CN115181321A - 胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法 - Google Patents
胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法 Download PDFInfo
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Abstract
本发明提供了胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，与现有技术相比，本发明具有如下的有益效果：1)介孔生物玻璃微球的引入增加了复合材料的负电荷。通过内源性途径加速凝血过程；2)介孔生物玻璃微球提供额外Ca2+源，使凝血过程所需Ca2+含量充足，防止血液因为缺钙而凝固速度减缓；3)通过低温淬火，制备多孔结构，提高材料的孔隙率和比表面积，高孔隙率和大比表面积可快速吸收血浆，使血细胞积聚在表面上，从而促进血液在伤口表面凝结。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的BCI为43.1％，具有高效快速止血能力。
Description
技术领域
本发明涉及一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，属于复合材料和生物医学材料领域。
背景技术
手术和战场上不可控失血是死亡的重要原因，据不完全统计，战场上有一半以上的的死亡是由于失血造成的。快速凝血预防失血是抢救生命的重要手段。目前止血主要分为内源性止血和外源性凝血两种。事实上，在紧急情况下，没有辅助器械和药物并不能完全止血。传统的止血方法主要是通过纱布按压和手术缝合，而以上方法仅用于微量出血。有许多不同类型的出血，例如，心血管、肝脏和肾脏等出血不能使用纱布按压的方法止血。而且伤口的出血是一个持续的过程。如果不能进行有效的止血，很容易导致休克或死亡。
体内理想的止血材料应具有良好的生物相容性、体内降解和促进伤口愈合。目前生物衍生物和植物多糖被广泛应用于止血材料，如胶原蛋白、纤维蛋白、明胶、壳聚糖、淀粉和海藻酸钠等。除此之外，一些无机材料，如生物活性玻璃、蒙脱石、高岭土和沸石等材料由于具有高孔隙率和大比表面积，能够快速吸收水分，也被广泛应用于止血材料。如何进一步提高材料的止血性能成为科学研究的热点。
发明内容：
本发明的目的在于提供一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，以解决现有技术中所存在的上述问题。
为了实现上述目的，本发明的技术方案如下：
一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其包括如下步骤：
制备介孔生物玻璃微球；
将胶原溶于盐酸溶液中，得到溶液A，将羧甲基纤维素溶于去离子水中，得到溶液B，将所述溶液A和溶液B混匀后，加入所述介孔生物玻璃微球，分散均匀，调节pH值至5～6，得到反应液；
将啉乙磺酸溶于去离子水中，调节pH值至5～6，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺，得到交联剂溶液；
将所述交联剂溶液加入反应液中，搅拌反应24h后，将产物进行透析，得到前驱体；
将所述前驱体在-50～-10℃下进行淬火后，真空冷冻干燥，得到所述胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。
作为优选方案，所述介孔生物玻璃微球的制备方法为：
将十六烷基三甲基溴化铵溶于乙醇和去离子水的混和液中，后调节pH值至10～12，搅拌条件下依次加入正硅酸四乙酯、磷酸三乙酯和硝酸钙，磁力搅拌反应4h，离心、乙醇和水洗涤3遍，真空干燥24h，在580～650℃下煅烧，得到所述介孔生物玻璃微球。
作为优选方案，所述正硅酸四乙酯、磷酸三乙酯和硝酸钙的质量比为(5～10)：(1～2)：(3～6)。
作为优选方案，所述反应液中，胶原、羧甲基纤维素和介孔生物玻璃微珠的质量比为(8～12)：(10～15)：(1～2)。
作为优选方案，所述交联剂溶液中，1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺的质量比为(2～4)：(1～2)。
一种由前述制备方法得到的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。
一种如前述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料在止血材料中的用途。
本发明的基本原理为：
以十六烷基三甲基溴化铵为表面活性剂，在氨水条件下水解正硅酸四乙酯、磷酸三乙酯和硝酸钙，最后煅烧等到介孔生物玻璃微球。
将胶原、羧甲基纤维素和介孔生物玻璃微球共混，得到混合液。将混合液采用EDS/NHS交联，透析、淬火最终得到胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。
与现有技术相比，本发明具有如下的有益效果：
1)介孔生物玻璃微球的引入增加了复合材料的负电荷。通过内源性途径加速凝血过程。
2)介孔生物玻璃微球提供额外Ca2+源，使凝血过程所需Ca2+含量充足，防止血液因为缺钙而凝固速度减缓。
3)通过低温淬火，制备多孔结构，提高材料的孔隙率和比表面积，高孔隙率和大比表面积可快速吸收血浆，使血细胞积聚在表面上，从而促进血液在伤口表面凝结。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为本发明制备的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的扫描电镜图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
本实施例涉及一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，具体包括如下步骤：
1)将1g的CTAB加入50mL乙醇和60mL的去离子水，搅拌溶解，加入1mL氨水搅拌15min，调节pH值至10～12，搅拌条件下依次加入3g正硅酸四乙酯、0.4g磷酸三乙酯、2g硝酸钙，磁力搅拌反应4h，离心、乙醇和水洗涤3遍，真空干燥24h。空气条件600℃煅烧3h得到介孔生物玻璃微球(mBN)。
2)将1g的胶原(Col)溶于50mL盐酸溶液中，1g羧甲基纤维素(CMC)溶于30mL去离子水中。混合上述溶液磁力搅拌，得到Col/CMC溶液。将0.1g介孔生物玻璃微球加入Col/CMC溶液中，磁力搅拌混合，得到Col/CMC/mBN混合液。
3)将吗啉乙磺酸(MES)溶于去离子水中，用NaOH调节pH为5，将0.1g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和0.1g N-羟基琥珀酰亚胺(NHS)加入MES溶液中得到EDC/NHS交联剂。将Na2HPO4溶液加入Col/CMC/mBN混合液溶液，调节pH至5，在常温下加入EDC/NHS交联剂，搅拌反应24h。将混合物装入透析袋中，透析24h，透析结束后置于低温冰箱中，-30℃低温淬火120min，淬火结束后真空冷冻干燥24h，得到Col/CMC/mBN复合材料。
实施例1制备的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的形貌如图1所示，复合材料呈现多孔状结构，孔大小均匀，孔径约为300～400nm，但是有部分孔被胶原所覆盖。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的孔隙率为84.1％，比表面积为10.2m2/g。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的BCI为43.1％。
实施例2
本实施例涉及一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，具体包括如下步骤：
1)将1g的CTAB加入50mL乙醇和60mL的去离子水，搅拌溶解，加入1mL氨水搅拌15min，调节pH值至10～12，搅拌条件下依次加入3.5g正硅酸四乙酯、0.5g磷酸三乙酯、2.3g硝酸钙，磁力搅拌反应4h，离心、乙醇和水洗涤3遍，真空干燥24h。空气条件620℃煅烧4h得到介孔生物玻璃微球(mBN)。
2)将0.8g的胶原(Col)溶于50mL盐酸溶液中，1.5g羧甲基纤维素(CMC)溶于30mL去离子水中。混合上述溶液磁力搅拌，得到Col/CMC溶液。将0.12g介孔生物玻璃微球加入Col/CMC溶液中，磁力搅拌混合，得到Col/CMC/mBN混合液。
3)将吗啉乙磺酸(MES)溶于去离子水中，用NaOH调节pH为5.5，将0.15g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和0.12gN-羟基琥珀酰亚胺(NHS)加入MES溶液中得到EDC/NHS交联剂。将Na2HPO4溶液加入Col/CMC/mBN混合液溶液，调节pH至5.2，在常温下加入EDC/NHS交联剂，搅拌反应24h。将混合物装入透析袋中，透析24h，透析结束后置于低温冰箱中，-15℃低温淬火100min，淬火结束后真空冷冻干燥24h，得到Col/CMC/mBN复合材料。
实施例2制备的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的孔隙率为83.9％，比表面积为10.8m2/g。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的BCI为44.6％。
实施例3
本实施例涉及一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，具体包括如下步骤：
1)将1g的CTAB加入50mL乙醇和60mL的去离子水，搅拌溶解，加入1mL氨水搅拌15min，调节pH值至10～12，搅拌条件下依次加入4g正硅酸四乙酯、0.5g磷酸三乙酯、2.2g硝酸钙，磁力搅拌反应4h，离心、乙醇和水洗涤3遍，真空干燥24h。空气条件590℃煅烧3h得到介孔生物玻璃微球(mBN)。
2)将1.2g的胶原(Col)溶于50mL盐酸溶液中，1.2g羧甲基纤维素(CMC)溶于30mL去离子水中。混合上述溶液磁力搅拌，得到Col/CMC溶液。将0.15g介孔生物玻璃微球加入Col/CMC溶液中，磁力搅拌混合，得到Col/CMC/mBN混合液。
3)将吗啉乙磺酸(MES)溶于去离子水中，用NaOH调节pH为5.8，将0.2g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和0.15gN-羟基琥珀酰亚胺(NHS)加入MES溶液中得到EDC/NHS交联剂。将Na2HPO4溶液加入Col/CMC/mBN混合液溶液，调节pH至5.5，在常温下加入EDC/NHS交联剂，搅拌反应24h。将混合物装入透析袋中，透析24h，透析结束后置于低温冰箱中，-20℃低温淬火150min，淬火结束后真空冷冻干燥24h，得到Col/CMC/mBN复合材料。
实施例3制备的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的孔隙率为86.9％，比表面积为11.9m2/g。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的BCI为42.5％。
对比例1
与实施例1不同的是步骤3)中，省略低温冰箱淬火，直接真空冷冻干燥，得到胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。该复合材料的孔隙率为75.2％、比表面积为7.12m2/g。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的BCI为51.6％。
对比例2
与实施例1不同的是步骤2)中，介孔生物玻璃微球复合材料的添加量为0，
最终得到胶原/羧甲基纤维素复合材料，该复合材料的孔隙率为85.1％，比表面积为11.1m2/g。采用凝血指数(BCI)在体外进行评估，通过血红蛋白溶液的吸光度值来判断其血液凝结速率。胶原/羧甲基纤维素复合材料的BCI为53.4％。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (7)
1.一种胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其特征在于，包括如下步骤：
制备介孔生物玻璃微球；
将胶原溶于盐酸溶液中，得到溶液A，将羧甲基纤维素溶于去离子水中，得到溶液B，将所述溶液A和溶液B混匀后，加入所述介孔生物玻璃微球，分散均匀，调节pH值至5～6，得到反应液；
将啉乙磺酸溶于去离子水中，调节pH值至5～6，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺，得到交联剂溶液；
将所述交联剂溶液加入反应液中，搅拌反应24h后，将产物进行透析，得到前驱体；
将所述前驱体在-50～-10℃下进行淬火后，真空冷冻干燥，得到所述胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。
2.如权利要求1所述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其特征在于，所述介孔生物玻璃微球的制备方法为：
将十六烷基三甲基溴化铵溶于乙醇和去离子水的混和液中，后调节pH值至10～12，搅拌条件下依次加入正硅酸四乙酯、磷酸三乙酯和硝酸钙，磁力搅拌反应4h，离心、乙醇和水洗涤3遍，真空干燥24h，在580～650℃下煅烧，得到所述介孔生物玻璃微球。
3.如权利要求2所述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其特征在于，所述正硅酸四乙酯、磷酸三乙酯和硝酸钙的质量比为(5～10)：(1～2)：(3～6)。
4.如权利要求1所述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其特征在于，所述反应液中，胶原、羧甲基纤维素和介孔生物玻璃微珠的质量比为(8～12)：(10～15)：(1～2)。
5.如权利要求1所述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料的制备方法，其特征在于，所述交联剂溶液中，1-(3-二甲氨基丙基)-3-乙基碳二亚胺和N-羟基琥珀酰亚胺的质量比为(2～4)：(1～2)。
6.一种由权利要求1～5中任意一项所述制备方法得到的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料。
7.一种如权利要求6所述的胶原/羧甲基纤维素/介孔生物玻璃微球复合多孔材料在止血材料中的用途。
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