技术领域technical field
本发明涉及一种海藻酸-多巴胺/纳米羟基磷灰石复合支架的制备方法，属于高分子材料和生物材料技术领域。The invention relates to a preparation method of an alginic acid-dopamine/nanometer hydroxyapatite composite scaffold, belonging to the technical field of polymer materials and biological materials.
技术背景technical background
近年来，随着骨修复材料临床需求的增加，骨修复材料已成为了生物医学领域的研究热点之一。人体自然骨是由磷灰石和高分子胶原纤维组成的无机-有机复合物，临床医学领域长期以来广泛使用的金属、陶瓷、高分子等单组分生物医学材料的成分与其不同。作为骨修复支架材料，其人体适应性以及与自然骨之间的相容性不是十分理想。为了克服单组分骨修复支架材料存在的局限性，将金属、陶瓷、高分子等基体材料通过复合或加入其它增强材料制备得到了骨修复复合材料。骨修复复合材料具有可设计性，可根据不同的应用需求调节基体材料与增强材料之间的比例，合成具有优异综合性能的骨修复材料。骨修复复合材料的发展为获得与人体骨组织相近结构、性能的生物医学材料提供了一种新的途径。In recent years, with the increasing clinical demand for bone repair materials, bone repair materials have become one of the research hotspots in the field of biomedicine. Human natural bone is an inorganic-organic composite composed of apatite and polymer collagen fibers. The composition of single-component biomedical materials such as metals, ceramics, and polymers, which have been widely used in the field of clinical medicine for a long time, is different from it. As a scaffold material for bone repair, its human adaptability and compatibility with natural bone are not ideal. In order to overcome the limitations of single-component bone repair scaffold materials, bone repair composite materials are prepared by combining metal, ceramic, polymer and other matrix materials or adding other reinforcing materials. Bone repair composite materials can be designed, and the ratio between the matrix material and the reinforcement material can be adjusted according to different application requirements, and bone repair materials with excellent comprehensive properties can be synthesized. The development of composite materials for bone repair provides a new way to obtain biomedical materials with structures and properties similar to human bone tissue.
羟基磷灰石(HA)是一种生物活性材料，其与人体之间存在较好的相容性，是公认性能良好的骨修复替代材料。羟基磷灰石植入人体后，对组织无刺激，不会产生免疫排斥作用，具有优异的骨传导性，可以引导骨生长；此外，羟基磷灰石带有多个羟基，具有强极性，能与机体组织形成较强的亲和力，使其与骨组织形成牢固的化学键合，一旦骨细胞在其表面附着、伸展，即可产生骨基质胶原，并进一步矿化形成骨组织。Hydroxyapatite (HA) is a bioactive material with good compatibility with the human body, and it is recognized as a good substitute material for bone repair. After implanted into the human body, hydroxyapatite has no stimulation to the tissue, does not produce immune rejection, has excellent osteoconductivity, and can guide bone growth; in addition, hydroxyapatite has multiple hydroxyl groups and has strong polarity. It can form a strong affinity with body tissue, making it form a firm chemical bond with bone tissue. Once bone cells attach and stretch on the surface, they can produce bone matrix collagen and further mineralize to form bone tissue.
研究发现，在贻贝丝足蛋白中存在大量的3,4-二羟基苯丙氨酸(DOPA)。DOPA中邻苯二酚基团具有很强的配位能力，能与矿物、金属、金属氧化物等材料表面产生双配位基作用力，形成可逆络合物，而且邻苯二酚被氧化成醌后能与多种基团反应形成共价键。其中多巴胺(DA)是DOPA一种非常重要的衍生物。其具有极强的防水黏附能力，这种不受水或潮湿环境影响的神奇黏合特性是已有人工合成黏合剂所无法媲美的，不仅如此，由于它是天然分泌产物，因此具有较好的细胞相容性、生物可降解性以及无毒性等特性，对人体细胞造成的侵害很小，也不会引发人体免疫反应，使其在生物医学领域具有十分广泛的应用前景。The study found that there is a large amount of 3,4-dihydroxyphenylalanine (DOPA) in mussel silk podoprotein. The catechol group in DOPA has a strong coordination ability, which can generate double-dentate interaction with the surface of minerals, metals, metal oxides and other materials to form a reversible complex, and catechol is oxidized into Quinone can react with various groups to form covalent bonds. Among them, dopamine (DA) is a very important derivative of DOPA. It has extremely strong waterproof adhesion ability, and this magical adhesive property that is not affected by water or humid environment is unmatched by existing synthetic adhesives. Not only that, because it is a natural secretion product, it has better cell adhesion. Compatibility, biodegradability, non-toxicity and other characteristics cause little damage to human cells and will not trigger human immune response, making it have a very wide application prospect in the field of biomedicine.
本专利发明了一种海藻酸-多巴胺/纳米羟基磷灰石复合支架的制备方法。本发明利用(3-氯-2-羟丙基)三甲基氯化铵(CHPTAC)对壳聚糖(CS)进行季铵化改性，制备季铵化壳聚糖(QCS)；并以其为有机质原位合成具有优异分散性能的季铵化壳聚糖/羟基磷灰石(QCHA)，利用多巴胺(DA)改性海藻酸(Alg)制备具有优异粘附性能的海藻酸-多巴胺(Alg-DA)改性大分子；通过Alg-DA与QCHA之间的静电作用，将Alg-DA与QCHA以不同配比进行复合，并利用氯化钙对其进行交联制备得到Alg-DA/QCHA复合支架。该种复合支架材料具有适宜骨细胞生长的孔隙率和良好的力学性能、矿化性能、药物负载性能，适宜的降解周期，优异的细胞相容性和细胞黏附性，在组织工程领域具有广阔的应用前景。This patent has invented a preparation method of alginic acid-dopamine/nano hydroxyapatite composite scaffold. The present invention utilizes (3-chloro-2-hydroxypropyl) trimethyl ammonium chloride (CHPTAC) to carry out quaternization modification to chitosan (CS), prepares quaternization chitosan (QCS); And with It is the in-situ synthesis of quaternized chitosan/hydroxyapatite (QCHA) with excellent dispersion properties from organic matter, and the use of dopamine (DA) to modify alginic acid (Alg) to prepare alginic acid-dopamine ( Alg-DA) modified macromolecule; through the electrostatic interaction between Alg-DA and QCHA, compound Alg-DA and QCHA in different proportions, and use calcium chloride to cross-link it to prepare Alg-DA/ QCHA composite bracket. This kind of composite scaffold material has porosity suitable for bone cell growth, good mechanical properties, mineralization properties, drug loading properties, suitable degradation cycle, excellent cell compatibility and cell adhesion, and has broad application in the field of tissue engineering. Application prospects.
发明内容Contents of the invention
本发明的目的是提供一种海藻酸-多巴胺/纳米羟基磷灰石复合支架的制备方法，得到复合支架具有适宜骨细胞生长的孔隙率和良好的力学性能、矿化性能、药物负载性能，适宜的降解周期，优异的细胞相容性和细胞黏附性。The purpose of the present invention is to provide a preparation method of alginic acid-dopamine/nano hydroxyapatite composite scaffold, the obtained composite scaffold has porosity suitable for bone cell growth and good mechanical properties, mineralization properties, drug loading properties, suitable for degradation cycle, excellent cell compatibility and cell adhesion.
本发明的设计思路是：利用(3-氯-2-羟丙基)三甲基氯化铵(CHPTAC)对壳聚糖(CS)进行季铵化改性，制备季铵化壳聚糖(QCS)；并以其为有机质模板原位合成具有良好分散性的季铵化壳聚糖/羟基磷灰石(QCHA)；利用多巴胺(DA)的可反应性，将其与海藻酸(Alg)发生酰胺化反应得到海藻酸-多巴胺(Alg-DA)改性生物大分子；再利用Alg-DA与QCHA之间的静电作用制备复合支架；并用氯化钙进一步交联调节支架孔隙率得到Alg-DA/QCHA复合支架材料。The design idea of the present invention is: utilize (3-chloro-2-hydroxypropyl) trimethyl ammonium chloride (CHPTAC) to carry out quaternization modification to chitosan (CS), prepare quaternization chitosan ( QCS); and use it as an organic template to synthesize in-situ quaternized chitosan/hydroxyapatite (QCHA) with good dispersion; utilize the reactivity of dopamine (DA) to combine it with alginic acid (Alg) Alginate-dopamine (Alg-DA) modified biomacromolecule was obtained by amidation reaction; the composite scaffold was prepared by using the electrostatic interaction between Alg-DA and QCHA; and the porosity of the scaffold was further adjusted by calcium chloride to obtain Alg-DA DA/QCHA composite scaffold material.
本发明的技术方案为：利用(3-氯-2-羟丙基)三甲基氯化铵(CHPTAC)对壳聚糖(CS)进行季铵化改性制备一系列不同季铵化程度的季铵化壳聚糖(QCS)，并以QCS为有机质模板，通过原位合成法制备具有良好分散性的季铵化壳聚糖/羟基磷灰石(QCHA)；通过酰胺化反应，利用具有化学反应性以及优异黏附性的多巴胺(DA)改性海藻酸(Alg)，合成海藻酸-多巴胺(Alg-DA)改性生物大分子；利用Alg-DA与QCHA之间的静电作用制备复合支架，并利用氯化钙对支架进行交联，进一步调节支架孔隙率，交联后用超纯水洗涤，冷冻干燥48h，Alg-DA/QCHA复合支架材料。The technical scheme of the present invention is: use (3-chloro-2-hydroxypropyl) trimethylammonium chloride (CHPTAC) to carry out quaternization modification to chitosan (CS) to prepare a series of different quaternization degrees Quaternized chitosan (QCS), and using QCS as an organic template, prepared quaternized chitosan/hydroxyapatite (QCHA) with good dispersion by in-situ synthesis; Dopamine (DA) modified alginic acid (Alg) with chemical reactivity and excellent adhesion, synthesis of alginic acid-dopamine (Alg-DA) modified biological macromolecules; preparation of composite scaffolds by using the electrostatic interaction between Alg-DA and QCHA , and use calcium chloride to cross-link the scaffold to further adjust the porosity of the scaffold, wash with ultrapure water after cross-linking, and freeze-dry for 48 hours to obtain the Alg-DA/QCHA composite scaffold material.
其中，其中QCS制备过程中CS与CHPTAC的投料比为1:1～1:8，QCS的季铵化程度为17.7～96.8％；QCHA原位合成过程中QCHA中HA与QCS的理论比值为9:1～7:3。酰胺化反应中Alg与DA的投料比为2:1～1:5，DA在Alg-DA中的取代度为18.9～52.6％；Alg-DA与QCHA复合时，Alg-DA与QCHA的配比为1:2～2:1。Alg-DA在超纯水中的浓度均为3wt％；氯化钙在超纯水中的浓度为5wt％。Among them, the ratio of CS to CHPTAC in the preparation process of QCS is 1:1-1:8, the degree of quaternization of QCS is 17.7-96.8%; the theoretical ratio of HA to QCS in QCHA in the in-situ synthesis of QCHA is 9 :1～7:3. In the amidation reaction, the feed ratio of Alg to DA is 2:1~1:5, and the substitution degree of DA in Alg-DA is 18.9~52.6%. When Alg-DA is compounded with QCHA, the ratio of Alg-DA to QCHA It is 1:2～2:1. The concentration of Alg-DA in ultrapure water is 3wt%; the concentration of calcium chloride in ultrapure water is 5wt%.
本发明的有益效果：用季铵化壳聚糖生物大分子作为有机质模板合成羟基磷灰石，可以模拟自然骨的生物矿化机理，从而控制羟基磷灰石的成核与生长的作用，同时使所得羟基磷灰石在水中具有较好的分散性。季铵化壳聚糖与海藻酸-多巴胺间具有更强的静电相互作用，将其两者复合可得到三维交联结构的复合凝胶，再通过氯化钙交联，使海藻酸分子链间发生交联，从而得到含有两种交联网络结构的支架材料，赋予了该支架具有更适宜的孔隙率和优异的力学性能。多巴胺改性后的材料，利用多巴胺的黏附性，使得支架能够有效黏附细胞，促进支架材料与组织界面快速结合，从而有效促进组织再生，具有修复组织的潜在应用价值。Beneficial effects of the present invention: using quaternized chitosan biomacromolecule as an organic template to synthesize hydroxyapatite can simulate the biomineralization mechanism of natural bone, thereby controlling the nucleation and growth of hydroxyapatite, and at the same time The obtained hydroxyapatite has better dispersibility in water. There is a stronger electrostatic interaction between quaternized chitosan and alginic acid-dopamine, and the composite gel of the three-dimensional cross-linked structure can be obtained by combining the two, and then cross-linked by calcium chloride to make the alginic acid molecular chains Cross-linking occurs to obtain a scaffold material containing two cross-linked network structures, endowing the scaffold with more suitable porosity and excellent mechanical properties. The dopamine-modified material utilizes the adhesion of dopamine to enable the scaffold to effectively adhere to cells and promote the rapid combination of the scaffold material and the tissue interface, thereby effectively promoting tissue regeneration and has potential application value in tissue repair.
附图说明Description of drawings
图1季铵化壳聚糖的核磁共振谱图The NMR spectrum of Fig. 1 quaternized chitosan
图2季铵化壳聚糖/羟基磷灰石的X射线衍射图Figure 2 X-ray diffraction pattern of quaternized chitosan/hydroxyapatite
图3海藻酸-多巴胺/纳米羟基磷灰石复合支架材料形貌图Figure 3 Morphology of alginic acid-dopamine/nano-hydroxyapatite composite scaffold material
具体实施方式detailed description
实施例1、季铵化壳聚糖(QCS)的合成Embodiment 1, the synthesis of quaternized chitosan (QCS)
4g的壳聚糖(CS)分散在100mL质量比为7:8:8:77的KOH-LiOH.H2O-urea-H2O混合溶液得到CS分散液，将其置于-20℃冰箱中冷冻过夜，之后在5℃下解冻、搅拌直至得到透明的CS溶液。然后将62.3mL的(3-氯-2-羟丙基)三甲基氯化铵溶液(CHPTAC)逐滴加入到CS溶液中，30℃下搅拌反应24h。反应完成后的溶液用盐酸中和，并在去离子水中透析一周后进行冷冻干燥，得到的白色絮状样品即为季铵化壳聚糖(QCS)，季铵化程度为96.8％。4g of chitosan (CS) was dispersed in 100mL of KOH-LiOH.H2O-urea-H2O mixed solution with a mass ratio of 7:8:8:77 to obtain a CS dispersion, which was placed in a -20°C refrigerator and frozen overnight. Then thaw at 5°C and stir until a transparent CS solution is obtained. Then 62.3 mL of (3-chloro-2-hydroxypropyl)trimethylammonium chloride solution (CHPTAC) was added dropwise into the CS solution, and the reaction was stirred at 30° C. for 24 h. After the reaction was completed, the solution was neutralized with hydrochloric acid, dialyzed in deionized water for one week, and then freeze-dried. The white flocculent sample obtained was quaternized chitosan (QCS), and the degree of quaternization was 96.8%.
需要说明的是，将实施例1中的CHPTAC的加入量改变为7.78、15.6、31.1mL，可以分别得到季铵化程度17.7、23.3、47.2％的季铵化壳聚糖(QCS)。It should be noted that, by changing the addition amount of CHPTAC in Example 1 to 7.78, 15.6, and 31.1 mL, quaternized chitosan (QCS) with quaternization degrees of 17.7, 23.3, and 47.2% can be obtained respectively.
实施例2、季铵化壳聚糖/羟基磷灰石(QCHA)的合成Embodiment 2, the synthesis of quaternized chitosan/hydroxyapatite (QCHA)
取一定量的QCS溶于0.3M Na2HPO4溶液中，常温搅拌1h；然后升温至90℃，在机械搅拌的条件下，以Ca/P为1.67的原子比将一定量的0.5M CaCl2溶液以2mL/min加入到上述QCS溶液中。在此过程中，利用1M NaOH调节反应溶液的pH在10左右。反应2h后离心得到白色沉淀，并用去离子水洗涤沉淀直至其pH值接近中性，冷冻干燥即可得到QCHA。其中季铵化壳聚糖与羟基磷灰石的理论比值分别为3:7，对应得到的QCHA标记为QCHA-30。Dissolve a certain amount of QCS in 0.3M Na2 HPO4 solution, stir at room temperature for 1 hour; then raise the temperature to 90°C, and mix a certain amount of 0.5M CaCl2 with an atomic ratio of Ca/P of 1.67 under mechanical stirring. The solution was added to the above QCS solution at 2 mL/min. During this process, the pH of the reaction solution was adjusted to about 10 with 1M NaOH. After reacting for 2 hours, centrifuge to obtain a white precipitate, wash the precipitate with deionized water until its pH value is close to neutral, and freeze-dry to obtain QCHA. The theoretical ratio of quaternized chitosan to hydroxyapatite is 3:7, and the corresponding QCHA is labeled as QCHA-30.
需要说明的是，将实施例2中季铵化壳聚糖与羟基磷灰石的理论比值改变为1:9、2:8，可分别得到QCHA-10以及QCHA-20。It should be noted that by changing the theoretical ratio of quaternized chitosan to hydroxyapatite in Example 2 to 1:9 and 2:8, QCHA-10 and QCHA-20 can be obtained respectively.
实施例3、海藻酸-多巴胺的制备Embodiment 3, the preparation of alginic acid-dopamine
称取1g海藻酸(Alg)，装入三口烧瓶中，加入100mL PBS缓冲液(50mM，pH＝5.5.)，常温搅拌溶解，待完全溶解后，依次加入1.94g 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)和2.32g N-羟基丁二酰亚胺(NHS)，n(COOH)/n(EDC)/n(NHS)＝1/2/4，室温活化30min后，加入4.79g盐酸多巴胺(DA)，反复抽真空、通氮气三次，以排除空气，防止DA氧化，在氮气氛围下室温反应24h，停止反应后在去离子水中透析以除去EDC和NHS及未反应单体，至透析液中无多巴胺紫外吸收峰后，冷冻干燥得到白色棉花状生物改性大分子Alg-DA，DA取代度为52.6％。Weigh 1g of alginic acid (Alg), put it into a three-necked flask, add 100mL of PBS buffer solution (50mM, pH=5.5.), stir and dissolve at room temperature, and after it is completely dissolved, add 1.94g of 1-ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 2.32g N-hydroxysuccinimide (NHS), n(COOH)/n(EDC)/n(NHS)=1/2 /4, after activation at room temperature for 30 min, add 4.79 g of dopamine hydrochloride (DA), repeatedly vacuumize and pass nitrogen three times to remove air and prevent DA oxidation, react at room temperature for 24 h under nitrogen atmosphere, and dialyze in deionized water after stopping the reaction EDC, NHS and unreacted monomers were removed until there was no dopamine ultraviolet absorption peak in the dialysate, and then freeze-dried to obtain a white cotton-like biomodified macromolecule Alg-DA with a DA substitution degree of 52.6%.
需要说明的是，将实施例3中DA的加入量改变为0.479、0.958、2.87g，可分别得到DA取代度为18.9、23.6、31.5％的Alg-DA。It should be noted that by changing the amount of DA added in Example 3 to 0.479, 0.958, and 2.87 g, Alg-DA with DA substitution degrees of 18.9, 23.6, and 31.5% can be obtained, respectively.
实施例4、Alg-DA/QCHA复合支架的制备Embodiment 4, the preparation of Alg-DA/QCHA composite support
将0.6g Alg-DA溶于PBS缓冲液(pH＝6.0)配制成浓度为3wt％的Alg-DA溶液，加入1.2g，QCHA-30到以上溶液中，机械搅拌8h后得到Alg-DA/QCHA2.0。将其加入到圆柱形模具中冷冻干燥48h后用5wt％的CaCl2溶液进行交联，交联后的样品再次冷冻干燥48h即得到Alg-DA/QCHA复合支架。Dissolve 0.6g of Alg-DA in PBS buffer (pH=6.0) to prepare an Alg-DA solution with a concentration of 3wt%, add 1.2g of QCHA-30 to the above solution, and mechanically stir for 8 hours to obtain Alg-DA/QCHA2.0 . Add it into a cylindrical mold and freeze-dry it for 48 hours, then cross-link it with 5wt% CaCl2 solution, and freeze-dry the cross-linked sample again for 48 hours to obtain the Alg-DA/QCHA composite scaffold.
需要说明的是，将实施例4中QCHA-30的量改变为0.6g、0.3g，得到的复合支架分别表示为Alg-DA/QCHA1.0，Alg-DA/QCHA0.5。It should be noted that the amount of QCHA-30 in Example 4 was changed to 0.6g and 0.3g, and the obtained composite scaffolds were expressed as Alg-DA/QCHA1.0 and Alg-DA/QCHA0.5 , respectively.
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