CN103641997B - 用于组织修复的温敏功能性聚合物、水凝胶的制备方法 - Google Patents
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Abstract
本发明公开了用于组织修复的温敏功能性聚合物的制备方法,步骤如下:在炔基内酯和内酯的混合物中加入单官能团聚乙二醇、二价锡类催化剂,在反应得到预聚物;在预聚物中加入等摩尔量的二异氰酸酯,进行偶联反应,合成嵌段共聚物;将嵌段共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到温敏功能性聚合物;或步骤如下:在炔基内酯和内酯的混合物中加入双官能团聚乙二醇、二价锡类催化剂,反应得到共聚物;将共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到温敏功能性聚合物。本发明还公开了用于组织修复的温敏功能性水凝胶的制备方法。本发明制备的产品具有功能性、温敏性和可生物降解性的优点。
Description
技术领域
本发明涉及组织修复体材料的制备领域,特别涉及用于组织修复的温敏功能性聚合物、水凝胶的制备方法。
背景技术
组织工程(TissueEngineering)是近年来兴起的新兴学科,由美国国家科学基金会在1987年第一次正式提出组织工程。组织工程学是一门交叉学科,它利用工程学和生命科学的原理,来研究和发展具有生物活性的人工替代物,用以维持、恢复或提高人体受损组织的功能。组织工程的基本原理和方法是:将少量组织经体外消化分离、培养扩增的大量正常组织细胞,吸附于一种生物相容性良好并可被机体降解吸收的生物支架材料上形成复合物,将细胞-支架材料复合物植入机体病损的组织或器官部位,细胞在生物支架材料逐渐被机体降解吸收的过程中,形成新的具有形态和功能的组织或器官,以达到修复缺损和重建功能的目的。
水凝胶是以水为分散介质的凝胶,具有空间网状结构,有化学键交联和物理聚集作用的一类高分子网络体系。具有性质柔软,能保持一定形状,能吸收大量的水,具有很高的孔隙率和范围宽广的孔径,可以作为组织工程中支架使用。化学交联的水凝胶在结构形成后,外形不能再次改变,其应用受到一定的限制。而具有物理交联结构的水凝胶,其外形可以发生变化,能够在流动的溶胶与凝固的凝胶间通过凝胶条件的控制,自由转换而具有更广泛的临床应用前景。尤其在作为可注射组织修复材料的研究中,获得更多的关注。
温敏型水凝胶是能对环境温度变化做出响应,自身发生相转变的水凝胶,能够在溶胶与凝胶间自由转变。温度敏感水凝胶分子结构中含有一定比例的亲水基团和疏水基团,环境温度的变化会破坏分子链之间以及分子链与水之间的氢键作用,从而引起分子链的亲水疏水平衡的变化,使凝胶结构改变。目前的温敏水凝胶在分子结构上由于缺乏能够引入生物活性分子的基团结构,虽然具有较好的温敏特性,但是其生物活性仍然有待改善。
发明内容
为了克服现有技术的上述缺点与不足,本发明的目的之一在于提供用于组织修复的温敏功能性聚合物,采用该功能性聚合物制备得到的温敏水凝胶具备组织修复的功能,并且具备可生物降解性。
本发明的另一目的在于提供组织修复的功能性水凝胶的制备方法。
本发明的目的通过以下技术方案实现:
用于组织修复的温敏功能性聚合物的制备方法,包括以下步骤:
(1)在炔基内酯和内酯的混合物中加入单官能团聚乙二醇、二价锡类催化剂,在80~130℃下反应6~12h,得到预聚物;所述炔基内酯为炔基己内酯、炔基戊内酯、炔基丙交酯或炔基乙交酯;所述内酯为己内酯、戊内酯、丙交酯或乙交酯;
所述炔基内酯与内酯的摩尔比为0.05~19;所述炔基内酯和内酯的混合物与单官能团聚乙二醇的质量比为2~0.4;所述二价锡类催化剂的加入量为炔基内酯和内酯的混合物的1wt‰~5wt‰;
(2)在步骤(1)得到的预聚物中加入等摩尔量的二异氰酸酯,进行偶联反应,合成嵌段共聚物;
(3)将步骤(2)得到的嵌段共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
所述单官能团聚乙二醇为单甲氧基聚乙二醇。
所述单官能团聚乙二醇的分子的分子量为350~5000。
用于组织修复的温敏功能性聚合物的制备方法,包括以下步骤:
(1)在炔基内酯和内酯的混合物中加入双官能团聚乙二醇、二价锡类催化剂,在80-130℃下反应6~24h,得到共聚物;
所述炔基内酯与内酯的摩尔量比为0.05~19,所述炔基内酯和内酯的混合物与双官能团聚乙二醇的质量比为0.5~2.5,所述二价锡类催化剂的加入量为炔基内酯和内酯的混合物的1wt‰~5wt‰;
(2)将步骤(1)得到的共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
所述双官能团聚乙二醇为两端都为羟基的聚乙二醇。
所述双官能团聚乙二醇的分子量为350~5000。
用于组织修复的温敏功能性水凝胶的制备方法,将上述用于组织修复的温敏功能性聚合物溶于水,放入4~15℃的冰箱中陈化12~48h,得到用于组织修复的温敏功能性水凝胶。
所述水凝胶的质量浓度为15%~65%。
与现有技术相比,本发明具有以下优点和有益效果:
(1)本发明通过采用在分子链上接枝炔基,通过炔基和叠氮化的短肽或者蛋白反应,使得整个分子链有生物活性。
(2)本发明制备的用于组织修复的温敏功能性水凝胶,通过在聚合物链段引入可降解链段(即疏水性内酯链段),可以通过调节可降解链段长度来控制水凝胶的降解速度。
(3)本发明制备的用于组织修复的温敏功能性水凝胶相对于传统方法制备的水凝胶具有可注射性,该种水凝胶是通过在温度较低时呈现溶胶状态,具有可流动性,在体温附近发生溶胶-凝胶相转变由溶胶变为凝胶,所以这种水凝胶可以在稍低于体温时注射进入人体达到组织修复能力。
(4)本发明制备的用于组织修复的温敏功能性水凝胶的相转变温度可通过亲水段和疏水段的链段长度进行调节。
附图说明
图1为本发明的实施例1制备得到的水凝胶的动态力学图。
图2为本发明的实施例1制备的用于组织修复的温敏功能性聚合物的功能单体的核磁共振谱图。
图3为本发明的实施例1制备的用于组织修复的温敏功能性聚合物的功能单体的红外图谱。
具体实施方式
下面结合实施例,对本发明作进一步地详细说明,但本发明的实施方式不限于此。
实施例1
称取8.8gε-己内酯与2.2gα-炔丙基-δ-戊内酯和5.5g单甲氧基聚乙二醇(分子量为550)于烧瓶中,加入0.08g辛酸亚锡后,升温至130℃,反应12h后,得到预聚物;降温至80℃,在预聚物中加入1.68gHMDI,进行偶联反应6h,冷却至常温,合成嵌段共聚物,分子量3300;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
称取上述温敏功能性聚合物,配制成质量分数30%的溶液,放入4℃冰箱中陈化12h后即得到所需要的用于组织修复的温敏功能性水凝胶,相变温度为37℃。
本实施例得到的用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-ε-己内酯共聚物,亲水链段为单甲氧基聚乙二醇。
图1为本实施例制备得到的用于组织修复的温敏功能性水凝胶的动态力学图,由图可知聚合物溶液从起始的溶胶态变为凝胶态的过程,起始时储能模量(G')和耗能模量(G'')接近于零,随着温度的升高,体系的储能模量逐渐增加,在接近37℃达到最大值,此时耗能模量和损耗(tgδ)都较小,此时体系处于凝胶态。
图2为本实施例制备的用于组织修复的温敏功能性聚合物的功能单体的核磁共振谱图,其数据见表1。
表1本实施例制备的用于组织修复的温敏功能性聚合物的功能单体的核磁共振数据
图3为本实施例制备的用于组织修复的温敏功能性聚合物的功能单体的红外图谱。图中在波数为1725cm-1处为分子链上的羰基C=O伸缩振动峰,在波数2118cm-1处为分子链上的炔基C-C伸缩振动峰,在波数2930cm-1处为甲基与亚甲基的伸缩振动峰,在波数3286cm-1处代表炔基上C-H伸缩振动峰。
实施例2
称取1.6625gε-己内酯与0.0875gα-炔丙基-ε-己内酯和3.5g单甲氧基聚乙二醇(分子量为350)于烧瓶中,加入0.00525g辛酸亚锡后,升温至80℃,反应12h后,得到预聚物;向烧瓶中加入1.68gHMDI,进行偶联反应24h,冷却至常温,得到嵌段共聚物,分子量为525;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-ε-己内酯共聚物,亲水链段为单甲氧基聚乙二醇。
称取上述温敏功能性聚合物,配制成质量分数15%的溶液,放入4℃冰箱中陈化12h后即得到所需要的用于组织修复的温敏功能性水凝胶,其相变温度为50℃。
实施例3
称取1.68gε-己内酯与11.875gα-炔丙基-ε-己内酯和5g单甲氧基聚乙二醇(分子量为5000)于烧瓶中,加入0.0875g辛酸亚锡后,升温至130℃,反应6h后,得到预聚物;降温至80℃,向烧瓶中加入0.168gHMDI,进行偶联反应6h,合成嵌段共聚物,分子量为17500;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-ε-己内酯共聚物,亲水链段为单甲氧基聚乙二醇。
称取温敏功能性聚合物,配制成质量分数65%的溶液,放入15℃冰箱中陈化48h后即得到所需要的用于组织修复的温敏功能性水凝胶,相变温度为5℃。
实施例4
称取5gα-炔丙基-ε-己内酯、10g乙交酯,5.5g单甲氧基聚乙二醇(分子量为550)于烧瓶中,加入0.08g辛酸亚锡后,升温至130℃,通氮气,反应12h后,得到预聚物;降温至80℃,向烧瓶中加入1.68gHMDI后,进行偶联反应6h,冷却至常温,得到嵌段共聚物,分子量为4100;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
称取温敏功能性聚合物,配制质量分数35%的溶液,放入4℃冰箱中陈化12h后,即得到所需要的水凝胶,其相变温度为21℃。
实施例5
称取11.875gε-己内酯与0.625gα-炔丙基-ε-己内酯和5g两端都为羟基的聚乙二醇(分子量1000)于烧瓶中,加入0.0175g辛酸亚锡,升温至150℃,反应6h后,冷却至常温,得到聚合物,分子量为3500;将聚合物与在一价铜离子催化下叠氮短肽RGD反应,生成分子主链含有RGD的三嵌段聚合物,即本实施例制备的用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-ε-己内酯共聚物,亲水链段为聚乙二醇。
将上述温敏功能性聚合物溶于水,放入4~15℃的冰箱中陈化12~48h,得到用于组织修复的温敏功能性水凝胶。
称取温敏功能性聚合物,配制质量分数15%的溶液,放入4℃冰箱中陈化12h后,即得到所需要的水凝胶,其相变温度为10℃。
实施例6
称取5gε-己内酯与2gα-炔丙基-ε-己内酯和15g两端都为羟基的聚乙二醇(分子量2000)于烧瓶中,加入0.1125g辛酸亚锡,升温至90℃,反应24h后。冷却至常温,得到聚合物,分子量为3000;将聚合物与在一价铜离子催化下叠氮短肽RGD反应,生成分子主链含有RGD的三嵌段聚合物,即本实施例制备的用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-ε-己内酯共聚物,亲水链段为聚乙二醇。
称取温敏功能性聚合物,配制质量分数15%的溶液,放入4℃冰箱中陈化48h后,即得到所需要的水凝胶,其相变温度为45℃。
实施例7
称取5gε-己内酯、2gα炔丙基-乙交酯,3.75g单甲氧基聚乙二醇(分子量为750)于烧瓶中,加入0.08g辛酸亚锡后,升温至130℃,通氮气,反应12h后,得到预聚物;降温至80℃,向烧瓶中加入1.68gHMDI后冷却至常温,得到嵌段聚合物,分子量为4500;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-乙交酯共聚物,亲水链段为单甲氧基聚乙二醇。
称取温敏功能性聚合物,配制质量分数35%的溶液,放入4℃冰箱中陈化12h后,即得到所需要的水凝胶,其相变温度为26℃。
实施例8
称取2gα-炔丙基-δ-戊内酯和4gδ-戊内酯,3.75g单甲氧基聚乙二醇(分子量为750)于烧瓶中,加入0.08g辛酸亚锡后,升温至130℃,通氮气,反应12h后,得到预聚物;降温至80℃,向烧瓶中加入1.68gHMDI后,冷却至常温,得到嵌段聚合物;将嵌段共聚物与叠氮短肽RGD在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-δ-戊内酯共聚物,亲水链段为单甲氧基聚乙二醇。
称取温敏功能性聚合物,配制质量分数35%的溶液,放入4℃冰箱中陈化12h后,即得到所需要的水凝胶,其相变温度为24℃。
实施例9
称取2gα-炔丙基-δ-戊内酯和10gδ-戊内酯,15g两端都为羟基的聚乙二醇(分子量2000)于烧瓶中,加入0.1g辛酸亚锡,升温至130℃,反应24h后,冷却至常温,得到聚合物;将聚合物与在一价铜离子催化下叠氮短肽RGD反应,生成分子主链含有RGD的三嵌段聚合物,即本实施例制备的用于组织修复的温敏功能性聚合物,疏水链段为侧基含有短肽RGD的ε-己内酯与α-炔丙基-δ-戊内酯共聚物,亲水链段为聚乙二醇。
称取温敏功能性聚合物,配制质量分数25%的溶液,放入4℃冰箱中陈化12h后,即得到所需要的水凝胶,其相变温度为36℃。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受所述实施例的限制,如单官能团聚乙二醇还可为α-琥珀酰亚胺碳酸酯基-ω-羟基聚乙二醇、α-叠氮基ω-羟基聚乙二醇或α-醛基-ω-羟基聚乙二醇,内酯还可为丙交酯,炔基内酯还可为炔基丙交酯等,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
1.用于组织修复的温敏功能性聚合物的制备方法,其特征在于,包括以下步骤:
(1)在炔基内酯和内酯的混合物中加入单官能团聚乙二醇、二价锡类催化剂,在80~130℃下反应6~12h,得到预聚物;所述炔基内酯为炔基己内酯、炔基戊内酯、炔基丙交酯或炔基乙交酯;所述内酯为己内酯、戊内酯、丙交酯或乙交酯;
所述炔基内酯与内酯的摩尔比为0.05~19;所述炔基内酯和内酯的混合物与单官能团聚乙二醇的质量比为2~0.4;所述二价锡类催化剂的加入量为炔基内酯和内酯的混合物的1wt‰~5wt‰;
(2)在步骤(1)得到的预聚物中加入等摩尔量的二异氰酸酯,进行偶联反应,合成嵌段共聚物;
(3)将步骤(2)得到的嵌段共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
2.根据权利要求1所述的用于组织修复的温敏功能性聚合物的制备方法,其特征在于,所述单官能团聚乙二醇为单甲氧基聚乙二醇。
3.根据权利要求1所述的用于组织修复的温敏功能性聚合物的制备方法,其特征在于,所述单官能团聚乙二醇的分子的分子量为350~5000。
4.用于组织修复的温敏功能性聚合物的制备方法,其特征在于,包括以下步骤:
(1)在炔基内酯和内酯的混合物中加入双官能团聚乙二醇、二价锡类催化剂,在80-130℃下反应6~24h,得到共聚物;
所述炔基内酯与内酯的摩尔量比为0.05~19,所述炔基内酯和内酯的混合物与双官能团聚乙二醇的质量比为0.5~2.5,所述二价锡类催化剂的加入量为炔基内酯和内酯的混合物的1wt‰~5wt‰;
(2)将步骤(1)得到的共聚物与端基叠氮化的具有生物活性分子在一价铜离子催化下进行反应,得到用于组织修复的温敏功能性聚合物。
5.根据权利要求4所述的用于组织修复的温敏功能性聚合物的制备方法,其特征在于,所述双官能团聚乙二醇为两端都为羟基的聚乙二醇。
6.根据权利要求4所述的用于组织修复的温敏功能性聚合物的制备方法,其特征在于,所述双官能团聚乙二醇的分子量为350~5000。
7.用于组织修复的温敏功能性水凝胶的制备方法,其特征在于,将权利要求1或4制备的用于组织修复的温敏功能性聚合物溶于水,放入4~15℃的冰箱中陈化12~48h,得到用于组织修复的温敏功能性水凝胶。
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