CN115322397A - 一种预防术后腹腔粘连的两性离子水凝胶及其制备方法 - Google Patents
一种预防术后腹腔粘连的两性离子水凝胶及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种预防术后腹腔粘连的两性离子水凝胶及其制备方法,属于医用生物材料领域。本发明的预防术后腹腔粘连的两性离子水凝胶以两性离子单体磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6‑氨基己酸和纳米氧化锌颗粒为原料,在引发剂和交联剂的作用下自由基聚合一锅法原位形成包覆纳米氧化锌颗粒的水凝胶。本发明得到的水凝胶原材料易获得,制备方法操作简便,具有优异的止血、防污及抗菌性能。本发明的水凝胶可通过注射或者涂敷的方式应用到腹腔的损伤部位,具有显著的促进伤口愈合、预防术后腹腔粘连的效果。
Description
技术领域
本发明属于医用生物材料领域,具体涉及一种具有防污、止血、抗菌性能,能促进伤口愈合并且预防术后腹腔粘连的两性离子水凝胶及其制备方法。
背景技术
腹腔粘连是由于腹腔手术导致的组织和器官之间的粘连,经历过腹腔手术的患者中约有93%的比例会发生腹腔内粘连,如今已经成为一个普遍存在的医学难题。术后粘连会造成很严重的并发症,如肠梗阻,女性不孕,长期难以忍受的疼痛等。并且在粘连处再次进行手术不但会延长麻醉,手术和恢复时间,还会对患者造成额外的风险,如失血,内脏损伤,甚至是肠道的切除。
目前在临床中应用的放粘连的药物种类丰富,其分类主要包括两大方面:防粘连药物和屏障材料。防粘连药物是为了减少纤维蛋白渗出、促进纤维蛋白降解,主要包括抗生素、抗炎药和抗凝血剂等。其缺点是抗生素、抗炎药和抗凝血剂类药物在腹腔内应用时,由于腹腔液的存在,药物很快被清除掉,无法发挥其效用。屏障材料则是可以和腹腔或器官直接接触,将受损的、纤维蛋白覆盖的、炎性的腹膜表面隔离开来,直至间皮细胞完成修复。防粘连屏障材料主要分为液态类和固态类。液态类防粘连材料能够实现对不规则创面的完全覆盖,但是由于此类材料容易降解且流动性太大无法长时间滞留在损伤处,限制了它的防粘连功效。固态类防粘连材料在腹腔手术后的应用虽然能起到一个物理隔离的作用,但不能完全覆盖不规则的创面,因此在临床应用上的效果不佳。
凝胶类材料综合了液态类和固态类两者的优点作为物理屏障防粘连材料。目前在临床中应用的防粘连凝胶类产品有聚乙二醇凝胶、透明质酸凝胶、纤维蛋白胶等。尽管凝胶类防粘连材料解决了一部分液态类和固态类防粘连材料存在的问题,但是仍然存在一些不足之处,比如在体内依然存在降解太快、功能过于单一、腹腔粘连效果差等问题。
发明内容
针对目前存在的技术问题,本发明旨在提供一种具有预防术后腹腔粘连的两性离子水凝胶,以两性离子单体磺基甜菜碱甲基丙烯酸酯和丙烯酰氯接枝的6-氨基己酸进行自由基聚合并原位包覆纳米氧化锌颗粒,一锅法制备两性离子水凝胶。将水凝胶通过注射或者涂敷的方式覆盖在腹腔损伤部位,首先,该水凝胶起到物理阻隔作用;其次,6-氨基己酸优异的止血性能使损伤部位快速止血,减少粘连的可能性;然后,纳米氧化锌颗粒优异的抗菌性能有助于减少炎症,释放的锌离子更是能促进伤口愈合;最重要的是,两性离子优异的防污性能可以阻止纤维蛋白和成纤维细胞的粘附,起到防止腹腔粘连的效果。
为了实现上述目的,本发明采用以下技术方案:
一种预防术后腹腔粘连的两性离子水凝胶的制备方法包括以下步骤:
1)将3.28g 6-氨基己酸,1g NaOH,10mL乙醚加入到50mL去离子水中,混合均匀,将2mL丙烯酰氯加入在10mL乙醚中,在冰浴条件下滴加进上述混合溶液,室温下反应4h。用2MNaOH调节反应溶液PH至10左右用乙酸乙酯萃取,接着用6M HCl调节反应溶液PH至2左右,乙酸乙酯萃取。经无水硫酸钠吸水后过滤,旋转蒸发得到丙烯酰氯接枝的6-氨基己酸。磺基甜菜碱甲基丙烯酸酯,纳米氧化锌颗粒均购自aladdin化学试剂。
2)将磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒溶于去离子水中,通过超声得到混合水溶液;
所述的混合水溶液中磺基甜菜碱甲基丙烯酸酯的浓度为0.1-0.4×10-3 mol/mL,丙烯酰氯接枝的6-氨基己酸的浓度为0.1-0.4×10-3 mol/mL,纳米氧化锌颗粒的浓度为1mg/mL。
3)将引发剂和交联剂加入到所述的混合水溶液中,在50℃下引发自由基聚合形成水凝胶。
进一步地,步骤1)中纳米氧化锌颗粒的大小为50±10nm。
进一步地,步骤3)中引发剂为过硫酸铵和四甲基乙二胺。
进一步地,每10mL混合水溶液中加入10-15mg过硫酸铵和100-150μL四甲基乙二胺。
进一步地,步骤3)中交联剂为N,N'-亚甲基双丙烯酰胺。
进一步地,每10mL混合水溶液中加入20-40mg N,N'-亚甲基双丙烯酰胺。
本发明的预防术后腹腔粘连的两性离子水凝胶具有优异的止血性能、抗菌性能、防污性能、良好的生物相容性、促进伤口愈合性能;其应用:通过注射或者涂敷的方式应用到腹腔的损伤部位以防止腹腔术后粘连。
与现有技术相比,本发明具有一下有益效果:
(1)本发明的预防术后腹腔粘连的两性离子水凝胶,通过自由基聚合一步法原位制备水凝胶,成本低廉,操作简单;反应单体无细胞毒性,具有良好的生物相容性。
(2)本发明的预防术后腹腔粘连的两性离子水凝胶,采用注射或涂敷的方式,可满足手术腹腔镜操作,方便治疗过程中的应用。
(3)本发明的预防术后腹腔粘连的两性离子水凝胶,将水凝胶通过注射或者涂敷的方式覆盖在腹腔损伤部位,首先,该水凝胶起到物理阻隔作用;其次,6-氨基己酸优异的止血性能使损伤部位快速止血,减少粘连的可能性;然后,纳米氧化锌颗粒优异的抗菌性能有助于减少炎症,释放的锌离子更是能促进伤口愈合;最重要的是,两性离子优异的防污性能可以阻止纤维蛋白和成纤维细胞的粘附,起到防止腹腔粘连的效果。
附图说明
图1为实施例1的水凝胶胶化前后形态图,图1(a)为磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒的混合水溶液,图1(b)为引发聚合后的水凝胶形态;
图2为实施例1的水凝胶经注射器注射的形态图,图2(a)为水凝胶经注射器注射成型图,图2(b)为水凝胶经注射器针头挤出放大图;
图3为实施例1和实施例2的水凝胶防污性能测试;图3(a)为水凝胶在荧光显微镜下细胞粘附的照片,图3(b)为水凝胶的蛋白质吸附含量图;
图4为实施例1和实施例2的水凝胶细胞相容性测试;
图5为实施例1和实施例2的水凝胶防腹腔粘连的效果图,图5(a)为各组的腹腔粘连情况拍摄图,图5(b)为各组的腹腔粘连情况打分图。
具体实施方式
为了进一步的理解本发明方案,下面将结合本发明实施例中的附图,让本发明更清晰直观的表述出来。
下面结合附图对本发明进行更详细的表述:
实施例1
配置磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒的混合水溶液,其混合水溶液中磺基甜菜碱甲基丙烯酸酯的浓度为0.4×10-3 mol/mL,丙烯酰氯接枝的6-氨基己酸的浓度为0.1×10-3 mol/mL,纳米氧化锌颗粒的浓度为1mg/mL。
取10mL上述混合水溶液,加入10mg过硫酸铵、150μL四甲基乙二胺和30mg N,N'-亚甲基双丙烯酰胺,在50℃下加热进行自由基聚合形成水凝胶。
如图1所示,图1(a)为磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒的混合水溶液图,图1(b)为引发聚合后的水凝胶形态,由此可见,上述的混合水溶液中加入引发剂、交联剂后经50℃下引发发生聚合形成了水凝胶。
如图2所示,实施例1的水凝胶经注射器针头注射成一定形状,可见水凝胶具有可注射性能。
一、实施例1的水凝胶的防污性能测试
采用细胞染色剂(AM/PI)对水凝胶上粘附的细胞进行染色。选用的细胞为NIH-3T3细胞。将实施例1的水凝胶制成直径10mm的圆盘状,放入24孔板中,并在37℃孵育1小时。将NIH-3T3细胞以1×104细胞/孔的密度接种到每个孔中,然后在5% CO2气氛中37℃孵育24小时。取出水凝胶用无菌PBS缓冲溶液稍微冲洗水凝胶。将水凝胶移到35mm的培养皿中,加入3mL一定浓度的染色工作液,37℃孵育20min后,用荧光倒置显微镜进行观察记录。
如图3(a)所示,对比于TCPS和HA凝胶,含有两性离子单体的水凝胶表面粘附的细胞数量极少,表明水凝胶具有良好的抗细胞粘附性能。
采用微量BCA蛋白测定试剂盒对吸附在水凝胶上的蛋白质含量进行测试。将实施例1的水凝胶制成直径10mm的圆盘状,放入24孔板中,加入1毫升BSA溶液(2mg/mL)。在37℃孵育2小时后,除去BSA溶液,用PBS缓冲溶液冲洗水凝胶圆盘三次,以除去松散吸附在表面的蛋白质。然后,用1%十二烷基硫酸钠(SDS)溶液处理2小时后,将牢固吸附在水凝胶上的BSA分离。通过用酶标仪测量570 nm波长的吸光度来获得吸附的蛋白质浓度。
如图3(b)所示,对比于TCPS和HA凝胶,含有两性离子单体的水凝胶表面吸附的蛋白质含量极少,表明水凝胶具有良好的抗蛋白质吸附性能。
二、实施例1的水凝胶的细胞相容性测试
采用CCK-8法来测试实施例1的水凝胶的细胞相容性。选用的细胞为NIH-3T3细胞。NIH-3T3细胞用DMEM完全培养基,在37℃、5%CO2的培养箱中进行培养。将密度为1×104/孔的NIH-3T3细胞悬液接种在96孔板中。培养24h后,弃去培养基,更换为等量凝胶浸液作为实验组,空白组更换新鲜的培养基。凝胶浸液设置一系列浓度梯度(0、25、50、100、200、400、800、1600μg/mL)。继续培养 24 h后加入10 μL CCK-8 溶液,在 37℃下孵育 4 h 后,使用酶标仪在450 nm处测定吸光度,计算细胞的存活率,细胞的存活率结果如图4所示。
如图4所示,不同浓度梯度(0、25、50、100、200、400、800、1600μg/mL)的凝胶浸液与细胞共培养24h后,NIH-3T3细胞的存活率均在80%以上,表明水凝胶具有良好的细胞相容性,对细胞无明显毒性。
三、实施例1的水凝胶防腹腔粘连的效果测试
选用雄性SD大鼠(200-230g)建立大鼠盲肠-腹壁粘连模型。大鼠禁食禁水12h,用4%水合氯醛腹腔注射麻醉SD大鼠。刮去腹部毛发,进行消毒。然后用手术剪刀沿腹壁中线切开一个4-5厘米长的切口。分离盲肠,用无菌手术纱布轻轻摩擦其浆膜表面,直到出现点状出血。用手术刀在相应的腹壁侧面造成1cm×2cm的腹膜缺损。在对盲肠和腹腔损伤部位进行治疗后将盲肠放回腹腔,缝合关腹。术后动物单笼饲养,并每天观察。于术后7天、14天进行腹腔麻醉,小心打开腹部,观察粘连情况并对粘连进行打分。
28只SD大鼠分为四组,每组7只大鼠:
第一组为生理盐水对照组,在损伤部位注射1mL生理盐水处理。
第二组为透明质酸钠凝胶组,在损伤部注射1mL透明质酸钠凝胶处理。
第三组为实验组对照组,在损伤部位注射未添加纳米氧化锌颗粒的水凝胶处理。
第四组为实施例1的水凝胶实验组,在损伤部位注射1mL的水凝胶处理。
术后第7天和14天,腹腔注射水合氯醛麻醉大鼠,小心打开腹部,观察腹腔粘连情况并按照国际标准粘连评分方法进行粘连评分。0分,无粘连;1分,一处较薄的粘连;2分,不止一处粘连;3分,较为紧密的粘连;4分,不止一处的紧密粘连;5分,大面积的血管化粘连。粘连结果如图5所示。
如图5(a)所示,术后第7天,生理盐水对照组和商用透明质酸钠凝胶组,腹腔和盲肠粘连情况均非常严重,无纳米氧化锌颗粒的水凝胶实验对照组中粘连情况有所变好,只有轻微粘连,实施例1的水凝胶实验组没有产生粘连。术后14天结果与第7天相似。如图5(b)所示,对各组大鼠腹腔粘连情况进行打分。生理盐水对照组粘连打分接近4分,商用透明质酸钠凝胶组粘连打分接近3分,无纳米氧化锌颗粒的水凝胶实验对照组粘连打分接近2分,实施例1的水凝胶实验组粘连打分接近0分。结果证明本发明的预防术后腹腔粘连的两性离子水凝胶具有良好的预防术后腹腔粘连的效果。
实施例2
配置磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸的混合水溶液,其混合水溶液中磺基甜菜碱甲基丙烯酸酯的浓度为0.4×10-3 mol/mL,丙烯酰氯接枝的6-氨基己酸的浓度为0.1×10-3 mol/mL。
取10mL上述混合水溶液,加入10mg过硫酸铵、150μL四甲基乙二胺和30mg N,N'-亚甲基双丙烯酰胺,在50℃下加热进行自由基聚合形成水凝胶。
实施例2的水凝胶各项测试与实施例1相同,性能与实施例1的水凝胶相比略有差别。
一、实施例2的水凝胶的防污性能测试
如图3(a)所示,对比于TCPS和HA凝胶,含有两性离子单体的水凝胶表面粘附的细胞数量极少,表明水凝胶具有良好的抗细胞粘附性能。如图3(b)所示,对比于TCPS和HA凝胶,含有两性离子单体的水凝胶表面吸附的蛋白质含量极少,表明水凝胶具有良好的抗蛋白质吸附性能。
二、实施例2的水凝胶的细胞相容性测试
如图4所示,不同浓度梯度(0、25、50、100、200、400、800、1600μg/mL)的凝胶浸液与细胞共培养24h后,NIH-3T3细胞的存活率均在80%以上,表明水凝胶具有良好的细胞相容性,对细胞无明显毒性。
三、实施例2的水凝胶防腹腔粘连的效果测试
如图5(a)所示,术后第7天,生理盐水对照组和商用透明质酸钠凝胶组,腹腔和盲肠粘连情况均非常严重,实施例2的水凝胶实验组中粘连情况有所变好,只有轻微粘连,实施例1的水凝胶实验组没有产生粘连。术后14天结果与第7天相似。如图5(b)所示,对各组大鼠腹腔粘连情况进行打分。生理盐水对照组粘连打分接近4分,商用透明质酸钠凝胶组粘连打分接近3分,实施例2的水凝胶实验组粘连打分接近2分,实施例1的水凝胶实验组粘连打分接近0分。结果证明纳米氧化锌颗粒的抗细菌感染作用对于预防术后腹腔粘连具有一定的效果。
实施例3
配置磺基甜菜碱甲基丙烯酸酯、丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒的混合水溶液,其混合水溶液中磺基甜菜碱甲基丙烯酸酯的浓度为0.3×10-3 mol/mL,丙烯酰氯接枝的6-氨基己酸的浓度为0.2×10-3 mol/mL,纳米氧化锌颗粒的浓度为1mg/mL。
取10mL上述混合水溶液,加入10mg过硫酸铵、150μL四甲基乙二胺和30mg N,N'-亚甲基双丙烯酰胺,在50℃下加热进行自由基聚合形成水凝胶。
实施例3的水凝胶经过各项测试,性能与实施例1的水凝胶相当。
以上所述内容仅为本发明的技术思想,并不局限本发明保护范围,本技术领域的普通专业人员阅读本发明之后,在没有做出创造性劳动的前提下所获得的所有其它实施实例,都属于本发明保护的范围。
Claims (8)
1.一种预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,包括以下步骤:
1)将6-氨基己酸,NaOH,乙醚加入到去离子水中,搅拌均匀得混合溶液,将丙烯酰氯加入乙醚中,在冰浴条件下滴入上述混合溶液,室温下反应4h,经萃取、过滤、旋转蒸发得到丙烯酰氯接枝的6-氨基己酸;
2)将磺基甜菜碱甲基丙烯酸酯、步骤1)得到的丙烯酰氯接枝的6-氨基己酸和纳米氧化锌颗粒溶于去离子水中,通过超声得到混合水溶液;
3)将引发剂和交联剂加入到所述的混合水溶液中,在50℃下引发自由基聚合形成水凝胶。
2.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,所述的混合水溶液中磺基甜菜碱甲基丙烯酸酯的浓度为0.1-0.4×10-3 mol/mL,丙烯酰氯接枝的6-氨基己酸的浓度为0.1-0.4×10-3 mol/mL,纳米氧化锌颗粒的浓度为1mg/mL。
3.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,步骤1)中纳米氧化锌颗粒的大小为50±10nm。
4.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,步骤3)中引发剂为过硫酸铵和四甲基乙二胺。
5.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,每10mL混合水溶液中加入10-15mg过硫酸铵和100-150μL四甲基乙二胺。
6.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,步骤3)中交联剂为N,N'-亚甲基双丙烯酰胺。
7.根据权利要求1所述的预防术后腹腔粘连的两性离子水凝胶的制备方法,其特征在于,每10mL混合水溶液中加入20-40mg N,N'-亚甲基双丙烯酰胺。
8.一种如权利要求1-7任一项所述的制备方法制得的预防术后腹腔粘连的两性离子水凝胶。
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