CN107501577B - 一种可降解原位凝胶的制备方法 - Google Patents
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Abstract
本发明公开了一种可降解原位凝胶的制备方法。该方法是以天然大分子壳聚糖和聚乙二醇为主要原料,制备出巯基化壳聚糖(CS‑SH)和炔基化聚乙二醇(Alkynyl‑PEG)。本发明按照不同的比例将其与胶原蛋白溶解混合后,能够通过点击反应快速形成原位凝胶。该凝胶以点击化学的方式制备,具有良好的稳定性;该凝胶以生物相容性好的天然大分子为主要原料,具备良好的可降解性能;该凝胶可以负载药物,凝胶网络的形成有利于药物分子的控制释放;该凝胶中含有胶原蛋白,能够起到促凝血作用;该凝胶模拟细胞外基质多糖与蛋白质的环境,可作为组织工程细胞培养用3D支架材料。
Description
【技术领域】:本发明涉及药物控制释放、凝血材料和生物支架材料领域,具体涉及一种可降解原位凝胶的制备方法。
【背景技术】:近些年来迅速发展起来的点击化学逐渐应用于载药原位凝胶领域中,其反应条件简单,依靠特定基团之间的精准性和高效性,已经成为目前最为有用和吸引人的合成理念之一。点击反应形成的键一般为共价键,这正是其具有较高稳定性的原因。
对于应用于人体的原位凝胶来说,材料的生物相容性和可降解性至关重要。壳聚糖作为一种生物相容性和可降解性良好可植入人体的天然大分子,含有大量的氨基和醇羟基可供改性,但是壳聚糖是不溶于水,因此各种水溶性壳聚糖衍生物被开发出来并逐步运用到原位凝胶的制备当中。巯基化壳聚糖具有良好的生物黏附性,原因是这些巯基化高分子能够通过二硫键的置换反应与黏膜糖蛋白的半胱氨酸富集子域相互作用。
聚乙二醇是经美国FDA认证的材料,具有高度的细胞安全性,被广泛应用于化工、医药、化妆品、分子生物学研究等行业。聚乙二醇末端羟基可被修饰为功能化官能团,从而拓宽其在合成方面的应用。
胶原蛋白是公认的第三代生物医用高分子材料,具有低免疫原性、优异的细胞相容性。胶原对血小板有凝聚作用,可形成血栓阻止流血,因而可用于制备凝血材料,比如胶原/壳聚糖复合膜的止血性能比明胶纤维等一般材料好得多。
查阅国内外文献发现,目前尚无巯基壳聚糖、胶原蛋白和炔基化聚乙二醇原位凝胶体系的报导。本发明综合考虑了壳聚糖与聚乙二醇生物相容性好、改性空间大与可降解性能优异的特点,在壳聚糖分子上引入巯基,聚乙二醇分子上引入炔基,混合胶原蛋白,利用点击反应制备了生物相容性好、可降解并具有止血性能的双网络原位凝胶。
【发明内容】:本发明目的在于提供一种可降解原位凝胶的制备方法,使原位凝胶具有生物相容性,可降解性能及止血性能的特点。
为实现上述目的,本发明提供了一种可降解原位凝胶的制备方法,包括下述步骤:
1)巯基化壳聚糖的合成:取3g壳聚糖粉末置于三口烧瓶中,氮气气氛下加入适量盐酸溶液搅拌至完全溶解,随后加入2.478g EDC·HCl,搅拌15-30min后加入2.1ml巯基乙酸,整个反应在氮气保护下反应8h。反应结束后,8KD透析袋无氧水透析三天,每天三次换水。最后取透析液冷冻干燥得到白色海绵状脆性物质即为巯基化壳聚糖。
2)炔基化聚乙二醇的合成:称取聚乙二醇转移至三口烧瓶,加入40mL二氯甲烷搅拌溶解,再依次加入4-二甲氨基吡啶(DMAP),丙炔酸,N,N′-二环己基碳酰亚胺(DCC),氮气保护下反应12-24h。将反应物抽滤三次除去沉淀,再将所得澄清液加入到乙醚沉淀。抽滤后将其用二氯甲烷溶解,分别用饱和碳酸氢钠和浓盐水反复洗涤三次,乙醚沉淀干燥得产物。其中,PEG的分子量可选取为2000-10000;PEG与丙炔酸的摩尔比为1∶1-1∶5,DMAP与DCC的摩尔比为1∶5-1∶10。
3)胶原蛋白的选取:本发明原料胶原蛋白为I型胶原蛋白,来源于鼠尾I型胶原蛋白。
4)原位凝胶的制备:分别取质量比为1∶0.5-1∶2的巯基壳聚糖(10-50mg/mL)与胶原蛋白的混合溶液0.5mL,与体积为0.2ml的10-50mg/mL炔基化聚乙二醇溶液混合,离心脱泡后迅速转移至圆柱形模具中静置成胶。
所述原位凝胶的原料壳聚糖和胶原蛋白是来源于天然的可降解大分子,。
所述原位凝胶的壳聚糖残留氨基与胶原蛋白对血液均具有良好的止血性能。
所述原位凝胶的改性原料巯基化壳聚糖能与炔基化聚乙二醇发生点击反应,原子利用率高,水相反应无毒无害,合成迅速。
所述的原位凝胶对药物的控制释放作用来源于凝胶网络的形成对药物分子的运动的阻碍。
与其他凝胶及其制备方法相比,本发明具有如下有益效果:
(1)本发明所制备的一种可降解原位凝胶所用的壳聚糖及胶原蛋白,能够在人体体液中酶的作用下代谢降解,且无毒无害;
(2)本发明所提供的一种可降解原位凝胶制备方法,反应条件温和,操作简便,成胶速度快,形成的凝胶稳定性高;
(3)本发明所制备的一种可降解原位凝胶,能够负载药物或凝血酶,对创伤伤口具有更好的抗菌止血性能。
(4)本发明所制备的一种可降解原位凝胶,能够用于封装细胞,模拟体内组织环境进行3D培养。
【附图说明】:
图1为实例1所制备原位水凝胶的SEM图
图2为L929细胞在材料表面的增殖图
【具体实施方式】:
下面结合具体实施方式对本专利的技术方案作进一步详细地说明。
实施例1:
1)巯基化壳聚糖的合成:取3g壳聚糖粉末置于三口烧瓶中,氮气气氛下加入100ml1.5%HCl溶液搅拌至完全溶解,随后加入2.478gEDC·HCl,搅拌15min后加入2.1ml巯基乙酸,整个反应在氮气保护下反应8h。反应结束后,8000KD透析袋无氧水透析三天,每天三次换水。最后取透析液冷冻12h后冻干得到白色海绵状脆性物质即为巯基化壳聚糖。
2)炔基化聚乙二醇的合成:称取2g聚乙二醇转移至三口烧瓶,加入40mL二氯甲烷搅拌溶解,再依次加入0.061g 4-二甲氨基吡啶,182μL丙炔酸,0.413g N,N′-二环己基碳酰亚胺,氮气保护下反应24h。将反应物抽滤三次除去沉淀,再将所得澄清液加入到乙醚沉淀。抽滤后将其用二氯甲烷溶解,分别用饱和碳酸氢钠和浓盐水反复洗涤三次,乙醚沉淀干燥得产物。
3)原位凝胶的制备:将25mg巯基壳聚糖与12.5g海狸鼠鼠尾胶原蛋白溶解于0.5mL0.9%NaCl溶液中,与体积为0.2ml的50mg/mL炔基化聚乙二醇溶液迅速混合,离心脱泡后迅速转移至圆柱形模具中静置成胶。
4)在步骤4所制备的凝胶与医用止血纱布上各加入全血1ml,加入20μl CaCl2溶液引发凝血,20min后加入2ml蒸馏水引发红细胞溶血,吸取上层溶血液200μl,使用酶标仪在530nm处测得吸光度,根据吸光度大小判定止血性能的差异。
5)将步骤4所制备的凝胶紫外灭菌后接种L929小鼠成纤维细胞,验证材料的安全性,接种密度为5×103个/mL。
实施例2:
1)巯基化壳聚糖的合成:取3g壳聚糖粉末置于三口烧瓶中,氮气气氛下加入100ml1.5%HCl溶液搅拌至完全溶解,随后加入2.478gEDC·HCl,搅拌15min后加入2.1ml巯基乙酸,整个反应在氮气保护下反应8h。反应结束后,8000KD透析袋无氧水透析三天,每天三次换水。最后取透析液冷冻12h后冻干得到白色海绵状脆性物质即为巯基化壳聚糖。
2)炔基化聚乙二醇的合成:称取2g聚乙二醇转移至三口烧瓶,加入40mL二氯甲烷搅拌溶解,再依次加入0.061g 4-二甲氨基吡啶,182μL丙炔酸,0.413gN,N′-二环己基碳酰亚胺,氮气保护下反应24h。将反应物抽滤三次除去沉淀,再将所得澄清液加入到乙醚沉淀。抽滤后将其用二氯甲烷溶解,分别用饱和碳酸氢钠和浓盐水反复洗涤三次,乙醚沉淀干燥得产物。
3)原位凝胶的制备:将25mg巯基壳聚糖与25mg鼠尾胶原蛋白溶解于0.5mL 0.9%NaCl溶液中,与体积为0.2ml的50mg/mL炔基化聚乙二醇溶液迅速混合,离心脱泡后迅速转移至圆柱形模具中静置成胶。
4)在步骤4所制备的凝胶与医用止血纱布上各加入全血1ml,加入20μl CaCl2溶液引发凝血,20min后加入2ml蒸馏水引发红细胞溶血,吸取上层溶血液200μl,使用酶标仪在530nm处测得吸光度,根据吸光度大小判定止血性能的差异。
5)将步骤4所制备的凝胶紫外灭菌后接种L929小鼠成纤维细胞,接种密度为5×103个/mL。
Claims (6)
1.一种可降解原位凝胶的制备方法,其特征在于,由以下步骤组成:
1)CS-SH的合成:室温下将壳聚糖粉末完全溶解于盐酸溶液中,随后加入EDC·HCl,之后缓慢加入巯基乙酸,氮气保护下反应8h-24h;反应结束后,将反应液置于8KD透析袋无氧透析三天,冷冻干燥制得CS-SH;
2)Alkynyl-PEG的合成:将PEG溶解于二氯甲烷,依次加入一定量的4-二甲氨基吡啶,丙炔酸,N,N′-二环己基碳酰亚胺,氮气保护下反应24h;抽滤三次除去沉淀物,将澄清液加入乙醚沉淀;再用二氯甲烷溶解,用饱和碳酸氢钠和浓盐水反复洗涤三次,乙醚沉淀干燥得产物;
3)原料胶原蛋白为I型胶原蛋白,来源于鼠尾I型胶原蛋白;
4)原位凝胶的制备:分别取不同比例的巯基壳聚糖与胶原蛋白的混合溶液,与炔基化聚乙二醇溶液混合,离心脱泡后迅速转移至圆柱形模具中静置成胶。
2.根据权利要求1所述的一种可降解原位凝胶的制备方法,其特征在于:原料壳聚糖和胶原蛋白均是可降解的天然大分子,对人体无毒无害。
3.根据权利要求1所述的一种可降解原位凝胶的制备方法,其特征在于:巯基化壳聚糖中含有大量的巯基,而炔基化聚乙二醇含有大量的炔基基团;巯基与炔基发生Click反应的条件简单,原子利用率高,副产物无害,合成迅速。
4.根据权利要求1所述的一种可降解原位凝胶的制备方法,其特征在于:所得原位凝胶的颜色为棕色,凝胶网络的形成能够对药物分子起到一定的控制释放作用。
5.根据权利要求1所述的一种可降解原位凝胶的制备方法,其特征在于:所得原位凝胶的凝胶网络对红细胞有很好的固定作用,胶原蛋白能够激活血小板,产生凝血作用。
6.根据权利要求1所述的一种可降解原位凝胶的制备方法,其特征在于:该凝胶成胶过程中可对种子细胞进行封装,胶原蛋白和壳聚糖组成的类细胞外基质环境能够模拟体内的组织环境,促进细胞在3D方向的生长。
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