking and swelling of the gel can be controlled by adjusting the amount of cross-linking agent. However, chemically cross-linked hydrogels use low-molecular cross-linking agents or modifiers with certain toxic and side effects, which inevitably brings about biocompatibility problems.
可注射水凝胶的材料来源主要分为合成和天然高分子。后者包括蛋白质和多糖，具有细胞外基质类似的生化结构与组成，生物相容性好，价格低廉，材料来源广泛。壳聚糖是一种天然的氨基葡萄糖聚合物，带正电荷，其结构与细胞外基中多糖相似，在体内的降解产物为氨基葡萄糖单体，能被人体所吸收。此外，壳聚糖还具有良好的生物相容性，对组织无不良反应，并且来源广泛，价格便宜，在组织工程中应用广泛。由于其分子内、分子间的氢键作用，使其呈紧密的晶态结构，所以不溶于水和大多数有机溶剂。溶解性差成为限制壳聚糖应用的主要因素。The sources of materials for injectable hydrogels are mainly divided into synthetic and natural polymers. The latter includes proteins and polysaccharides, has a biochemical structure and composition similar to the extracellular matrix, has good biocompatibility, is cheap, and has a wide range of sources. Chitosan is a natural glucosamine polymer with a positive charge. Its structure is similar to the polysaccharide in the extracellular matrix. The degradation product in the body is glucosamine monomer, which can be absorbed by the human body. In addition, chitosan also has good biocompatibility, has no adverse reaction to tissues, has a wide range of sources, is cheap, and is widely used in tissue engineering. Due to the hydrogen bond between its molecules and molecules, it has a compact crystalline structure, so it is insoluble in water and most organic solvents. Poor solubility has become the main factor limiting the application of chitosan.
发明内容Contents of the invention
为了解决现有技术问题，本发明的目的在于克服已有技术存在的不足，提供一种多重交联多糖可注射型水凝胶制备方法，以壳聚糖为主要组分，以多糖类高分子或多糖类高分子混合物作为第二组分，对两组分进行改性，通过席夫碱反应及静电作用获得机械性能好、生物相容性良好并且能够快速成型的可注射用壳聚糖多重交联水凝胶。本发明对壳聚糖进行水溶性改性，使其能够应用于低成本和安全的可注射水凝胶体系。In order to solve the problems of the prior art, the object of the present invention is to overcome the deficiencies in the prior art, and provide a method for preparing a multi-crosslinked polysaccharide injectable hydrogel, with chitosan as the main component and polysaccharides with high Molecule or polysaccharide polymer mixture is used as the second component, and the two components are modified to obtain injectable chitosan with good mechanical properties, good biocompatibility and rapid prototyping through Schiff base reaction and electrostatic interaction. Sugar multiple cross-linked hydrogels. The invention carries out water-solubility modification on chitosan, so that it can be applied to a low-cost and safe injectable hydrogel system.
为达到上述发明创造目的，本发明采用下述技术方案：In order to achieve the above invention creation purpose, the present invention adopts the following technical solutions:
一种多重交联多糖可注射型水凝胶制备方法，以经过化学改性后具有羧基基团或羟基基团的水溶性壳聚糖作为第一组分，以进行醛基化化学改性的多糖类高分子或进行醛基化化学改性的多糖类高分子混合物作为第二组分，通过两种改性的组分之间的静电作用和希夫碱反应，获得具有多重交联网络结构的水凝胶。A preparation method for injectable hydrogel of multiple cross-linked polysaccharides, using water-soluble chitosan with carboxyl groups or hydroxyl groups after chemical modification as the first component to carry out aldydization chemical modification Polysaccharide polymers or polysaccharide polymer mixtures chemically modified by formylation are used as the second component, and a multi-crosslinked network is obtained through electrostatic interaction and Schiff base reaction between the two modified components. structured hydrogels.
作为本发明优选的技术方案，分别制备质量浓度为0.5~3wt%的改性壳聚糖水溶液和质量浓度为0.5~3wt%的醛基化改性多糖水溶液，分别作为第一组分和第二组分，将两组分以体积比9:1~1:9混合，通过两种改性的组分之间的静电作用和希夫碱反应，获得具有多重交联网络结构的水凝胶。As the preferred technical scheme of the present invention, the aqueous solution of modified chitosan and the aqueous solution of 0.5 ~ 3wt% mass concentration of modified chitosan and mass concentration are respectively prepared as the first component and the second component respectively Components, the two components are mixed at a volume ratio of 9:1 to 1:9, and the hydrogel with multiple cross-linked network structures is obtained through the electrostatic interaction and Schiff base reaction between the two modified components.
作为本发明更加优选的技术方案，以羟基酸类改性剂或酸酐类改性剂对壳聚糖进行化学改性，获得具有羧基基团或羟基基团的水溶性壳聚糖，羟基酸类改性剂采用羟基乙酸、乳酸或乳糖酸，酸酐类改性剂采用丁二酸酐、戊二酸酐或己二酸酐。As a more preferred technical scheme of the present invention, chitosan is chemically modified with a hydroxyacid modifier or an acid anhydride modifier to obtain water-soluble chitosan with a carboxyl group or a hydroxyl group, and the hydroxyacids The modifier is glycolic acid, lactic acid or lactobionic acid, and the anhydride modifier is succinic anhydride, glutaric anhydride or adipic anhydride.
作为上述技术方案的第一种优选方案，配制质量百分比浓度为0.1~1wt%的壳聚糖水溶液，按改性剂与壳聚糖重复单元摩尔比0.5:1~6:1，向壳聚糖水溶液中加入羟基酸类改性剂之后，按N-羟基琥珀酰亚胺或1-羟基苯并三唑与壳聚糖重复单元摩尔比为0.5:1~3:1的加到上述溶液中溶解，调节溶液pH为4~7，加入活化剂1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐，按照1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐与N-羟基琥珀酰亚胺摩尔比为0.5:1~5:1，将活化剂加入壳聚糖水溶液体系。使壳聚糖水溶液体系反应进行1~48h之后，将壳聚糖水溶液体系的pH值调至7，然后产物透析冻干，即得到经过羟基酸类改性的具有羟基基团的水溶性壳聚糖。N-羟基琥珀酰亚胺或1-羟基苯并三唑并不是羟基酸类改性剂，是一种辅助活化剂，来作为活化剂1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐的补充，起提高活化效率的作用。As the first preferred version of the above-mentioned technical scheme, the chitosan aqueous solution that the mass percent concentration is prepared is 0.1 ~ 1wt%, according to the molar ratio of modifying agent and chitosan repeating unit 0.5:1 ~ 6:1, to chitosan After adding hydroxyacid modifier to the aqueous solution, add N-hydroxysuccinimide or 1-hydroxybenzotriazole to chitosan repeating unit molar ratio of 0.5:1~3:1 into the above solution for dissolution , adjust the pH of the solution to be 4~7, add activator 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, according to 1-ethyl-3-(3-dimethyl The molar ratio of aminopropyl) carbodiimide hydrochloride to N-hydroxysuccinimide is 0.5:1 to 5:1, and the activator is added to the chitosan aqueous solution system. After reacting the chitosan aqueous solution system for 1~48h, the pH value of the chitosan aqueous solution system is adjusted to 7, and then the product is dialyzed and freeze-dried to obtain a water-soluble chitosan with hydroxyl groups modified by hydroxy acids. sugar. N-Hydroxysuccinimide or 1-Hydroxybenzotriazole is not a hydroxyacid modifier, but a co-activator, used as an activator 1-Ethyl-3-(3-Dimethylaminopropane Base) supplementation of carbodiimide hydrochloride plays a role in improving the activation efficiency.
作为上述技术方案的第二种优选方案，配制质量百分比浓度为0.1~1wt%的壳聚糖水溶液，按改性剂与壳聚糖重复单元摩尔比0.5:1~6:1，向壳聚糖水溶液中加入酸酐类改性剂，使壳聚糖水溶液体系反应进行10~48h之后产物丙酮沉淀，将壳聚糖水溶液体系的pH值调至7，然后将产物透析冻干，即得到经过酸酐类改性的具有羟基基团的水溶性壳聚糖。As the second preferred version of the above-mentioned technical scheme, the chitosan aqueous solution that the mass percent concentration is prepared is 0.1 ~ 1wt%, and the molar ratio of modifier and chitosan repeating unit is 0.5:1 ~ 6:1, and the chitosan An acid anhydride modifier is added to the aqueous solution to react the chitosan aqueous solution system for 10 to 48 hours, and then the product acetone precipitates, and the pH value of the chitosan aqueous solution system is adjusted to 7, and then the product is dialyzed and freeze-dried to obtain an anhydride-treated product. Modified water-soluble chitosan with hydroxyl groups.
作为上述技术方案的优选方案，采用氧化剂，对重复单元含邻羟基或相邻羟基/氨基的多糖进行氧化改性，得到醛基化改性的多糖衍生物。As a preferred solution of the above technical solution, an oxidizing agent is used to oxidize and modify polysaccharides whose repeating units contain adjacent hydroxyl groups or adjacent hydroxyl groups/amino groups to obtain aldydated polysaccharide derivatives.
作为上述技术方案的更加优选方案，配制质量百分比浓度为0.1~1wt%的多糖类高分子水溶液，加入氧化剂，氧化剂与多糖高分子重复单元摩尔比为0.1:1~1:1，在避光条件下反应1~5h之后，再向多糖类高分子水溶液体系中加入乙二醇，乙二醇与氧化剂摩尔比为1:1~2:1，然后将改性产物透析冻干，即得到醛基化改性的多糖衍生物。As a more preferred solution of the above-mentioned technical solution, prepare an aqueous polysaccharide polymer solution with a mass percentage concentration of 0.1 to 1 wt%, add an oxidizing agent, and the molar ratio of the oxidizing agent to the polysaccharide polymer repeating unit is 0.1:1 to 1:1. After reacting for 1 to 5 hours under the same conditions, add ethylene glycol to the polysaccharide polymer aqueous solution system, the molar ratio of ethylene glycol to oxidant is 1:1 to 2:1, and then dialyze and freeze-dry the modified product to obtain Aldehydated polysaccharide derivatives.
上述氧化剂优选采用高碘酸钠、重铬酸钾、双氧水或亚硫酸钠。The above-mentioned oxidant is preferably sodium periodate, potassium dichromate, hydrogen peroxide or sodium sulfite.
上述多糖类高分子优选采用羧甲基壳聚糖、透明质酸、羧甲基纤维素或海藻酸钠。 The above-mentioned polysaccharide polymer is preferably carboxymethyl chitosan, hyaluronic acid, carboxymethyl cellulose or sodium alginate. the
本发明与现有技术相比较，具有如下显而易见的突出实质性特点和显著优点：Compared with the prior art, the present invention has the following obvious outstanding substantive features and significant advantages:
1. 本发明针对化学交联水凝胶和物理交联水凝胶的缺陷，制备了基于静电作用及希夫碱化学交联的可注射水凝胶，对壳聚糖进行化学改性，引入羧基、羟基等基团，制备在中性条件下溶解的水溶性壳聚糖，将羧酸盐类多糖进行部分氧化处理，得到醛基化多糖衍生物，通过改性壳聚糖上的氨基与醛基化多糖衍生物上的醛基之间的席夫碱反应以及氨基与多糖上羧基之间的静电作用，成功制备得到了壳聚糖可注射水凝胶；1. The present invention aims at the defects of chemical cross-linked hydrogel and physical cross-linked hydrogel, prepares injectable hydrogel based on electrostatic interaction and chemical cross-linking of Schiff base, chemically modifies chitosan, introduces carboxyl, hydroxyl and other groups, to prepare water-soluble chitosan dissolved under neutral conditions, and to partially oxidize carboxylate polysaccharides to obtain aldylated polysaccharide derivatives. By modifying the amino groups on chitosan and Chitosan injectable hydrogel was successfully prepared through the Schiff base reaction between the aldehyde groups on the aldylated polysaccharide derivatives and the electrostatic interaction between the amino groups and the carboxyl groups on the polysaccharides;
2. 本发明制备的水凝胶可有效避免小分子交联剂的使用，提高了水凝胶的生物相容性，同时可增强单一作用水凝胶的稳定性和机械强度；2. The hydrogel prepared by the present invention can effectively avoid the use of small molecule cross-linking agents, improve the biocompatibility of the hydrogel, and simultaneously enhance the stability and mechanical strength of the single-action hydrogel;
3. 本发明制备的可注射水凝胶成胶时间在5~200s之间，采用多重交联的成胶工艺，使得该水凝胶具有良好的机械性能，通过改变壳聚糖及多糖的改性率、两组分的摩尔比以及水凝胶的固含量可以对成胶时间、力学强度、微观形貌、含水量进行调控；3. The gelation time of the injectable hydrogel prepared by the present invention is between 5 and 200s, and the gelation process of multiple cross-linking is adopted, so that the hydrogel has good mechanical properties. By changing chitosan and polysaccharide The gelation time, mechanical strength, microscopic morphology, and water content can be adjusted by the property ratio, the molar ratio of the two components, and the solid content of the hydrogel;
4. 本发明制备的水凝胶的凝胶网络内部含有的大量氨基、羧基、醛基等活性基团，可以通过共价键与药物及蛋白结合；4. A large number of active groups such as amino groups, carboxyl groups, and aldehyde groups contained in the gel network of the hydrogel prepared by the present invention can be combined with drugs and proteins through covalent bonds;
5. 本发明制备的水凝胶作为一种新型的生物相容性优良的新型医用材料，在组织工程、药物控释、再生医学等领域有良好的应用前景。5. As a new type of medical material with excellent biocompatibility, the hydrogel prepared by the present invention has good application prospects in the fields of tissue engineering, drug controlled release, and regenerative medicine.
具体实施方式Detailed ways
本发明的优选实施例详述如下：Preferred embodiments of the present invention are described in detail as follows:
实施例一：Embodiment one:
在本实施例中，一种多重交联多糖可注射型水凝胶制备方法，其制备过程如下：In this example, a method for preparing a multiple cross-linked polysaccharide injectable hydrogel, the preparation process is as follows:
称取0.3g壳聚糖，溶于100ml水中，加入0.264mL乳酸，待完全搅拌溶解后，加入N-羟基琥珀酰亚胺0.424g，调节pH至4.8，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐1.411g，反应36h，将pH调到7.0。产物透析冻干；称取海藻酸2.5g加入到50mL的水中，在水浴中搅拌溶解，待完全溶解后，加入高碘酸钠1.08g，在避光条件下反应3h，加入600μL乙二醇终止反应。产物透析冻干。分别将改性壳聚糖和海藻酸配制成0.5wt%的水溶液，等体积混合，156s后得到水凝胶，储能模量为132 pa。Weigh 0.3g chitosan, dissolve it in 100ml water, add 0.264mL lactic acid, after stirring and dissolving completely, add 0.424gN -hydroxysuccinimide, adjust the pH to 4.8, 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride 1.411g, reacted for 36h, and adjusted the pH to 7.0. The product was dialyzed and freeze-dried; Weighed 2.5g of alginic acid and added it to 50mL of water, stirred and dissolved in a water bath, after it was completely dissolved, added 1.08g of sodium periodate, reacted for 3h under dark conditions, and added 600μL of ethylene glycol to stop reaction. The product was dialyzed and lyophilized. The modified chitosan and alginic acid were respectively prepared into 0.5wt% aqueous solution, mixed in equal volumes, and a hydrogel was obtained after 156s with a storage modulus of 132 Pa.
本实施例通过静电作用和希夫碱化学交联制备具有多重交联结构的水凝胶，并赋予其良好的机械性能。通过改变壳聚糖及另一组分多糖的改性率、两组分的摩尔比以及水凝胶的固含量可以对成胶时间、力学强度、微观形貌、含水量进行调控。凝胶网络内部含有的大量氨基和醛基等活性基团可以通过共价键与药物及蛋白结合。In this example, hydrogels with multiple crosslinked structures were prepared by electrostatic interaction and Schiff base chemical crosslinking, and good mechanical properties were endowed to them. By changing the modification rate of chitosan and another component polysaccharide, the molar ratio of the two components and the solid content of the hydrogel, the gelation time, mechanical strength, microscopic morphology and water content can be regulated. A large number of active groups such as amino groups and aldehyde groups contained in the gel network can be combined with drugs and proteins through covalent bonds.
实施例二：Embodiment two:
本实施例与实施例一基本相同，特别之处在于：This embodiment is basically the same as Embodiment 1, especially in that:
在本实施例中，称取0.3g壳聚糖，溶于100mL水中，加入0.132mL羟基乙酸，逐步滴加一定量盐酸至壳聚糖完全溶解后，加入N-羟基琥珀酰亚胺0.424g，调节pH至4.7，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐1.411g，反应48h后，将pH调到7.0。产物透析冻干；称取透明质酸钠2.5g加入到50mL的水中，在水浴中搅拌溶解，待完全溶解后，加入高碘酸钠1.08g，在避光条件下反应4h，加入600μL乙二醇终止反应。产物透析冻干。分别将改性壳聚糖和透明质酸钠配制成1wt%的水溶液，等体积混合，70s后得到水凝胶，储能模量为257 pa。In the present embodiment, take 0.3g chitosan, be dissolved in 100mL water, add 0.132mL glycolic acid, gradually drop a certain amount of hydrochloric acid until chitosan is completely dissolved, addN -hydroxysuccinimide 0.424g, Adjust the pH to 4.7, 1.411 g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, and adjust the pH to 7.0 after 48 hours of reaction. The product was dialyzed and freeze-dried; Weighed 2.5g of sodium hyaluronate and added it to 50mL of water, stirred and dissolved in a water bath. Alcohol terminates the reaction. The product was dialyzed and lyophilized. The modified chitosan and sodium hyaluronate were prepared into 1wt% aqueous solution, mixed in equal volumes, and a hydrogel was obtained after 70 s with a storage modulus of 257 pa.
实施例三：Embodiment three:
本实施例与前述实施例基本相同，特别之处在于：This embodiment is basically the same as the previous embodiment, and the special features are:
在本实施例中，称取0.3g壳聚糖，溶于100mL水中，加入0.132mL乳酸，逐步滴加一定量盐酸至壳聚糖完全溶解后，加入N-羟基琥珀酰亚胺0.636g，调节pH至4.7，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐2.116g，反应48h后，将pH调到7.0。产物透析冻干；称取羧甲基壳聚糖2.5g加入到50mL的水中，在水浴中搅拌溶解，待完全溶解后，加入高碘酸钠1.08g，在避光条件下反应3h，加入600μL乙二醇终止反应。产物过滤，丙酮沉降，再溶解透析冻干。分别将两种改性壳聚糖制成1wt%的水溶液，等体积混合，113s后得到水凝胶，储能模量为195 pa。In this embodiment, weigh 0.3g chitosan, dissolve it in 100mL water, add 0.132mL lactic acid, gradually drop a certain amount of hydrochloric acid until the chitosan is completely dissolved, add 0.636gN -hydroxysuccinimide, adjust pH to 4.7, 2.116 g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, after 48 hours of reaction, the pH was adjusted to 7.0. The product was dialyzed and freeze-dried; weighed 2.5g of carboxymethyl chitosan and added it to 50mL of water, stirred and dissolved in a water bath. Ethylene glycol terminates the reaction. The product was filtered, settled with acetone, redissolved, dialyzed and freeze-dried. The two kinds of modified chitosan were made into 1wt% aqueous solution, mixed in equal volumes, and hydrogel was obtained after 113s, with a storage modulus of 195 pa.
实施例四：Embodiment four:
本实施例与前述实施例基本相同，特别之处在于：This embodiment is basically the same as the previous embodiment, and the special features are:
在本实施例中，称取0.3g壳聚糖，溶于100mL醋酸水溶液中，醋酸水溶液的质量浓度1wt%，加入0.6738mL丁二酸酐，反应24h，再将pH调到7.0。产物过滤，透析冻干；称取羧甲基纤维2.5g加入到50mL的水中，在水浴中搅拌溶解，待完全溶解后，加入高碘酸钠1.62g，在避光条件下反应1h，加入800μL乙二醇终止反应。产物透析冻干。分别将改性壳聚糖和羧甲基纤维素配制成3wt%的水溶液，等体积混合，18s后得到水凝胶，储能模量为1528 pa。In this example, weigh 0.3g chitosan, dissolve it in 100mL acetic acid aqueous solution, the mass concentration of acetic acid aqueous solution is 1wt%, add 0.6738mL succinic anhydride, react for 24h, and then adjust the pH to 7.0. The product was filtered, dialyzed and freeze-dried; Weighed 2.5g of carboxymethyl fiber and added it to 50mL of water, stirred and dissolved in a water bath. Ethylene glycol terminates the reaction. The product was dialyzed and lyophilized. Modified chitosan and carboxymethyl cellulose were prepared into 3wt% aqueous solutions, mixed in equal volumes, and a hydrogel was obtained after 18s with a storage modulus of 1528 Pa.
实施例五：Embodiment five:
本实施例与前述实施例基本相同，特别之处在于：This embodiment is basically the same as the previous embodiment, and the special features are:
在本实施例中，称取0.3g壳聚糖，溶于100mL水中，加入0.132mL乳酸，逐步滴加一定量盐酸至壳聚糖完全溶解后，加入N-羟基琥珀酰亚胺0.636g，调节pH至4.7，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐2.116g，反应48h，再将pH调到7.0。产物过滤，透析冻干；称取海藻酸钠2.5g加入到50mL的水中，在水浴中搅拌溶解，待完全溶解后，加入高碘酸钠1.08g，在避光条件下反应1h，加入600μL乙二醇终止反应。产物透析冻干。分别将改性壳聚糖和海藻酸钠配制成2.5wt%的水溶液，以体积2:8混合，65s后得到水凝胶，储能模量为912 pa。In this embodiment, weigh 0.3g chitosan, dissolve it in 100mL water, add 0.132mL lactic acid, gradually drop a certain amount of hydrochloric acid until the chitosan is completely dissolved, add 0.636gN -hydroxysuccinimide, adjust pH to 4.7, 2.116 g of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, reacted for 48 hours, and then adjusted the pH to 7.0. The product was filtered, dialyzed and freeze-dried; Weighed 2.5g of sodium alginate and added it to 50mL of water, stirred and dissolved in a water bath, after it was completely dissolved, added 1.08g of sodium periodate, reacted for 1h under dark conditions, and added 600μL of ethyl alcohol The diol terminates the reaction. The product was dialyzed and lyophilized. Modified chitosan and sodium alginate were prepared into 2.5wt% aqueous solution and mixed at a volume of 2:8. After 65s, a hydrogel was obtained with a storage modulus of 912 Pa.
本发明不限于上述实施例，还可以根据本发明的发明创造的目的做出多种变化，凡依据本发明技术方案的精神实质和原理下做的改变、修饰、替代、组合、简化，均应为等效的置换方式，只要符合本发明的发明目的，只要不背离本发明多重交联多糖可注射型水凝胶制备方法的技术原理和发明构思，都属于本发明的保护范围。The present invention is not limited to above-mentioned embodiment, can also make various changes according to the purpose of invention creation of the present invention, and all changes, modifications, substitutions, combinations, simplifications done under the spirit and principle of the technical solution of the present invention, all should be It is an equivalent replacement method, as long as it meets the purpose of the present invention, and as long as it does not deviate from the technical principle and inventive concept of the method for preparing the multi-crosslinked polysaccharide injectable hydrogel of the present invention, it belongs to the protection scope of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410589982.2ACN104479150A (en) | 2014-10-29 | 2014-10-29 | Preparation method of multiple cross-linked polysaccharide injectable hydrogel |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410589982.2ACN104479150A (en) | 2014-10-29 | 2014-10-29 | Preparation method of multiple cross-linked polysaccharide injectable hydrogel |
| Publication Number | Publication Date |
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| CN104479150Atrue CN104479150A (en) | 2015-04-01 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410589982.2APendingCN104479150A (en) | 2014-10-29 | 2014-10-29 | Preparation method of multiple cross-linked polysaccharide injectable hydrogel |
| Country | Link |
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| CN (1) | CN104479150A (en) |
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