CN112773942B - 一种可注射自愈合抗菌水凝胶的制备方法 - Google Patents
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Abstract
本发明涉及一种可注射自愈合抗菌水凝胶的制备方法,采用氢氧化钾/尿素水溶液为溶剂,在常温下快速搅拌并超声后使天然蚕丝剥离为纳米纤维,然后经过分离制得均匀的蚕丝纳米纤维溶液。将蚕丝纳米纤维选择性氧化后与甲壳素季铵盐溶液或壳聚糖季铵盐溶液混合,得到可注射自愈合抗菌蚕丝纳米纤维/甲壳素或壳聚糖季铵盐水凝胶。所得水凝胶同时具有优异的生物活性、生物可降解性。
Description
技术领域
本发明涉及一种可注射自愈合抗菌水凝胶的制备方法,属于纳米材料和生物应用组织工程领域。
背景技术
近年,由于动态化学可逆的性质在气体吸附和分离、纳米复合材料制备和新材料的构筑等方面有广泛应用,受到越来越多研究者们的关注。此外,动态化学也被用于设计并构筑具有可注射性或自修复能力的水凝胶,可注射水凝胶由于其突出的优点在载药、细胞培养以及组织工程等方面具有广泛应用。在已报道构筑适合细胞封装、生物医用组织工程的水凝胶中,具有自修复能力的可注射水凝胶拥有巨大的优势。
季铵化甲壳素和季铵化壳聚糖是天然聚多糖衍生物,具有优异的生物可降解性、抗菌性和生物活性。蚕丝是天然动物丝蛋白,具有优良的机械性能和理化性质,如柔韧性和抗拉伸强度、透气透湿性、缓释性等。纳米尺度的蚕丝纳米纤维表面具有丰富的醛基、硫醇基、羟基、羧基等基团,拓展了蚕丝纳米纤维的应用。蚕丝纳米纤维的制备方法包括自上而下和自下而上这两种方式。自下而上的方法首先利用溶剂如无机盐溶液(溴化锂水溶液(Adv.Mater.2017,29,1702769.)、氯化钙/乙醇水溶液(Sci.Rep.2017,7,2107.))、浓酸(Adv.Sci.2017,4,1700191.)或离子液体(J.Phys.Chem.B 2017,121,6108-6116.)溶解丝蛋白,然后通过自组装成丝蛋白纳米纤维。在这种方法中,破坏丝蛋白分子间的氢键作用,由于溶解过程中蚕丝原纤维结构的破坏,再生丝纳米纤维的结构与天然丝不同,由蚕丝纳米纤维所制备的材料性能往往不如天然蚕丝。另一方面,自上而下的方法涉及使用较弱的溶剂,如盐酸/甲酸(Mater.Sci.Eng.,C 2015,48,444-452)、甲酸-氯化钙(J.Mater.Chem.B2014,2,3879-3885)、甲酸-溴化锂(Biomacromolecules 2016,17,3000-3006.)和六氟异丙醇(Nat.Commun.2017,8,1387.)使蚕丝选择性溶解得到蚕丝纳米纤维。此外,将脱胶蚕丝加入到预冷至-12℃的氢氧化钠/尿素溶液中,经过多次循环冷冻-解冻后透析至中性,然后进行超声处理,可以得到蚕丝纳米纤维溶液(ACS Nano 2018,12,11860-11870)。虽然氢氧化钠和氢氧化钾化学性质类似,但是蚕丝在氢氧化钠/尿素水溶液中必须采用循环冷冻-解冻方法才能有效剥离蚕丝纤维得到纳米纤维,不仅耗时、耗能,而且剥离效率并不明显,依然存在许多微米级的蚕丝纤维无法剥离,因而难以实际应用。而本申请通过选择氢氧化钾/尿素水溶液可以在在室温条件下将蚕丝纤维完全剥离成纳米纤维,因而是一种高效、低成本、节能的“绿色”工艺。而且进一步将蚕丝纳米纤维进行选择性氧化,与具有抗菌性的季铵化甲壳素或季铵化壳聚糖之间通过形成动态共价键,得到具有可注射自愈合的抗菌蚕丝纳米纤维/甲壳素或壳聚糖季铵盐水凝胶。这种新型水凝胶在创面修复、组织工程支架、药物和蛋白缓控释等生物医用材料领域有广泛应用前景。
发明内容
本发明针对现有技术存在的问题,提供了一种同时具有可注射、自愈合、抗菌性、生物活性良好、生物可降解的蚕丝纳米纤维/甲壳素或壳聚糖季铵盐水凝胶的制备方法。
本发明解决上述技术问题所采用的方案是:
一种可注射自愈合抗菌水凝胶的制备方法,其特征在于,包括如下步骤:
(1)采用氢氧化钾/尿素水溶液为溶剂,其中氢氧化钾的浓度为10wt%~25wt%,尿素的浓度为5wt%~30wt%,以蚕丝为溶质,在室温下快速搅拌1分钟~6小时,超声后使天然蚕丝剥离为纳米纤维,经过分离制得均匀的蚕丝纳米纤维溶液,然后将蚕丝纳米纤维选择性氧化;
(2)将上述所得蚕丝纳米纤维溶液或者选择性氧化后的蚕丝纳米纤维溶液与甲壳素季铵盐溶液或壳聚糖季铵盐溶液在4℃~37℃条件下混合,使其凝胶化得到蚕丝纳米纤维增强的可注射自愈合抗菌水凝胶。
优选地,所述甲壳素季铵盐或壳聚糖季铵盐的取代度为0.2~0.6,所述甲壳素季铵盐或壳聚糖季铵盐溶液的质量分数为1wt%~4wt%,所述甲壳素季铵盐或壳聚糖季铵盐中氨基的比例与蚕丝纳米纤维中醛基的比为0.7~1.8。
优选地,步骤(1)所得蚕丝纳米纤维溶液中蚕丝的固含量为1wt%~12wt%,在步骤(2)混合前将所得蚕丝纳米纤维溶液稀释或者浓缩至固含量为1wt%~3wt%。
优选地,步骤(1)超声处理的功率为100w~1200w,超声时间不超过6小时。
优选地,将所得的蚕丝纳米纤维溶液与甲壳素季铵盐或壳聚糖季铵盐混合前,将所述蚕丝纳米纤维选择性氧化,使蚕丝纳米纤维发生氧化反应得到有更多醛基的蚕丝纳米纤维溶液,所得的氧化蚕丝纳米纤维中醛基含量可达到25%~45%。
优选地,所述的甲壳素季铵盐采用如下方法制备:配置含氢氧化钾,尿素的水溶液,加入甲壳素,低温机械搅拌直到得到透明澄清的甲壳素溶液;向甲壳素溶液中滴加季铵化试剂,使得季铵化试剂与甲壳素单元的摩尔比为4:1~16:1,反应温度-10℃~40℃,搅拌3小时~48小时后加入HCl调节至中性;反应液经蒸馏水透析,冷冻干燥,即得到甲壳素季铵盐。
优选地,所述的壳聚糖季铵盐采用如下方法制备:配置含氢氧化钾,尿素的水溶液,加入壳聚糖,低温机械搅拌直到得到透明澄清的壳聚糖溶液;向壳聚糖溶液中滴加季铵化试剂,使得季铵化试剂与壳聚糖单元的摩尔比为4:1~16:1,反应温度-10℃~40℃,搅拌3小时~48小时后加入HCl调节至中性;反应液经蒸馏水透析,冷冻干燥,即得到壳聚糖季铵盐。
优选地,所述季铵化试剂有:2,3-环氧丙基三甲基氯化铵、2,3-环氧丙基三丙基氯化铵、3-氯-2-羟丙基三甲基氯化铵中的任一种或多种。
优选地,所述其他衍生化试剂包括氯乙酸、氯丙酸、氯丁酸、氯乙酸钠、环氧乙烷硫酸二甲酯、对甲基苯磺酰氯、琥珀酸酐、马来酸酐、丙烯酰胺、丙烯腈中的任一种或多种。
本发明采用氢氧化钾/尿素溶液体系下室温搅拌超声分散蚕丝,能够简单高效快速地剥离得到蚕丝纳米纤维,同时溶解过程中不破坏蚕丝的化学结构,得到的蚕丝纳米纤维表面有丰富的化学基团,如-SH、-COO、-OH和-CHO,并且可以通过氧化反应使蚕丝纳米纤维表面获得更多的醛基。由于季铵化甲壳素或壳聚糖分子表面含有丰富的氨基(-NH2),可以与蚕丝纳米纤维表面的醛基通过席夫碱反应形成动态的化学键,进而得到可注射自愈合抗菌水凝胶,同时由于蚕丝纳米纤维良好的力学性能,能够赋予所得混合物水凝胶优异的力学强度和生物活性。通过调节材料的浓度和官能团的比例还可以控制混合溶液在体温条件下的凝胶化时间以及力学强度。能够将细胞、蛋白质、酶和治疗性药物加入到该溶液中,在体温条件下快速形成水凝胶,可以作为细胞的支架材料、药物的载体等;甲壳素、壳聚糖衍生物以及蚕丝纳米纤维都具有很好的生物相容性和生物活性,形成的水凝胶可以用来做创面愈合的伤口敷料;因此,蚕丝纳米纤维/甲壳素或壳聚糖季铵盐水凝胶非常适合应用于生物应用与组织工程领域。
附图说明
图1为实施例6所得季铵化壳聚糖溶液;
图2为实例18所得蚕丝纳米纤维溶液光照实验下的丁达尔效应;
图3为实施例22所得蚕丝纳米纤维增强的可注射自愈合抗菌水凝胶,其中a为季铵化壳聚糖溶液、b为蚕丝纳米纤维溶液、c为a和b混合后快速形成的凝胶。
具体实施方式
为更好的理解本发明,下面的实施例是对本发明的进一步说明,但本发明的内容不仅仅局限于下面的实施例。
实施例1
配置含20wt%氢氧化钾,4wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g甲壳素,机械搅拌30分钟后得到透明澄清的2wt%甲壳素溶液;向甲壳素溶液中加5.96g的3-氯-2-羟丙基三甲基氯化铵,使得季铵化试剂与甲壳素单元的摩尔比为4:1,反应温度25℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状甲壳素季铵盐样品,测得所得样品取代度DQ=0.18,NH2含量=15%。
实施例2~6的制备方法与实施例1类似,区别点如下表1所示。
表1实施例1~6制备参数与所得季铵盐样品的取代度和NH2含量
实施例7
配置含18wt%氢氧化钾,6wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g壳聚糖,机械搅拌30分钟后得到透明澄清的2wt%壳聚糖溶液;向壳聚糖溶液中加的7.53g 3-氯-2-羟丙基三甲基氯化铵,使得季铵化试剂与壳聚糖单元的摩尔比为4:1,反应温度-30℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状壳聚糖季铵盐样品(DQ=0.39,NH2=78%)。
实施例8~12的制备方法与实施例7类似,区别点如下表2所示。
表2实施例7~12制备参数与所得季铵盐样品的取代度和NH2含量
实施例13:
配置含20wt%氢氧化钾,4wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g甲壳素,机械搅拌30分钟后得到透明澄清的2wt%甲壳素溶液;向甲壳素溶液中加3-氯-2-羟丙基三甲基氯化铵,然后加入氯乙酸,使得季铵化试剂与甲壳素单元的摩尔比为4:1,使得氯乙酸与甲壳素单元的摩尔比为4:1,反应温度40℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状季铵化羧甲基甲壳素样品,测得所得样品取代度季铵盐取代度DQ=0.18,羧甲基取代度DS=0.15,NH2含量为35%。
实施例14:
配置含20wt%氢氧化钾,4wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g甲壳素,机械搅拌30分钟后得到透明澄清的2wt%甲壳素溶液;向甲壳素溶液中加3-氯-2-羟丙基三甲基氯化铵,然后加入环氧乙烷,使得季铵化试剂与甲壳素单元的摩尔比为4:1,使得环氧乙烷与甲壳素单元的摩尔比为4:1反应温度40℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状季铵化羟丙基甲壳素样品,测得所得样品取代度季铵盐取代度DQ=0.18,羟乙基取代度DS=0.16,NH2含量为34%。
实施例15:
配置含20wt%氢氧化钾,4wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g甲壳素,机械搅拌30分钟后得到透明澄清的2wt%甲壳素溶液;向甲壳素溶液中加2,3-环氧丙基三丙基氯化铵,然后加入氯乙酸,使得季铵化试剂与甲壳素单元的摩尔比为4:1,使得环氧乙烷与甲壳素单元的摩尔比为4:1反应温度40℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状季铵化羟丙基甲壳素样品,测得所得样品取代度季铵盐取代度DQ=0.17,羧甲基取代度DS=0.16,NH2为34%。
实施例16
配置含18wt%氢氧化钾,6wt%尿素的水溶液98g,预冷至-30℃,室温下加入2g壳聚糖,机械搅拌30分钟后得到透明澄清的2wt%壳聚糖溶液;向壳聚糖溶液中加的3-氯-2-羟丙基三甲基氯化铵,然后加入氯乙酸,使得季铵化试剂与壳聚糖单元的摩尔比为4:1,使得氯乙酸与壳聚糖单元的摩尔比为4:1,反应温度25℃,搅拌24小时后加入HCl中和反应液;反应液经蒸馏水透析7天,冷冻干燥,即得到白色纤维状羧甲基壳聚糖季铵盐样品,测得所得样品取代度季铵盐取代度DQ=0.39,羧甲基取代度DS=0.36,NH2为78%。
实施例17:
将4g蚕丝原料加入到总质量为100g的10wt%氢氧化钾/20wt%尿素溶液中,在室温下快速搅拌3h,得到分散均匀的蚕丝纤维溶液,转入透析袋中用去离子水透析至中性。然后转移到烧杯中,在细胞破碎仪中以600w的功率超声30分钟,得到淡蓝色的蚕丝纳米纤维溶液。将所得的溶液以8000r/min的速度离心,上层液体倒入广口瓶中密封保存于4℃的冰箱中。取部分溶液进行冻干,用称重法计算所得的蚕丝纳米纤维的含量为千分之八。根据总体积计算出蚕丝纳米纤维溶液中蚕丝的总质量,然后计算出纳米纤维的转化率为66%,醛基含量=9.5%。
实施例18~21的制备方法与实施例17类似,区别点如下表3所示。
表3实施例18~21制备参数与产物参数
实施例22
将上述实施例21得到的蚕丝纳米纤维溶液配成1wt%溶液,逐滴加入预先溶解于10mL水中的NaIO4(0.1g),于25℃避光搅拌2h后加入0.4mL乙二醇终止反应,继续搅拌1h后透析,得到醛基含量更高的蚕丝纳米纤维,醛基含量24.5%。
实施例23
将上述实施例21得到的蚕丝纳米纤维溶液配成1wt%溶液,逐滴加入预先溶解于10mL水中的NaIO4(0.2g),于40℃避光搅拌2h后加入0.4mL乙二醇终止反应,继续搅拌1h后透析,得到醛基含量更高的蚕丝纳米纤维,醛基含量33.8%。
实施例24
将上述实施例21得到的蚕丝纳米纤维溶液配成1wt%溶液,逐滴加入预先溶解于10mL水中的NaIO4(0.3g),于25℃避光搅拌2h后加入0.4mL乙二醇终止反应,继续搅拌1h后透析,得到醛基含量更高的蚕丝纳米纤维,醛基含量42%。
实施例25
将实施例6制得的季铵化甲壳素配成2wt%的溶液,取实施例14得到的蚕丝纳米纤维,根据氨基和醛基含量比0.7~1.8配制一定浓度的蚕丝纳米纤维溶液,然后将两种溶液与37℃下混合,5min内溶液即快速固化形成凝胶。
实施例26~35的制备方法与实施例25类似,区别点如下表3所示。
表3实施例22~35制备参数与产物凝胶时间
以上所述是本发明的优选实施方式而已,当然不能以此来限定本发明之权利范围,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和变动,这些改进和变动也视为本发明的保护范围。
Claims (9)
1.一种可注射自愈合抗菌水凝胶的制备方法,其特征在于,包括如下步骤:
(1)采用氢氧化钾/尿素水溶液为溶剂,其中氢氧化钾的浓度为10wt%~25wt%,尿素的浓度为5wt%~30wt%,以蚕丝为溶质,在室温下快速搅拌1分钟~6小时,超声后使天然蚕丝剥离为纳米纤维,经过分离制得均匀的蚕丝纳米纤维溶液,然后将蚕丝纳米纤维选择性氧化;
(2)将上述所得蚕丝纳米纤维溶液或者选择性氧化后的蚕丝纳米纤维溶液与甲壳素季铵盐溶液或壳聚糖季铵盐溶液在4℃~37℃条件下混合,使其凝胶化得到可注射自愈合抗菌蚕丝纳米纤维/甲壳素或壳聚糖季铵盐水凝胶,所述甲壳素季铵盐或壳聚糖季铵盐中氨基与蚕丝纳米纤维中醛基的摩尔比为0.7~1.8。
2.根据权利要求1所述的制备方法,其特征在于,所述甲壳素季铵盐或壳聚糖季铵盐的取代度为0.2~0.6,所述甲壳素季铵盐或壳聚糖季铵盐溶液的质量分数为1wt%~4wt%。
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)所得蚕丝纳米纤维溶液中蚕丝的固含量为1wt%~12wt%,在步骤(2)混合前将所得蚕丝纳米纤维溶液稀释或者浓缩至固含量为1wt%~3wt%。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)超声处理的功率为100~1200w,超声时间不超过6小时。
5.根据权利要求1所述的制备方法,其特征在于,所述的甲壳素季铵盐采用如下方法制备:配置含氢氧化钾,尿素的水溶液,加入甲壳素,低温机械搅拌直到得到透明澄清的甲壳素溶液;向甲壳素溶液中滴加季铵化试剂,使得季铵化试剂与甲壳素单元的摩尔比为4:1~16:1,反应温度-10℃~40℃,搅拌3小时~48小时后加入HCl调节至中性;反应液经蒸馏水透析,冷冻干燥,即得到甲壳素季铵盐。
6.根据权利要求1所述的制备方法,其特征在于,所述的壳聚糖季铵盐采用如下方法制备:配置含氢氧化钾,尿素的水溶液,加入壳聚糖,低温机械搅拌直到得到透明澄清的壳聚糖溶液;向壳聚糖溶液中滴加季铵化试剂,使得季铵化试剂与壳聚糖单元的摩尔比为4:1~16:1,反应温度-10℃~40℃,搅拌3小时~48小时后加入HCl调节至中性;反应液经蒸馏水透析,冷冻干燥,即得到壳聚糖季铵盐。
7.根据权利要求5或6所述的制备方法,其特征在于:所述季铵化试剂为2,3-环氧丙基三甲基氯化铵、2,3-环氧丙基三丙基氯化铵、3-氯-2-羟丙基三甲基氯化铵中的任一种或多种。
8.根据权利要求5或6所述的制备方法,其特征在于:在加入季铵化试剂的同时加入其他衍生化试剂,所述其他衍生化试剂与甲壳素或壳聚糖单体单元摩尔比为4:1~16:1。
9.根据权利要求8所述的制备方法,其特征在于:所述其他衍生化试剂包括氯乙酸、氯丙酸、氯丁酸、氯乙酸钠、环氧乙烷硫酸二甲酯、对甲基苯磺酰氯、琥珀酸酐、马来酸酐、丙烯酰胺、丙烯腈中的任一种或多种。
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