CN110917395A - 二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法 - Google Patents
二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法 Download PDFInfo
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- black phosphorus
- polylactic acid
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Abstract
本发明公开一种二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其目的是提供一种多功能化改性的聚乳酸支架的制备方法。其特征在于：以黑磷纳米片为药物载体负载抗炎药物布洛芬，并以天然高分子材料海藻酸钠作为包覆材料，通过锶离子的交联作用得到载药微球，利用静电相互作用将海藻酸钠载药微球均匀掺杂到经支化聚乙烯亚胺氨解改性的、富含活性氨基基团的改性聚乳酸基体材料中，经过冷冻相分离得到具有网状纳米纤维结构的改性聚乳酸支架。本发明的特点在于所制备的包埋载药微球的改性聚乳酸纳米纤维支架是一种具有光热治疗、促骨生长、抗菌消炎、智能释药的多功能体系，是理想的骨修复材料。
Description
技术领域
本发明涉及一种二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，属于骨修复生物材料制备技术。
背景技术
骨组织工程是近几年发展起来的治疗骨科疾病的有效措施之一，其中细胞、生长因子和支架材料是其必要的三大成分。复合支架由于具有多级孔径结构和多元的成分，可以模仿天然骨组织细胞外基质的结构和成分，促进细胞的黏附、增殖和分化。因此用于制备复合支架的材料应该根据其生物相容性、生物降解性和机械性能等进行严格地选材。人工合成高分子材料聚乳酸由于其具有良好的生物相容性、降解产物的无毒性和良好的机械性能等优点而被广泛用于组织工程支架的制备，但聚乳酸是一种强疏水性材料，表面缺乏细胞特异性识别位点，不利于细胞在其表面的粘附、增殖和生长，因此生物活性比较低。解决这一问题的有效途径之一是通过接枝改性将亲水性的−NH2、−OH以及−COOH等活性基团引入聚乳酸分子链中来改善支架材料的亲水性，使细胞易于在其表面黏附、增殖和分化，从而提高支架的生物活性。但亲水性改善后的聚乳酸支架仍存在成骨活性低、机械性能不足、降解产生的酸性产物易引发无菌性炎症反应等问题。黑磷纳米薄片是一种新兴的二维纳米材料，因其具有优异的光热转化性质、良好的生物相容性、较大的比表面积且表面易于功能化修饰改性等而在癌症治疗、药物递送、生物成像和生物传感等领域拥有广阔的应用前景。利用二维纳米黑磷所具有的光热治疗、促骨生长的作用来修饰改性聚乳酸材料可以提高聚乳酸支架的成骨活性。此外，借助黑磷纳米片对抗炎药物的有效负载和智能控释还可赋予聚乳酸支架抗菌消炎的性能，从而实现多功能修复体系的构建。但黑磷存在性能上的不稳定性，其在可见光和潮湿环境下易发生氧化，降解生成磷氧化物和磷酸根，光热性能变差，且黑磷负载的药物易因在体液中发生溶解而快速释放。因此，如何提高黑磷的稳定性及对药物的缓释性能是成功构建多功能化改性的聚乳酸支架所必须解决的关键技术问题。
发明内容
针对上述情况，本发明的目的是提供一种由二维纳米黑磷修饰改性的集光热治疗、药物控释和成骨作用于一体的多功能化改性聚乳酸纳米纤维支架的制备方法。
本发明的目的是这样实现的，一种二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于：包括如下步骤：
Ⅰ、以聚左旋乳酸为原料，支化聚乙烯亚胺为改性剂，通过氨解反应得到氨基化改性聚乳酸；
Ⅱ、以N-甲基吡咯烷酮为溶剂，采用液相剥离法制备二维黑磷纳米片；
Ⅲ、以步骤Ⅱ制得的黑磷纳米片为药物载体，布洛芬为模型药物，采用浸渍吸附法制备载药黑磷；
Ⅳ、以海藻酸钠包裹步骤Ⅲ制得的载药黑磷，以二价锶离子为交联固化剂，采用反相乳液法制备载药黑磷/海藻酸钠复合微球；
Ⅴ、利用步骤Ⅳ制得的载药黑磷/海藻酸钠复合微球与步骤Ⅰ制得的氨基化改性聚乳酸之间的静电相互作用将载药黑磷/海藻酸钠复合微球均匀分散到氨基化改性聚乳酸溶液中，经过冷冻诱导的热致相分离过程得到二维纳米黑磷修饰的多功能化改性聚乳酸纳米纤维支架。
上述步骤Ⅱ所述的黑磷纳米片是以块状黑磷通过液相剥离法制得的，具体为：采用溶剂为N-甲基吡咯烷酮，配成含黑磷的N-甲基吡咯烷酮溶液，溶液中所含黑磷的浓度为1mg/mL，在冰水浴中变频超声8~10 h后制备黑磷纳米片，变频频率分别为45HZ，80HZ，100HZ。
上述步骤Ⅲ所述的载药黑磷是通过浸渍吸附法制备的，具体制备条件为：黑磷纳米片的用量为5 mg，布洛芬药物溶液的浓度为15~20 mg/mL，载药温度为室温，载药时间为15~20 h。
上述步骤Ⅳ所述的载药黑磷/海藻酸钠复合微球是通过反相乳液法制备的，具体制备条件为：选择的油相是环己烷，其用量为100 g，分散稳定剂为司班60和吐温60的混合物，司班60和吐温60的质量比为3:1，载药黑磷的用量为7.0~8.0 mg，海藻酸钠溶液的浓度为9~12 mg/mL，交联剂氯化锶溶液的浓度为0.15~0.25 mol/L。
上述步骤Ⅰ所述的氨基化改性聚乳酸是通过聚乳酸与聚乙烯亚胺发生氨解反应制备的，具体制备条件为：所用的溶剂为1,4-二氧六环，聚乳酸溶液的浓度为7.0~9.0 wt%，支化聚乙烯亚胺改性剂的浓度为0.8~1.2 %，氨解反应的温度为60 ℃，氨解反应时间为15~30min。
上述步骤Ⅴ中的载药黑磷/海藻酸钠复合微球是通过静电相互作用而均匀分散到氨基化改性聚乳酸溶液中，并采用冷冻诱导的热致相分离技术获得具有网状纳米纤维结构的支架，冷冻诱导的热致相分离过程中的冷冻相分离温度为-25~-40℃，冷冻时间为24 h。
本发明以具有生物相容性的合成高分子材料聚乳酸为基体材料，支化聚乙烯亚胺为改性剂，通过氨解反应在聚乳酸分子链中引入活性氨基官能团来改善聚乳酸支架的亲水性。同时以块状黑磷通过液相剥离法得到的黑磷纳米薄片为药物载体负载抗炎药物布洛芬，以天然高分子材料海藻酸钠包裹载药黑磷并在锶离子的交联作用下制得载药黑磷/海藻酸钠复合微球以防止黑磷的氧化和药物的快速释放。利用微球与改性聚乳酸之间的静电相互作用将微球均匀地分散到改性聚乳酸基质中，最后利用制备纳米纤维支架常用的热致相分离技术使样品在低温下冷冻发生相分离而得到二维纳米黑磷修饰的多功能化改性聚乳酸纳米纤维支架。
实现本发明目的的具体技术方案，具体包括如下步骤：
1）将块状黑磷加入到N-甲基吡咯烷酮溶剂中得到混合液（浓度为1 mg/mL），在无氧条件下将所述混合液置于冰水浴中超声8~10 h，1000 rpm离心后收集上清液，将上清液再以10000 rpm离心15 min后收集沉淀，得到二维黑磷纳米片。用无水乙醇清洗沉淀三次，得到的沉淀放入-80℃冷冻干燥机中干燥备用。
2）将5 mg步骤1制备得到的黑磷纳米片加入到一定浓度的布洛芬溶液中，室温下震荡吸附15~20 h后离心分离，吸取上清液用紫外-可见分光光度法检测其中的药物浓度，根据载药前后药物溶液浓度的变化计算黑磷的载药量，收集沉淀并干燥备用。
3）往装有高速搅拌器的三颈烧瓶中加入100 g环己烷、10 g分散稳定剂（司班60和吐温60的质量比为3:1），强力搅拌至分散稳定剂全部溶解，得到溶液A。与此同时，将步骤2得到的载药黑磷超声分散到浓度为9~12 mg/mL的海藻酸钠水溶液中（记为溶液B）。以一定的滴加速度将溶液B逐滴加入溶液A中，滴加完全后将搅拌速度控制在2000 rpm。继续搅拌1h之后，逐滴加入浓度为0.15~0.25 mol/L的氯化锶溶液。持续搅拌1 h至完全交联，最后加入一定量的无水乙醇，在500 rpm的搅拌速度下破乳30 min。将得到的溶液离心，弃去上清液，用无水乙醇洗涤沉淀三次，放入-80℃冷冻干燥机中干燥1 d 备用。
4）用一定量的1,4-二氧六环溶剂充分溶解聚乳酸得到浓度为7.0~9.0 wt%的均相溶液，往所得的溶液中加入浓度为0.8~1.2 %的聚乙烯亚胺水溶液，氨解反应15~30 min后得到氨基化改性的聚乳酸溶液。将包裹载药黑磷的海藻酸钠微球用1,4-二氧六环超声分散后加入到改性聚乳酸溶液中，充分搅拌至分散均匀后迅速倒入模具并置于-25~-40℃冰箱中冷冻24 h后取出，用4℃的去离子水抽提去除溶剂，-80℃下冷冻干燥3 d后即可得到二维纳米黑磷修饰的多功能化改性聚乳酸纳米纤维支架。
本发明的有益效果为：采用上述方案得到的纳米纤维复合支架具有如下特点：①以多氨基化合物聚乙烯亚胺为改性剂，利用氨解结合热致相分离技术制备的氨基化改性聚乳酸纳米纤维支架不仅亲水性得到改善，而且还具有仿生天然细胞外基质的纳米纤维结构，有利于细胞在其表面的黏附和生长，因此生物活性得到显著地改善。②利用黑磷纳米片层状蜂窝结构所具有的高比表面积的结构特点以及黑磷与抗炎药物布洛芬之间的p-π共轭作用实现了黑磷对布洛芬的有效负载。吸附的药物在黑磷的表面形成了一层疏水性的保护膜，有效阻止黑磷被氧化而发生降解，由此增加了黑磷的稳定性。③以天然高分子材料海藻酸钠包覆载药黑磷，并采用二价锶离子进行交联固化，不仅可以进一步地保护黑磷、提高其稳定性，实现对药物的控制释放和长效作用，而且还可以提高载药黑磷在聚乳酸中的分散性，减少团聚。此外，还可以利用锶离子所具有的促成骨、抗破骨和抗炎等多效作用来提高聚乳酸支架的成骨活性和抗炎的功效。④采用本实验方法制备的复合支架是一种集光热治疗、药物控释、促骨生长以及抗菌消炎等性能于一体的多功能骨修复材料。
具体实施方式
实施例1
1）黑磷纳米片的制备：将块状黑磷研磨至粉末后加入到N-甲基吡咯烷酮溶剂中，获得黑磷N-甲基吡咯烷酮溶液浓度为1 mg/mL。冰水浴中变频超声（45 HZ，80 HZ，100 HZ）8 h后以10000 rpm的速度离心分离得到黑磷纳米片沉淀，将沉淀干燥，获得黑磷纳米片备用。
2）载药黑磷的制备：称取5 mg步骤1）制得的黑磷纳米片加入到浓度为18 mg/mL的布洛芬溶液中，恒温震荡吸附20 h后离心分离，将沉淀干燥，获得载药黑磷备用。
3）载药黑磷/海藻酸钠复合微球的制备：往三颈烧瓶中加入100 g环己烷、10 g分散稳定剂（司班60和吐温60的混合物，质量比为3:1），高速搅拌（2000 rpm）至分散稳定剂全部溶解，得到溶液A。称取0.3 g海藻酸钠溶于30 mL去离子水中，加入7.2 mg步骤2）制得的载药黑磷，超声分散均匀后将其逐滴加入溶液A中。滴加完全后继续搅拌一小时至形成均匀的乳液，然后再逐滴加入0.15 mol/L的氯化锶溶液，搅拌一小时至完全交联固化后将搅拌速度降至500 rpm，加入无水乙醇破乳30 min，将得到的溶液离心，弃去上清液，用无水乙醇洗涤沉淀三次，置于-80℃冷冻干燥机中干燥，获得载药黑磷/海藻酸钠复合微球备用。
4）复合支架的制备：用一定量的1,4-二氧六环溶剂充分溶解聚乳酸得到浓度为9.0 wt%的均相溶液，往所得的溶液中加入1.0 wt%的聚乙烯亚胺溶液，氨解反应30 min后得到氨基化改性的聚乳酸溶液。将所步骤3）制备的载药黑磷/海藻酸钠复合微球用1,4-二氧六环超声分散后加入到氨基化改性的聚乳酸溶液中，在60℃下搅拌10 min后迅速倒入模具并置于-40℃冰箱中进行冷冻24 h致完全相分离后取出，用4℃的去离子水抽提3 d（天）至溶剂完全去除，-80℃下冷冻干燥3 d（天）后得到二维纳米黑磷修饰改性的聚乳酸支架，扫描电镜观察所制备的支架具有网状纳米纤维的结构。
实施例2：
1）黑磷纳米片的制备：将块状黑磷研磨至粉末后加入到N-甲基吡咯烷酮溶剂中（浓度为1 mg/mL）。冰水浴中变频超声（45HZ，80HZ，100HZ）10 h后以10000 rpm的速度离心分离得到黑磷纳米片沉淀，将沉淀干燥备用。
2）载药黑磷的制备：称取5 mg黑磷纳米片加入浓度为20 mg/mL的布洛芬溶液中，恒温震荡吸附15 h后离心分离，将沉淀干燥备用。
3）载药黑磷/海藻酸钠复合微球的制备：往三颈烧瓶中加入100 g环己烷，加入12g分散稳定剂（司班60和吐温60的混合物，质量比为3:1）高速搅拌（2000 rpm）至分散稳定剂全部溶解，得到溶液A。称取0.45 g海藻酸钠溶于50 mL去离子水中，加入8.0 mg载药黑磷，超声分散均匀后将其逐滴地加入到溶液A中。滴加完全后继续搅拌一小时至形成均匀的乳液，然后再逐滴加入0.2 mol/L的氯化锶溶液，搅拌一小时至完全交联固化后将搅拌速度降至500 rpm，加入无水乙醇破乳15 min，将得到的溶液离心，弃去上清液，用无水乙醇洗涤沉淀三次，置于-80℃冷冻干燥机中干燥备用。
4）复合支架的制备：用一定量的1,4-二氧六环溶剂充分溶解聚乳酸得到浓度为7.0 wt%的均相溶液，往所得的溶液中加入0.8 %的聚乙烯亚胺溶液，氨解反应30 min后得到氨基化改性的聚乳酸溶液。将所制备的复合微球用1,4-二氧六环超声分散后加入到改性聚乳酸溶液中，在60℃下搅拌5 min后迅速倒入模具并置于-40℃冰箱中进行冷冻24 h致完全相分离后取出，用4℃的去离子水抽提3 d至溶剂完全去除，-80℃下冷冻干燥3 d后得到二维纳米黑磷修饰改性的聚乳酸纳米纤维支架。
实施例3：
1）黑磷纳米片的制备：将块状黑磷放入研钵中研磨至粉末后加入到N-甲基吡咯烷酮溶剂中（浓度为1 mg/mL）。冰水浴中变频超声（45HZ，80HZ，100HZ）9 h后以10000 rpm的速度离心分离得到黑磷纳米片沉淀，将沉淀干燥备用。
2）载药黑磷的制备：称取5 mg黑磷纳米片加入到浓度为15 mg/mL的布洛芬溶液中，恒温震荡吸附20 h后离心分离，将沉淀干燥备用。
3)载药黑磷/海藻酸钠复合微球的制备：往三颈烧瓶中加入100 g环己烷，加入10g分散稳定剂（司班60和吐温60的混合物，质量比为3:1），高速搅拌（2000 rpm）至分散稳定剂全部溶解，得到溶液A。称取0.6 g海藻酸钠溶于50 mL去离子水中，加入7.2 mg载药黑磷，超声分散均匀后将其逐滴加入到溶液A中。滴加完全后继续搅拌一小时至形成均匀的乳液，然后再逐滴加入0.25 mol/L的氯化锶溶液，搅拌一小时至完全交联固化后将搅拌速度降至500 rpm，加入无水乙醇破乳15 min，将得到的溶液离心，弃去上清液，用无水乙醇洗涤沉淀三次，置于-80 ℃冷冻干燥机中干燥备用。
4）复合支架的制备：用一定量的1,4-二氧六环溶剂充分溶解聚乳酸得到浓度为9.0 wt%的均相溶液，往所得的溶液中加入1.2 %的聚乙烯亚胺溶液，氨解反应15 min后得到氨基化改性的聚乳酸溶液。将所制备的复合微球用1,4-二氧六环超声分散后加入到改性聚乳酸溶液中，在60℃下搅拌8 min后迅速倒入模具并置于-25℃冰箱中进行冷冻24 h致完全相分离后取出，用4℃的去离子水抽提3 d至溶剂完全去除，-80℃下冷冻干燥3 d后得到二维纳米黑磷修饰改性的聚乳酸纳米纤维支架。
Claims (6)
1.一种二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于：包括如下步骤：
Ⅰ、以聚左旋乳酸为原料，支化聚乙烯亚胺为改性剂，通过氨解反应得到氨基化改性聚乳酸；
Ⅱ、以N-甲基吡咯烷酮为溶剂，采用液相剥离法制备二维黑磷纳米片；
Ⅲ、以步骤Ⅱ制得的黑磷纳米片为药物载体，布洛芬为模型药物，采用浸渍吸附法制备载药黑磷；
Ⅳ、以海藻酸钠包裹步骤Ⅲ制得的载药黑磷，以二价锶离子为交联固化剂，采用反相乳液法制备载药黑磷/海藻酸钠复合微球；
Ⅴ、利用步骤Ⅳ制得的载药黑磷/海藻酸钠复合微球与步骤Ⅰ制得的氨基化改性聚乳酸之间的静电相互作用将载药黑磷/海藻酸钠复合微球均匀分散到氨基化改性聚乳酸溶液中，经过冷冻诱导的热致相分离过程得到二维纳米黑磷修饰的多功能化改性聚乳酸纳米纤维支架。
2.根据权利要求1所述的二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于步骤Ⅱ所述的黑磷纳米片是以块状黑磷通过液相剥离法制得的，具体为：采用溶剂为N-甲基吡咯烷酮，配成含黑磷的N-甲基吡咯烷酮溶液，溶液中所含黑磷的浓度为1 mg/mL，在冰水浴中变频超声8~10 h后制备黑磷纳米片，变频频率分别为45HZ，80HZ，100HZ。
3.根据权利要求1所述的二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于步骤Ⅲ所述的载药黑磷是通过浸渍吸附法制备的，具体制备条件为：黑磷纳米片的用量为5 mg，布洛芬药物溶液的浓度为15~20 mg/mL，载药温度为室温，载药时间为15~20 h。
4.根据权利要求1所述的二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于步骤Ⅳ所述的载药黑磷/海藻酸钠复合微球是通过反相乳液法制备的，具体制备条件为：选择的油相是环己烷，其用量为100 g，分散稳定剂为司班60和吐温60的混合物，司班60和吐温60的质量比为3:1，载药黑磷的用量为7.0~8.0 mg，海藻酸钠溶液的浓度为9~12 mg/mL，交联剂氯化锶溶液的浓度为0.15~0.25 mol/L。
5.根据权利要求1所述的二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于步骤Ⅰ所述的氨基化改性聚乳酸是通过聚乳酸与聚乙烯亚胺发生氨解反应制备的，具体制备条件为：所用的溶剂为1,4-二氧六环，聚乳酸溶液的浓度为7.0~9.0wt%，支化聚乙烯亚胺改性剂的浓度为0.8~1.2 %，氨解反应的温度为60 ℃，氨解反应时间为15~30 min。
6.根据权利要求1所述的二维纳米黑磷功能化修饰改性的聚乳酸纳米纤维支架的制备方法，其特征在于步骤Ⅴ中的载药黑磷/海藻酸钠复合微球是通过静电相互作用而均匀分散到氨基化改性聚乳酸溶液中，并采用冷冻诱导的热致相分离技术获得具有网状纳米纤维结构的支架，冷冻诱导的热致相分离过程中的冷冻相分离温度为-25~-40℃，冷冻时间为24h。
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