CN114369441A - 一种多酚基医用组织胶黏剂、制备方法及应用 - Google Patents

一种多酚基医用组织胶黏剂、制备方法及应用 Download PDF

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CN114369441A
CN114369441A CN202111617307.2A CN202111617307A CN114369441A CN 114369441 A CN114369441 A CN 114369441A CN 202111617307 A CN202111617307 A CN 202111617307A CN 114369441 A CN114369441 A CN 114369441A
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polyphenol
based medical
tissue adhesive
medical tissue
polyethylene glycol
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鲁玺丽
李一波
贺乔柏
孟鑫鑫
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Harbin Engineering University
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Abstract

本发明公开了一种多酚基医用组织胶黏剂、制备方法及其应用,属于生物医用材料制备和生物医学应用领域。该胶黏剂通过多酚化合物溶液、无机纳米粒子及聚乙二醇溶液在特定条件下制备而成。本发明制备的多酚基医用胶黏剂具有粘结强度高、止血性与抗菌性优异、抗氧化性好、安全无毒、生物相容性好、价格低廉等特点,并且使用操作简单易行,可用于皮肤、血管、脏器、肌肉、骨等大部分受损组织,具有粘合组织、覆盖创面、止血、抗菌、抗氧化等作用,可作为的止血抗菌抗氧化粘合材料,具有广泛的临床应用前景。

Description

一种多酚基医用组织胶黏剂、制备方法及应用
技术领域
本发明属于生物医用材料制备和生物医学应用领域,具体涉及一种具有高粘结强度和优异生物功能性的多酚基医用组织胶黏剂、制备方法及其应用。
背景技术
人们在生产和生活中难免遇到外伤或疾病损伤,容易形成开放性创伤,使敏感组织暴露于物理、化学和病原的侵袭,如果没有适当的治疗,这些伤口可能会被微生物感染,延误伤口愈合,甚至可能导致组织坏死。在传统医学中一般采用缝合线进行组织修复,这需要复杂的操作且在后期拆线的过程中容易感染伤口,妨碍了伤口的愈合,甚至会成为患者的负担。随着现代医疗科学技术的发展和进步,人们一直在探索功能强大、使用操作简单的材料用于组织修复,这些需求使得医用组织胶黏剂逐渐成为研究热点。医用组织胶黏剂是指在医疗上可黏附在组织表面或使组织之间发生黏合的材料,使用胶黏剂要比传统手术节省时间,使用操作简单。目前临床上常用的两种胶黏剂分别为纤维蛋白胶和氰基丙烯酸酯胶。前者通常具备优异的生物相容性和生物可降解性,但价格昂贵,粘结强度低并且存在潜在的促炎性和免疫原性,一定程度上导致了它们无法广泛的使用。后者粘结强度高,但生物相容性差,而且还可能存在细胞毒性、慢性炎症、在体内难以降解等问题。综上所述,发展一种在生理条件下粘结强度高、生物相容性好同时具有良好生物活性的胶黏剂,在组织和伤口愈合、创伤敷料、骨组织修复和再生等生物医学应用领域具有迫切需求。
多酚类化合物在自然界的动植物体内广泛存在,多元酚结构赋予它一系列独特的化学活性和生理活性,其结构中相邻的两个酚羟基之间形成强大的氢键,使得其可以与水竞争氢键位点,有利于其对材料表面的吸附,且邻苯酚结构容易被氧化为醌式或半醌式结构,进而与基材的氨基或巯基发生Michael加成或Schiff碱反应增强粘附力,同时大部分多酚类化合物本身具有一定的抗菌性、止血性及抗氧化性,使其在组织胶黏剂开发方面极具潜力。聚乙二醇(PEG)具有良好的生物相容性,是一种通用的生物材料,已广泛用于各种再生生物医学领域。所用的无机纳米粒子可与多酚化合物形成配位键,增强胶黏剂的内聚力,使胶黏剂具有较高的粘结强度,同时赋予胶黏剂更加优异的止血性能。
发明内容
本发明旨在提供一种在生理条件下粘结强度高、生物相容性好同时具有优异生物功能性的组织胶黏剂、制备方法及应用,该组织胶黏剂不仅在生理条件下具有较高的粘结强度,并创新性的利用无机纳米粒子构建双网络凝胶,赋予该组织胶黏剂优异的生物功能性,此多酚基医用组织胶黏剂的构建及制备方法均未见报道。
具体的技术方案如下:
一种多酚基医用组织胶黏剂的制备方法,包括如下步骤:
A.按比例称取多酚类化合物、聚乙二醇,分别溶于水或Tris-HCl缓冲液,把两种溶液混合,在水浴条件下加热搅拌反应,得到多酚类化合物-聚乙二醇复合物;
B.将无机纳米粒子加入所述的步骤A的复合物中,在水浴条件下加热搅拌反应,得到湿态粘附力强的多酚基医用组织胶黏剂。
进一步的,所述多酚类化合物包括儿茶素、花青素、表儿茶素、槲皮素、单宁酸、没食子酸、鞣酸等多酚类化合物在内的一种或一种以上按比例均匀混合的混合物。
进一步的,所述无机纳米粒子包括羟基磷灰石、氧化镁、二氧化钛、蒙脱石、生物活性玻璃、氧化锌等无机纳米粒子在内的一种或一种以上按比例均匀混合的混合物。
进一步的,多酚基医用组织胶黏剂,其特征在于所用的多酚类化合物溶液浓度为30~50wt%。
进一步的,多酚基医用组织胶黏剂,其特征在于所用的聚乙二醇溶液浓度为8~50wt%,所用的聚乙二醇分子量为1000-100000。
进一步的,所述无机纳米粒子用量为多酚类化合物用量的0.5~10wt%,根据无机纳米粒子种类的不同做相应调整,所述无机纳米粒子的粒径范围小于100纳米大于10纳米。
进一步的,所述水浴加热搅拌反应温度为20~60℃,根据多酚类化合物种类的不同做相应调整,水浴加热搅拌反应时间为1~3h。
进一步的,搅拌的转速为200~500rpm/min,多酚类化合物与聚乙二醇的质量比为1:10~10:1。
一种多酚基医用组织胶黏剂,由上面任意一项所述的方法制备而成。
一种多酚基医用组织胶黏剂的应用,包括皮肤、血管、脏器、肌肉、骨等组织的粘结和修复,也可用于医用敷料等方面。
与现有技术相比,有益效果是:
(1)本发明的医用组织胶黏剂创新性的利用无机纳米粒子构建双网络凝胶,首先借助多酚类化合物与聚乙二醇分子间的自组装,构建第一层网络结构(氢键网络),其次将无机纳米粒子引入到胶黏剂配方中,构建第二层网络结构(离子键网络)。双层网络结构使得本发明的医用组织胶黏剂具有很高的粘结强度,远高于商品化纤维蛋白胶,可以实现湿态环境下(包括水、PBS缓冲液、血液环境)的快速粘合。
(2)多酚类化合物赋予该组织胶黏剂优异的抗菌性、止血性和抗氧化性,无机纳米粒子的加入使胶黏剂的止血性能进一步提升,与已有的单宁酸-聚乙二醇体系相比,止血性能提高了5倍,对预防感染和促进组织愈合有重要作用,可作为皮肤、血管、脏器、肌肉、骨等组织的止血抗菌抗氧化粘合材料。
(3)本发明的医用组织胶黏剂所用原料及制备过程无毒无害,产品对人体无刺激,具有优异的生物相容性,且制备方法简单,工艺参数易于控制。
附图说明
图1:家兔心脏止血实验图;
图2:大鼠肝脏出血量图
图3:大鼠肝脏止血实验图;其中(a)空白对照组大鼠肝脏出血图、(b)使用明胶海绵大鼠肝脏出血图、(c)未添加粒子大鼠肝脏出血图、(d)添加粒子大鼠肝脏出血图;
图4:常规剪切强度测试图;
图5:猪皮粘结强度测试图。
具体实施方式
下面通过实际例子对本发明的具体实施过程进行说明。
实施例1
A.按质量比1:2称取1g单宁酸和2g聚乙二醇(20000Da),分别倒入称量瓶中,加入Tris-Hcl缓冲液搅拌10h,得到浓度为50wt%的单宁酸溶液和浓度为12wt%的聚乙二醇溶液,把两种溶液混合,400r/min搅拌3h,温度控制在60℃,反应得到单宁酸-聚乙二醇复合物。
B.称取0.08g生物活性玻璃粉末加入到所述的步骤A的复合物中,400r/min搅拌2h,温度控制在60℃,制得多酚基医用组织胶黏剂,经测试,常规剪切强度为227.8KPa,猪皮粘结强度为28.2KPa,可在5s内快速有效实现血液环境下的伤口止血粘合。
实施例2
A.按质量比1:1称取1g单宁酸和10g聚乙二醇(70000Da),分别倒入称量瓶中,加入Tris-Hcl缓冲液搅拌10h,得到浓度为50wt%的单宁酸溶液和浓度为8wt%的聚乙二醇溶液,把两种溶液混合,400r/min搅拌3h,温度控制在60℃,反应得到单宁酸-聚乙二醇复合物。
B.称取0.08g羟基磷灰石粉末加入到所述的步骤A的复合物中,400r/min搅拌2h,温度控制在60℃,制得多酚基医用组织胶黏剂,经测试,常规剪切强度为168.1KPa。
实施例3
(1)首先利用多酚类化合物与聚乙二醇分子间的自组装,构建一级网络结构(氢键网络),其次将无机纳米粒子引入到胶黏剂配方中,构建第二级网络结构(离子键网络)。
(2)一种多酚基医用组织胶黏剂的具体制备步骤如下:
A.按比例称取多酚类化合物、聚乙二醇(多酚类化合物与聚乙二醇的质量比为1:10~10:1),分别溶于水或Tris-HCl缓冲液,制成一定浓度的溶液,混合均匀加热搅拌,转速为200~500rpm/min,水浴温度范围为20~60℃,反应时间为1~3h,多酚类化合物溶液浓度为30~50wt%,聚乙二醇溶液浓度为8~50wt%,聚乙二醇分子量为1000-100000,反应得到多酚类化合物-聚乙二醇复合物。
B.称取无机纳米粒子加入到所述的步骤A的复合物中,混合均匀加热搅拌,转速为200~500rpm/min,水浴温度范围为20~60℃,反应时间为1~3h,无机纳米粒子用量为多酚类化合物用量的1~15wt%,制得多酚基医用组织胶黏剂。
本发明公开了一种多酚基医用组织胶黏剂、制备方法及其应用,属于生物医用材料制备和生物医学应用领域。该胶黏剂通过多酚化合物溶液、无机纳米粒子及聚乙二醇溶液在特定条件下制备而成。本发明制备的多酚基医用胶黏剂具有粘结强度高、止血性与抗菌性优异、抗氧化性好、安全无毒、生物相容性好、价格低廉等特点,并且使用操作简单易行,可用于皮肤、血管、脏器、肌肉、骨等大部分受损组织,具有粘合组织、覆盖创面、止血、抗菌、抗氧化等作用,可作为的止血抗菌抗氧化粘合材料,具有广泛的临床应用前景。

Claims (10)

1.一种多酚基医用组织胶黏剂的制备方法,其特征在于:包括如下步骤:
A.按比例称取多酚类化合物、聚乙二醇,分别溶于水或Tris-HCl缓冲液,把两种溶液混合,在水浴条件下加热搅拌反应,得到多酚类化合物-聚乙二醇复合物;
B.将无机纳米粒子加入所述的步骤A的复合物中,在水浴条件下加热搅拌反应,得到湿态粘附力强的多酚基医用组织胶黏剂。
2.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:所述多酚类化合物包括儿茶素、花青素、表儿茶素、槲皮素、单宁酸、没食子酸、鞣酸等多酚类化合物在内的一种或一种以上按比例均匀混合的混合物。
3.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:所述无机纳米粒子包括羟基磷灰石、氧化镁、二氧化钛、蒙脱石、生物活性玻璃、氧化锌等无机纳米粒子在内的一种或一种以上按比例均匀混合的混合物。
4.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:多酚基医用组织胶黏剂,其特征在于所用的多酚类化合物溶液浓度为30~50wt%。
5.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:多酚基医用组织胶黏剂,其特征在于所用的聚乙二醇溶液浓度为8~50wt%,所用的聚乙二醇分子量为1000-100000。
6.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:所述无机纳米粒子用量为多酚类化合物用量的0.5~10wt%,根据无机纳米粒子种类的不同做相应调整,所述无机纳米粒子的粒径范围小于100纳米大于10纳米。
7.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:所述水浴加热搅拌反应温度为20~60℃,根据多酚类化合物种类的不同做相应调整,水浴加热搅拌反应时间为1~3h。
8.根据权利要求1所述的多酚基医用组织胶黏剂的制备方法,其特征在于:搅拌的转速为200~500rpm/min,多酚类化合物与聚乙二醇的质量比为1:10~10:1。
9.一种多酚基医用组织胶黏剂,其特征在于:由权利要求1-8任意一项所述的方法制备而成。
10.一种多酚基医用组织胶黏剂的应用,其特征在于:包括皮肤、血管、脏器、肌肉、骨等组织的粘结和修复,也可用于医用敷料等方面。
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