CN109897235A - 一种甲壳素/石墨烯复合海绵及制备方法与应用 - Google Patents

一种甲壳素/石墨烯复合海绵及制备方法与应用 Download PDF

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CN109897235A
CN109897235A CN201910100643.6A CN201910100643A CN109897235A CN 109897235 A CN109897235 A CN 109897235A CN 201910100643 A CN201910100643 A CN 201910100643A CN 109897235 A CN109897235 A CN 109897235A
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chitin
preparation
graphene
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王小英
李晓云
黎珊珊
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South China University of Technology SCUT
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Priority to US17/053,795 priority patent/US20210260241A1/en
Priority to PCT/CN2019/114539 priority patent/WO2020155708A1/zh
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Abstract

本发明公开了一种甲壳素/石墨烯复合止血海绵及其制备方法。所述方法为：将一定量的鳞片石墨和甲壳素混合球磨后溶于NaOH/尿素溶剂中，离心分离，分散均匀后使用环氧氯丙烷交联剂交联，静置，透析后冻干，获得甲壳素/石墨烯复合海绵。该复合海绵不仅具有优良的凝血止血效果，而且具有良好的生物可降解性和细胞相容性。与现有技术相比，本发明使用球磨辅助的剥离方法制备甲壳素/石墨烯复合材料，制备方法简单易行；甲壳素和石墨烯的协同作用使止血海绵具有优异的止血性能；由于使用甲壳素作为原料，制备的复合海绵生物可降解，细胞相容性好，避免了止血治疗后止血材料的取出而导致二次出血的风险。

Description

一种甲壳素/石墨烯复合海绵及制备方法与应用
技术领域
本发明属于功能材料领域，具体涉及一种甲壳素/石墨烯复合止血海绵及其制备方法，可用于医疗、卫生等相关领域。
背景技术
目前，不可吸收降解止血材料在使用后需要进行二次手术取出，存在血痂的破裂和拉扯伤害的风险。而可吸收降解性止血材料（常用的透明质酸凝胶、胶原蛋白海绵等）虽然具有良好生物可降解性，但是所使用的原料存在成本高、提纯工艺复杂等问题。因此，使用低成本、易制备的原料来开发可降解性止血材料具有广大的应用前景。
甲壳素价格低廉，来源丰富，提取工艺简单。同时，具有优异生物相容性和生物可降解性能的甲壳素材料已被证实具有良好的润胀性能可以用于止血材料。然而单纯的甲壳素只是通过润胀来引起血细胞的聚集，从而凝血，不能满足快速止血的要求。
目前大部分止血材料通过加入功能性材料来增强止血效果，常用的功能性材料包括吸附性粘土、石墨烯和介孔型生物活性玻璃等。功能性材料具有大的比表面积及丰富的孔道结构，能够吸附血浆、激活血小板等促进凝血。粘土在止血的过程放热，且存在泄露的问题限制了粘土类止血材料的商品化应用。石墨烯拥有较大的比表面积，易与血液相互作用促进凝血。
然而，常用的石墨烯制备方法存在反应过程冗长，使用试剂有毒，环境不友好，高成本，难以大规模生产等问题。
发明内容
本发明的目的在于针对现有技术的不足，提供一种制备绿色，成本低廉，生物可降解的甲壳素/石墨烯止血海绵及其制备方法。本发明结合甲壳素的润胀能力和石墨烯的吸附促凝血的能力，采用将鳞片石墨和甲壳素混合剥离得到甲壳素/石墨烯复合材料，并将其制备成复合止血海绵。
本发明具体通过以下技术方案实现。
将鳞片石墨和甲壳素混合球磨后获得甲壳素/石墨烯复合材料，溶于NaOH/尿素溶剂中，离心分离后使用环氧氯丙烷交联剂交联，静置，透析后冻干，获得甲壳素/石墨烯复合止血海绵。
进一步的，甲壳素/石墨烯复合海绵的制备方法，具体包括如下步骤：
（1）甲壳素/石墨烯复合材料的制备：将鳞片石墨和甲壳素混合后在80~105℃的真空烘箱中干燥4~8 h，然后球磨4~8 h；
（2）甲壳素/石墨烯复合水凝胶的制备：将步骤（1）得到的复合材料通过冻融法溶于NaOH/尿素溶剂中，经过离心除去未剥离的石墨片层后将交联剂环氧氯丙烷滴加到溶液中，在0~4 ℃下搅拌0.2~2 h，得到均匀的溶液，然后在0~4 ℃静置8~24 h获得甲壳素/石墨烯水凝胶；
（3）甲壳素/石墨烯复合止血海绵的制备：将步骤（2）得到的复合水凝胶在40~60 ℃加热条件下透析7 ~14 d，在-40~-80 ℃冷冻干燥48~72 h。
优选的，步骤（1）中所述甲壳素与鳞片石墨的质量比为200:1~20:1。
优选的，步骤（2）中复合材料与溶剂的质量比为1:100~6:100。
优选的，步骤（1）用的球磨的条件为间歇式操作，每20~30 min停顿10~15 min，转速为180~210 r/min。
优选的，所述冻融法为在-20~-40 ℃条件下冷冻，在20~30 ℃环境下边融化边搅拌，循环2~6次使复合材料均匀分散在溶剂中。
优选的，所述NaOH/尿素溶剂中NaOH和尿素的质量分数分别为8~15 %和2~8 %。
优选的，所述的低速离心转速为1800~3000 rpm，时间为5~20 min。
优选的，每10 g溶液需要的交联剂用量为0.5~2 mL。
所述的甲壳素/石墨烯复合海绵应用于可降解创伤止血材料中，其凝血指数在9.6~18.8范围内，在6~12 h范围内降解了80%以上。
与现有技术相比，本发明具有以下优点：
（1）微机械剥离法能大规模绿色生产低成本石墨烯材料，所以本发明制备方法绿色、低成本、简便；
（2）结合甲壳素的润胀能力和石墨烯的吸附促凝血的能力，本发明制备的海绵具有优良的止血效果；
（3）本发明制备的海绵生物可降解，大大减少因止血材料取出而导致二次出血的风险。
附图说明
图1为不同复合止血海绵的凝血指数。
图2为不同复合止血海绵的体外降解时间。
具体实施方式
下面结合具体实施例对本发明作进一步说明，但不限于此。
实施例1：
将质量比为200:1甲壳素和鳞片石墨混合粉末在105 ℃的真空烘箱中干燥4 h。然后在间歇式操作（每20 min停顿10 min，转速为180 r/min）球磨8 h得到复合材料。
将得到的复合材料以质量比为2:100加入到10 % NaOH/4 %尿素溶剂中，在-40 ℃条件下冷冻后，在23 ℃环境下边融化边搅拌，冻融2次使其分散均匀，经过低速离心（转速为1800 rpm，时间为20 min）除去未剥离的石墨片层。将1 mL交联剂环氧氯丙烷滴加到每10g溶液中，在0 ℃下搅拌0.2 h，得到均匀的溶液。继续在2 ℃静置12 h获得甲壳素/石墨烯水凝胶。
将上述水凝胶在50 ℃加热条件下透析10 d，然后在-40 ℃冷冻干燥48 h得到甲壳素/石墨烯复合海绵。
制备所得的复合止血海绵的凝血指数为16.1±2.7，降解6 h后降解率超80%。
实施例2：
将质量比为100:1甲壳素和鳞片石墨混合粉末在100 ℃的真空烘箱中干燥6 h。然后在间歇式操作（每25 min停顿12 min，转速为200 r/min）球磨4 h得到复合材料。
将得到的复合材料以质量比为1:100加入到8 % NaOH/2 %尿素溶剂中，在-30 ℃条件下冷冻后，在30 ℃环境下边融化边搅拌，冻融4次使其分散均匀，经过低速离心（转速为2000 rpm，时间为18 min）除去未剥离的石墨片层。将0.5 mL交联剂环氧氯丙烷滴加到每10 g溶液中，在4 ℃下搅拌1.2 h，得到均匀的溶液。继续在4 ℃静置8 h获得甲壳素/石墨烯水凝胶。
将上述水凝胶在40 ℃加热条件下透析14 d，然后在-80 ℃冷冻干燥52 h得到甲壳素/石墨烯复合海绵。
制备所得的复合止血海绵的凝血指数为11.2±1.6，降解8 h后降解率超80%。
实施例3：
将质量比为20:1甲壳素和鳞片石墨混合粉末在80 ℃的真空烘箱中干燥8 h。然后在间歇式操作（每30 min停顿15 min，转速为210 r/min）球磨5 h得到复合材料。
将得到的复合材料以质量比为6:100加入到15 % NaOH/8 %尿素溶剂中，在-20 ℃条件下冷冻后，在20 ℃环境下边融化边搅拌，冻融6次使其分散均匀，经过低速离心（转速为3000 rpm，时间为5 min）除去未剥离的石墨片层。将2 mL交联剂环氧氯丙烷滴加到每10g溶液中，在0 ℃下搅拌2 h，得到均匀的溶液。继续在0℃静置24 h获得甲壳素/石墨烯水凝胶。
将上述水凝胶在60 ℃加热条件下透析7 d，然后在-50 ℃冷冻干燥72 h得到甲壳素/石墨烯复合海绵。
制备所得的复合止血海绵的凝血指数为16.0±2.1，降解12h后降解率超80%。
甲壳素/石墨烯海绵的效果评价
1.凝血指数（Blood Clotting Index, BCI）：称量0.05g甲壳素/石墨烯海绵，然后将凝结剂10 μL的CaCl2（0.2 M）溶液与0.1 mL柠檬酸钠抗凝的兔血快速混合后滴加到海绵上。在37℃下振荡（30 rpm）孵育5分钟后，然后加入12.5 mL生理盐水溶解未凝结的血液。紫外测定542 nm处血红蛋白溶液的吸光度值。测试时，设置空白对照组。凝血指数通过吸光度值比计算得到：BCI%=A1/A0×100% 。
2.降解率：称量0.05g甲壳素/石墨烯海绵，然后浸入10 mL的PBS中，并向其中加入10 mg溶菌酶。在37℃温度下孵育，并在确定的时间点转移到透析袋中。测量每个时间间隔的重量损失百分比，得出降解率。
图1给出了实施例1~3的海绵、PVF®及空白对照组的凝血指数。其中3CH为3%固含量的纯甲壳素止血海绵，即不含石墨烯，PVF®为商品化的医用聚乙烯醇海绵。对比发现，PVF®的凝血指数为27.0±4.7，甲壳素止血海绵的凝血指数为23.0±1.5，可见甲壳素止血海绵本身具有较好的凝血效果。加入石墨烯后的凝血指数比单纯甲壳素的凝血效果更好，而且当甲壳素与鳞片石墨的质量比为100:1时，凝血指数显著下降至11.2，所以本发明制备的止血海绵具有优良的止血效果。
为了测量海绵的凝血能力，将凝结剂10 μL的CaCl2（0.2 M）溶液与0.1 mL柠檬酸钠抗凝的兔血快速混合后滴加到海绵上。在37℃下振荡（30 rpm）孵育5分钟后，然后加入12.5 mL生理盐水溶解未凝结的血液。紫外测定542 nm处血红蛋白溶液的吸光度值。测试时，设置空白对照组。凝血指数（Blood Clotting Index, BCI）通过吸光度值比计算得到：
BCI%=A1/A0×100%
其中，A1为加入止血海绵后的吸收值，A0为空白组吸收值。BCI的数值越小，表明材料的止血性能越好。图2给出了实施例1~3制备的海绵及PVF®的降解时间，从图2中可以得出，本发明中制备的不同石墨烯含量的复合止血海绵几乎在12 h内降解80%以上，而PVF ®在12h后降解不到10 %，由此证明了本发明的复合止血海绵具有优异的生物可降解性。体外降解试验在模拟的生理条件下进行。将50 mg样品浸入10 mL的PBS中，并向其中加入10 mg溶菌酶。在37℃温育，并在确定的时间点转移到透析袋中。测量每个时间间隔的重量损失百分比。
以上实施例仅为本发明较优的实施方式，仅用于解释本发明，而非限制本发明，本领域技术人员在未脱离本发明精神实质下所作的改变、替换、修饰等均应属于本发明的保护范围。

Claims (10)

1.一种甲壳素/石墨烯复合海绵的制备方法，其特征在于：首先将鳞片石墨与甲壳素混合球磨得到甲壳素/石墨烯复合材料；甲壳素/石墨烯复合材料均匀分散在溶剂中，经过离心除去未剥离的石墨片层，与环氧氯丙烷交联，透析，冻干下得到所述复合海绵。
2.根据权利要求1所述的制备方法，其特征在于：具体包括如下步骤：
（1）甲壳素/石墨烯复合材料的制备：将鳞片石墨和甲壳素混合后在80~105℃的真空烘箱中干燥4~8 h，然后球磨4~8 h；
（2）甲壳素/石墨烯复合水凝胶的制备：将步骤（1）得到的复合材料通过冻融法溶于NaOH/尿素溶剂中，经过离心除去未剥离的石墨片层后将交联剂环氧氯丙烷滴加到溶液中，在0~4 ℃下搅拌0.2~2 h，得到均匀的溶液，然后在0~4 ℃静置8~24 h获得甲壳素/石墨烯水凝胶；
（3）甲壳素/石墨烯复合止血海绵的制备：将步骤（2）得到的复合水凝胶在40~60 ℃加热条件下透析7 ~14 d，在-40~-80 ℃冷冻干燥48~72 h。
3.根据权利要求2所述的制备方法，其特征在于，所述步骤（1）中所述甲壳素与鳞片石墨的质量比为200:1~20:1，所述步骤（2）中复合材料与溶剂的质量比为1:100~6:100。
4. 根据权利要求2所述的制备方法，其特征在于，所述步骤（1）中的球磨条件为间歇式操作，每20~30 min停顿10~15 min，转速为180~210 r/min。
5. 根据权利要求2所述的制备方法，其特征在于，所述冻融法为在-20~-40 oC条件下冷冻，在20~30 ℃环境下边融化边搅拌，循环2~6次使复合材料均匀分散在溶剂中。
6. 根据权利要求2所述的制备方法，其特征在于，所述NaOH/尿素溶剂中NaOH和尿素的质量分数分别为8~15 %和2~8 %。
7. 根据权利要求2所述的制备方法，其特征在于，所述离心的转速为1800~3000 rpm，时间为5~20 min。
8. 根据权利要求2所述的制备方法，其特征在于，所述步骤（2）中每10 g溶液需要的交联剂用量为0.5~2 mL。
9.由权利要求1-8所述的制备方法制备得到的甲壳素/石墨烯复合海绵。
10. 权利要求9所述的甲壳素/石墨烯复合海绵应用于可降解创伤止血材料中，其特征在于：其凝血指数为9.6~18.8，在6~12 h范围内降解了80%以上。
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