CN106977670B - 一种光交联丝素蛋白的改性及其原位药物负载水凝胶的制备方法 - Google Patents
一种光交联丝素蛋白的改性及其原位药物负载水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了一种光交联丝素蛋白的改性及其原位药物负载水凝胶的制备方法,该方法用硅烷偶联剂类改性剂或丝素蛋白改性剂,对丝素蛋白进行光交联改性。再将改性丝素蛋白与光引发剂、光固化单体、交联剂及药物等均匀混合,经特定光源辐照原位制备药物负载丝素蛋白复合水凝胶。该方法可使丝素蛋白与单体及交联剂在低温环境下发生共价交联,显著改善丝素蛋白复合水凝胶的物理机械性能;可通过对改性剂用量和种类的选用调控丝素蛋白复合水凝胶体系的交联密度和生物可降解性;可根据个体患者的病情差异,对添加药物的种类及计量进行定制。本发明制备的光交联丝素蛋白复合水凝胶在组织工程及生物医药等领域有广阔的应用前景。
Description
技术领域
本发明涉及一种光交联复合水凝胶材料,尤其是一种光交联丝素蛋白的改性技术及其原位药物负载复合水凝胶的制备方法。
背景技术
水凝胶是一类具有三维空间网状结构的高分子材料,具有溶胀性、触变性、透过性等优良性能,其作为创口敷料具有加速愈合、易更换、载药及缓释等优点,在医疗卫生领域具有广阔的市场前景。合成高分子水凝胶虽然具备诸多优点,如结构稳定、性能优良、产量大、成本低等,但往往存在生物相容性问题。丝素蛋白(Silk Fibroin,SF)富含对人体有益的18种氨基酸,具有优异的生物相容性、生物可降解性及药物缓释功能,将其与合成高分子水凝胶复配,可兼具两者的优异性能,制备出理想的水凝胶敷料。
丝素蛋白复合水凝胶一般可通过物理交联和化学交联两种方法制备。物理交联法主要通过丝素蛋白和合成高分子链段的纠缠方式形成一定的网络结构,其主要制备方法有冷冻干燥法,超声法和紫外线法等。然而,通过物理交联制备的复合水凝胶往往存在溶胀后结构稳定性和机械强度较差等不足;丝素蛋白复合水凝胶的化学交联法则主要通过化学交联剂的共价交联方式形成一定的三维网络结构。常用的交联剂有多元醛类、碳化二亚胺类等。采用化学交联法虽然可改善复合水凝胶的结构稳定型和物理机械性能,化学交联过程往往需要较长时间或较高温度,无法满足载药丝素蛋白复合水凝胶低温制备要求。此外,常用的醛类等化学交联剂通常具有一定的细胞毒性,影响其在生物医药领域的应用。因此,制备一种具有良好物理机械性能和生物相容性的丝素蛋白复合水凝胶具有重要的应用价值。
发明内容
本发明的目的在于提供一种光交联丝素蛋白的改性及其原位药物负载水凝胶的制备方法,解决目前丝素复合水凝胶敷料存在的不足,该方法工艺灵活、可操作性强,能提供原位药物负载所需的低温环境,并可显著改善丝素蛋白复合水凝胶的物理机械性能和生物相容性,在创伤修复等生物医药领域具有广阔应用前景。
为了解决上述技术问题,采用如下技术方案:
一种光交联丝素蛋白的改性及其原位药物负载水凝胶的制备方法,其特征在于包括如下步骤:
(1)制备光交联丝素蛋白改性剂:
将二异氰酸酯与含羟基的自由基光固化单体或含羟基的阳离子光固化单体或含羟基的巯基化合物,按nNCO:nOH为1:(1~2)的摩尔百分比于室温下混合并搅拌均匀,然后于40~75℃条件下搅拌反应1~4h后制得光交联丝素蛋白改性剂。
所述的丝素蛋白改性剂化学结构式为:NCO—R—X,中X为含羟基自由基或阳离子单体,如:(甲基)丙烯酸羟烷基酯类,羟烷基乙烯基醚类,羟烷基环氧类,羟烷基巯基类单体,其中R为如下结构中的一种:
(2)光交联改性丝素蛋白的制备:
将步骤(1)得到的丝素蛋白改性剂或硅烷偶联改性剂溶于特定溶剂中,并加入丝素蛋白,搅拌均匀,于60~80℃条件下反应1~3h左右,制得具有光交联活性的改性丝素蛋白;其中,丝素蛋白改性剂或硅烷偶联改性剂与特定溶剂的质量比为(1:10~100),丝素蛋白与特定溶剂的质量比为(1:10~100)
(3)将步骤(2)得到的可光交联改性丝素蛋白与光引发聚合体系按照如下质量百分比在室温下混合:
混合后,得到光交联丝素蛋白复合水凝胶聚合前驱液,将其倒入模板中,在氮气氛围中辐照2~10min得到光交联丝素蛋白复合水凝胶。
优选后,所述二异氰酸酯选自异佛尔酮二异氰酸酯、4,4-二异氰酸酯二环己基甲烷、甲苯-2,4-二异氰酸酯中的一种。
优选后,所述含羟基的自由基光固化单体选自丙烯酸羟乙酯,甲基丙烯酸羟乙酯或丙烯酸羟丙酯中的一种;所述含羟基的阳离子光固化单体选自4-羟丁基乙烯基醚或环己基-1,4-二甲醇单乙烯基醚中的一种;所述含羟基的巯基化合物选自巯基乙酸,3-巯基丙酸,1-硫代甘油或2-巯基乙醇中的一种。
优选后,所述特定溶剂选自N-甲基吡咯烷酮,N,N-二甲基丙烯酰胺或去离子水中的一种。
优选后,所述硅烷偶联剂类改性剂选自γ的缩水甘油醚氧丙基三甲氧基硅烷,3-(甲基丙烯酰氧)丙基三甲氧基硅烷,γ-巯丙基三甲氧基硅烷中的一种;所述硅烷偶联剂类改性剂使用前,需要在30mL去离子水中超声水解30min。
优选后,所述光引发剂选用樟脑醌/叔胺体系或二苯甲酮/叔胺体系中的一种。
优选后,所述叔胺选自4-二甲氨基苯甲酸乙酯或N,N-二甲基丙烯酰胺中的一种。
优选后,所述交联剂选自聚乙二醇二丙烯酸酯250、聚乙二醇二丙烯酸酯600、聚乙二醇二丙烯酸酯1000或N,N'-亚甲基双丙烯酰胺中的一种。
优选后,所述单体选自丙烯酸钠、丙烯酰胺或丙烯酸羟乙酯中的一种或两种。
由于采用上述技术方案,具有以下有益效果:
1、利用本发明对可溶性丝素蛋白进行光交联接枝改性,可使处于无规线团状态的丝素蛋白与单体及交联剂发生共价交联,显著改善丝素蛋白复合水凝胶溶胀前后的物理机械性能;
2、利用本发明可通过改变改性剂用量来调控丝素蛋白大分子结构上的可光交联官能团数量,从而有效控制丝素蛋白复合水凝胶体系的交联密度;并可通过选用巯基类改性剂,获得具有良好生物降解性能的丝素蛋白复合水凝胶。
3、利用本发明可实现载药丝素蛋白复合水凝胶的低温原位制备,避免了外加负载方式引起的药物分布不均及热聚合或热交联原位负载方式导致的药物高温失效等问题。
具体实施方式
下面结合具体的实施例对发明作进一步说明:
实施例1:
(1)光交联改性丝素蛋白的制备:
按1:1的摩尔比,将异佛尔酮二异氰酸酯与丙烯酸羟乙酯于室温下混合搅拌均匀,然后于60℃条件下反应1.5h,得到光交联丝素蛋白改性剂。向其加入4%丝素蛋白的N-甲基吡咯烷酮分散液,80℃条件下搅拌反应2h,制得光交联改性丝素蛋白,备用;
(2)光固化药物负载水凝胶前驱液的制备:
表1光固化药物负载水凝胶前驱液的配方
根据表1配方准确称取各药品。在2.0g去离子水中加入0.01g樟脑醌、0.01g 4-二甲氨基苯甲酸乙酯、0.0050g聚乙二醇二丙稀酸酯1000、2.0g丙烯酸钠及0.02mg重组人表皮生长因子,超声分散均匀,备用。
(3)光交联丝素蛋白复合水凝胶的制备:
将1.0g可光交联改性丝素蛋白加入到4.4g光固化水凝胶前驱液中,超声分散至溶解,倒入模具中,选用与光引发体系相匹配的光源进行辐照固化,制得光交联丝素蛋白复合水凝胶。
实施例2
与实施例1不同之处在于:二异氰酸酯种类不同,其它条件与实施例1同。具体不同之处如下所述:
(1)可光交联改性丝素蛋白的制备:
按1:1的摩尔比,将丙烯酸羟乙酯缓慢滴加到1,6-己二异氰酸酯中,然后于60℃条件下反应1.5h。再加入4%丝素蛋白的N-甲基吡咯烷酮分散液,80℃条件下搅拌反应2h,制得光交联改性丝素蛋白。
实施例3:
与实施例1不同之处在于:含羟基的丙烯酸酯不同,其它条件与实施例1同。具体不同之处如下所述:
(1)光交联改性丝素蛋白的制备:
按1:1的摩尔比,将异佛尔酮二异氰酸酯与丙烯酸羟丙酯混合搅拌均匀,于60℃条件下反应1.5h。再加入4%丝素蛋白的N-甲基吡咯烷酮分散液。80℃条件下搅拌反应2h,制得光交联丝素蛋白。
实施例4:
与实施例1不同之处在于:光交联丝素蛋白改性的制备方法不同,其它条件与实施例1同。具体不同之处如下所述:
(1)光交联改性丝素蛋白的制备:
将一定量的KH570(硅烷偶联剂)加入到30mL去离子水中,调节pH值,超声0.5h,使其均匀混合,然后再加入1g丝素蛋白粉体,搅拌后在振荡水浴锅里反应2h,得到样品。将样品用去离子水清洗2遍,烘干研磨称重,然后将研磨后的样品加入到50mL去离子水中,超声0.5h,再静置1h,取出上层漂浮的粉体,烘干称重,备用。
实施例5:
与实施例1不同之处在于:光固化药物负载水凝胶前驱液体系不同,其它条件与实施例1同。具体不同之处如下所述:
表2光固化药物负载水凝胶前驱液的配方
根据表2配方准确称取各药品。在2.0g去离子水中加入0.01g二苯甲酮、0.01g N,N-二甲基丙烯酰胺、0.0050g聚乙二醇二丙稀酸酯1000、2.0g丙烯酸钠及0.02mg重组人表皮生长因子,超声分散均匀,备用。
以上仅为本发明的具体实施例,但本发明的技术特征并不局限于此。任何以本发明为基础,为解决基本相同的技术问题,实现基本相同的技术效果,所作出地简单变化、等同替换或者修饰等,皆涵盖于本发明的保护范围之中。
Claims (4)
1.一种基于光交联丝素蛋白的改性制备复合水凝胶方法,其特征在于包括如下步骤:
(1)制备光交联丝素蛋白改性剂:将二异氰酸酯与含羟基的自由基光固化单体,含羟基的阳离子光固化单体或含羟基的巯基化合物,按nNCO:nOH为1:(1~2)的摩尔百分比于室温下混合并搅拌均匀,然后于40~75℃条件下搅拌反应1~4h后制得光交联丝素蛋白改性剂;
其中,所述含羟基的自由基光固化单体选自丙烯酸羟乙酯,甲基丙烯酸羟乙酯或丙烯酸羟丙酯中的一种;所述含羟基的阳离子光固化单体选自4-羟丁基乙烯基醚或环己基-1,4-二甲醇单乙烯基醚中的一种;所述含羟基的巯基化合物选自巯基乙酸,3-巯基丙酸,1-硫代甘油或2-巯基乙醇中的一种;
(2)光交联改性丝素蛋白的制备:
将步骤(1)得到的丝素蛋白改性剂或硅烷偶联改性剂溶于特定溶剂中,再向特定溶剂中加入丝素蛋白,搅拌均匀,于60~80℃条件下反应1~3h左右,制得光交联改性丝素蛋白;其中,丝素蛋白改性剂或硅烷偶联改性剂与特定溶剂的质量比为(1:10~100),丝素蛋白与特定溶剂的质量比为(1:10~100);其中,所述特定溶剂选自N-甲基吡咯烷酮,N,N-二甲基丙烯酰胺或去离子水中的一种;其中,所述硅烷偶联改性剂选自γ-缩水甘油醚氧丙基三甲氧基硅烷,3-(甲基丙烯酰氧)丙基三甲氧基硅烷,γ-巯丙基三甲氧基硅烷中的一种;所述硅烷偶联改性剂使用前,需要在30mL去离子水中超声水解30min;
(3)将步骤(2)得到的光交联改性丝素蛋白与光固化引发聚合体系按照如下质量百分比在室温下混合:
混合后,得到光交联丝素蛋白复合水凝胶聚合前驱液,将其倒入模板中,在氮气氛围中辐照2~10min得到光交联丝素蛋白复合水凝胶;其中,所述交联剂选自聚乙二醇二丙烯酸酯250、聚乙二醇二丙烯酸酯600、聚乙二醇二丙烯酸酯1000或N,N'-亚甲基双丙烯酰胺中的一种;所述单体选自丙烯酸钠、丙烯酰胺或丙烯酸羟乙酯中的一种或两种。
2.根据权利要求1所述一种基于光交联丝素蛋白的改性制备复合水凝胶方法,其特征在于:所述二异氰酸酯选自异佛尔酮二异氰酸酯、4,4-二异氰酸酯二环己基甲烷、甲苯-2,4-二异氰酸酯中的一种。
3.根据权利要求1所述一种基于光交联丝素蛋白的改性制备复合水凝胶方法,其特征在于:所述光引发剂选用樟脑醌/叔胺体系或二苯甲酮/叔胺体系中的一种。
4.根据权利要求3所述一种基于光交联丝素蛋白的改性制备复合水凝胶方法,其特征在于:所述叔胺选自4-二甲氨基苯甲酸乙酯或N,N-二甲基丙烯酰胺中的一种。
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