CN118490879A - 一种负载石墨烯量子点的神经鞘管及其制备方法与应用 - Google Patents
一种负载石墨烯量子点的神经鞘管及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及周围神经修复领域，提供一种负载石墨烯量子点的神经鞘管及其制备方法与应用；负载石墨烯量子点的神经鞘管，包括：呈中空圆柱状的鞘管主体、涂覆于鞘管主体内壁的内涂层以及涂覆于鞘管主体外壁的外涂层；其中，鞘管主体的组分包括：石墨烯量子点以及I型胶原；鞘管主体的侧壁上沿其径向方向开设有若干微孔；内涂层以及外涂层均由聚多巴胺制得；本发明通过加入石墨烯量子点提高了神经鞘管在周围神经修复中的效果，多巴胺有优异的神经亲和性，通过化学手段制备成为涂层后可形成稳定的神经亲和性保护膜，且聚多巴胺涂层能避免石墨烯量子点直接暴露于血液及体液，提升了神经鞘管的生物相容性。
Description
技术领域
本发明涉及周围神经修复领域，尤其涉及一种负载石墨烯量子点的神经鞘管及其制备方法与应用。
背景技术
周围神经损伤常见于直接的、严重的机械性创伤，并引起不同程度的感觉与运动功能丧失，虽然周围神经在损伤后具有一定的自我修复和重新激活内在生长程序的能力，但是严重神经损伤会导致永久性的神经功能丧失，包括神经再植失败、慢性疼痛和肌萎缩的发展。目前临床治疗周围神经缺损的金标准是自体神经移植，然而这一方法存在诸多缺陷，如供体有限、尺寸不匹配以及供区组织损伤等，同时，即使自体神经移植物为促进轴突再生提供桥接的支架，感觉与运动能恢复也是缓慢和有限的，极大地限制了患者日常生活与运动。
随着组织工程技术的进展，负载石墨烯基材料的神经鞘管在修复周围神经损伤方面展现出良好的前景。Qian等人报道了负载石墨烯的聚己内酯神经导管可有效修复大鼠坐骨神经缺损。Convertino等人对其机制进行探究发现：石墨烯材料可提高损伤轴突处的神经营养因子浓度以促进周围神经再生。Pampaloni等人发现：石墨烯材料可通过改变神经元膜外离子分布从而促进神经元放电活动。然而二维石墨烯的生物相容性仍具有争议。
石墨烯量子点是指石墨烯片层尺寸在100nm以内，片层层数在10层以下的一种新兴零维碳纳米材料，在保有石墨烯原本优异电化学性质的同时，可大大提高生物相容性。并且，Kim等人发现石墨烯量子点可在体内随着尿液排出体外，相比传统石墨烯更适合负载入体内植入物使用。现有专利CN201980045605.3公开了石墨烯量子点在神经蛋白异常纤维化或凝聚相关的疾病、阿尔茨海默病、帕金森病、亨廷顿病、卢伽雷病、痴呆症、中风、淀粉样变性、纤维化、脑病及多发性硬化症等疾病中的应用，尚无文件报道石墨烯量子点在周围神经再生领域的应用。
胶原蛋白是一种天然蛋白，它在神经组织基质的形成中起重要作用。例如，围绕轴突-施万细胞单元的基底膜管(神经内鞘)由胶原蛋白组成，神经外鞘和会阴鞘(围绕神经束并加强神经)由纵向取向的胶原纤维组成。该基质在再生过程中也起着重要作用。胶原蛋白已被用于制造神经管，并且单通道胶原蛋白管已经商业化：(Integra公司)、和(均为Stryker公司)。天然可降解材料I型胶原制备的生物材料具备上述优点且已获得我国CFDA的批准，是一种制备人工神经移植物的理想基材。美国梅奥诊所的研究者们使用已商业化的I型胶原神经植入物(Integra公司)修复大鼠1cm坐骨神经缺损，发现I型胶原神经植入物的疗效相比“金标准”自体神经移植较差，主要表现为有髓神经纤维数量和密度的下降以及靶器官复合动作电位的减弱。
负载石墨烯及其衍生物的神经导管虽在修复周围神经损伤方面有大量研究表明其有效性，但是石墨烯材料的生物安全性仍然存在争议，未经修饰的或粒径过大的石墨烯基材直接暴露于血液及体液，可能对细胞产生毒性及产生炎症反应，从而影响神经再生。
发明内容
本发明的目的是针对现有技术中的不足，提供一种负载石墨烯量子点的神经鞘管及其制备方法与应用。
为实现上述目的，本发明采取的技术方案是：
本发明的第一方面是提供一种负载石墨烯量子点的神经鞘管，包括：呈中空圆柱状的鞘管主体、涂覆于所述鞘管主体内壁的内涂层以及涂覆于所述鞘管主体外壁的外涂层；
其中，所述鞘管主体包括：石墨烯量子点以及I型胶原；所述鞘管主体的侧壁上沿其径向方向开设有若干微孔，若干所述微孔沿所述鞘管主体的轴向方向等距设置；
所述内涂层以及所述外涂层均由聚多巴胺制得。
优选地，所述神经鞘管的内径为1.2mm-8mm，所述神经鞘管的长度为0.5cm-5cm，所述神经鞘管的厚度为0.35mm-1mm。
优选地，所述微孔的直径为40nm-60nm，相邻所述微孔之间的间距大于1mm。
优选地，所述石墨烯量子点的厚度为1.5nm-2nm，所述石墨烯量子点的粒径为5nm-10nm。
本发明的第二方面是提供一种上述神经鞘管的制备方法，步骤包括：
S1、称取所述I型胶原溶解于六氟异丙醇中，制得第一溶液；
S2、在所述第一溶液中加入所述石墨烯量子点，低温环境下进行超声处理，制得原料液；
S3、采用静电纺丝技术或3D打印技术将所述原料液制备成管状物，采用打孔装置对所述管状物进行打孔处理后，对所述管状物进行裁剪，制得开设有若干所述微孔的所述鞘管主体；
S4、采用自然氧化法或化学还原法对所述鞘管主体的壁面进行覆膜处理，即得所述神经鞘管。
优选地，所述石墨烯量子点与所述I型胶原的质量比为(0.1-1)：100。
优选地，多巴胺与所述I型胶原的质量比为(0.1-1)：100。
优选地，所述超声处理的时间为20min-60min。
本发明的第三方面是提供一种上述神经鞘管或上述制备方法制得的神经鞘管在制备周围神经修复产品中的应用。
本发明采用以上技术方案，与现有技术相比，具有如下技术效果：
本发明通过加入石墨烯量子点提高了神经鞘管在周围神经修复中的效果，超小粒径的石墨烯量子点具有优越的细胞内吞效应，可被生物体排出，相比大粒径的石墨烯材料拥有更好的生物相容性；多巴胺作为一种天然神经递质，有优异的神经亲和性，通过化学手段制备成为涂层后可形成稳定的神经亲和性保护膜，且聚多巴胺涂层能避免石墨烯量子点直接暴露于血液及体液，提升了所述神经鞘管的生物相容性。
附图说明
图1为本发明负载石墨烯量子点的神经鞘管的基本结构示意图；
图中的附图标记包括：
鞘管主体1；微孔11；内涂层2；外涂层3。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
需要说明的是，在不冲突的情况下，本发明中的实施例及实施例中的特征可以相互组合。
下面结合附图和具体实施例对本发明作进一步说明，但不作为本发明的限定。
实施例
本实施例提供一种负载石墨烯量子点的神经鞘管的制备方法，步骤包括：
S1、称取1g所述I型胶原溶解于10mL六氟异丙醇中，制得第一溶液；
S2、在所述第一溶液中加入10mg所述石墨烯量子点，低温环境下超声处理30min，制得原料液；
S3、采用静电纺丝技术将所述原料液制成管状物，采用打孔装置对所述管状物进行打孔处理后，对所述管状物进行裁剪，制得开设有若干所述微孔11的所述鞘管主体1；
其中，所述静电纺丝技术包括：将所述原料液加入纺丝针筒，纺丝针筒采用21号针头，将纺丝机中纤维排布方式调节为取向排布，纺丝厚度调节为0.35mm-1mm，针头尖端和接收器之间的距离为15cm，针头端连接16kV正高压，接收器端连接-4kV负高压，针筒以0.5mL/h的速度进行推注，接收装置以3000r/min的速度接收取向排布的静电纺丝，在低温无菌环境下纺制制得一体成型的管状物；
所述打孔处理包括：使用打孔机在管状物上打直径为50nm的微孔11，每个微孔11间隔1mm；
S4、采用化学还原法对所述鞘管主体1的壁面进行覆膜处理，即得所述神经鞘管；
其中，所述覆膜处理包括：将37.5mg五水合硫酸铜和60μL双氧水加入30mL pH为8.0的Tris-盐酸缓冲溶液中，搅拌均匀，再称取10mg多巴胺置于上述混合溶液中，搅拌均匀制得第二溶液；将制备的鞘管主体1浸泡于第二溶液中，4℃恒温摇床震荡1h，使多巴胺充分聚合形成聚多巴胺并附着于鞘管主体1内表面。
检测实施例
使用PC12细胞系模拟多巴胺能神经元，在不同复合膜上培养指定时间，使用CCK-8法测定相对细胞活力，结果如表1所示；
表1
| 相对细胞活力 | 培养1日 | 培养3日 | 培养7日 |
| 不使用聚多巴胺包覆的神经鞘管 | 87.1±5.5％ | 71.8±12.1％ | 62.3±18.2％ |
| 聚多巴胺包覆的神经鞘管 | 92.1±4.1％ | 85.9±9.9％ | 77.6±15.1％ |
注：不使用聚多巴胺包覆的神经鞘管的制备方法同实施例S1-S3。
结果显示，相比于不使用聚多巴胺包覆的神经鞘管，使用聚多巴胺包覆的神经鞘管可更好地提升神经元的活性，可为周围神经再生提供理想的界面。
使用SD大鼠坐骨神经1cm缺损伤模拟周围神经损伤，使用不同神经鞘管治疗，在指定时间点进行步态实验并使用坐骨神经指数测定相对运动功能恢复，结果如表2所示；
表2
注：不负载石墨烯量子点的聚多巴胺包覆的神经鞘管的制备方法参照实施例，区别为舍去步骤S2，将S1制得的第一溶液作为静电纺丝的原料液。
结果显示，相比于不负载石墨烯量子点的聚多巴胺包覆的神经鞘管，本发明负载石墨烯量子点的聚多巴胺包覆的神经鞘管可更好地提升周围神经损伤后的运动功能恢复。
使用SD大鼠坐骨神经1cm缺损伤模拟周围神经损伤，使用不同复合支架治疗，在指定时间点进行周围神经电生理实验并使用神经传导速度测定神经电生理恢复，结果如表3所示；
表3
结果显示，相比于不负载石墨烯量子点的聚多巴胺包覆的神经鞘管，本发明负载石墨烯量子点的聚多巴胺包覆的神经鞘管可更好地提升周围神经损伤后的神经电生理活性。
应用实施例1
使用环氧乙烷法对实施例所述制备方法制得的神经鞘管进行灭菌，灭菌后将神经鞘管沿其轴向方向剖开并包绕于周围神经受损部位，采用6-0可吸收缝线缝合，用于治疗周围神经非缺损伤，发挥防黏连促再生的效果。
应用实施例2
使用环氧乙烷法对实施例所述制备方法制得的神经鞘管进行灭菌，灭菌后选取合适大小的神经鞘管，使用6-0生物可吸收缝合线，将近端神经缺损段的外膜与神经鞘管的一端缝合，将远端神经缺损段的外膜与神经鞘管的另一端缝合，每个缺损端均采用“三点法”进行缝合，即每端接口处通过三个间隔均匀的缝合点进行缝合，缝合后注射适量青霉素减少炎症反应。
综上所述，本发明通过加入石墨烯量子点提高了神经鞘管在周围神经修复中的效果，超小粒径的石墨烯量子点具有优越的细胞内吞效应，可被生物体排出，相比大粒径的石墨烯材料拥有更好的生物相容性；多巴胺作为一种天然神经递质，有优异的神经亲和性，通过化学手段制备成为涂层后可形成稳定的神经亲和性保护膜，且聚多巴胺涂层能避免石墨烯量子点直接暴露于血液及体液，提升了所述神经鞘管的生物相容性。
以上所述仅为本发明较佳的实施例，并非因此限制本发明的实施方式及保护范围，对于本领域技术人员而言，应当能够意识到凡运用本发明说明书及图示内容所作出的等同替换和显而易见的变化所得到的方案，均应当包含在本发明的保护范围内。
Claims (9)
1.一种负载石墨烯量子点的神经鞘管，其特征在于，包括：呈中空圆柱状的鞘管主体(1)、涂覆于所述鞘管主体(1)内壁的内涂层(2)以及涂覆于所述鞘管主体(1)外壁的外涂层(3)；
其中，所述鞘管主体(1)包括：石墨烯量子点以及I型胶原；所述鞘管主体(1)的侧壁上沿其径向方向开设有若干微孔(11)，若干所述微孔(11)沿所述鞘管主体(1)的轴向方向等距设置；
所述内涂层(2)以及所述外涂层(3)均由聚多巴胺制得。
2.根据权利要求1所述的神经鞘管，其特征在于，所述神经鞘管的内径为1.2mm-8mm，所述神经鞘管的长度为0.5cm-5cm，所述神经鞘管的厚度为0.35mm-1mm。
3.根据权利要求1所述的神经鞘管，其特征在于，所述微孔(11)的直径为40nm-60nm，相邻所述微孔(11)之间的间距大于1mm。
4.根据权利要求1所述的神经鞘管，其特征在于，所述石墨烯量子点的厚度为1.5nm-2nm，所述石墨烯量子点的粒径为5nm-10nm。
5.一种如权利要求1-4任一项所述神经鞘管的制备方法，其特征在于，步骤包括：
S1、称取所述I型胶原溶解于六氟异丙醇中，制得第一溶液；
S2、在所述第一溶液中加入所述石墨烯量子点，低温环境下进行超声处理，制得原料液；
S3、采用静电纺丝技术或3D打印技术将所述原料液制成管状物，采用打孔装置对所述管状物进行打孔处理后，对所述管状物进行裁剪，制得开设有若干所述微孔(11)的所述鞘管主体(1)；
S4、采用自然氧化法或化学还原法对所述鞘管主体(1)的壁面进行覆膜处理，即得所述神经鞘管。
6.根据权利要求5所述的制备方法，其特征在于，所述石墨烯量子点与所述I型胶原的质量比为(0.1-1)：100。
7.根据权利要求5所述的制备方法，其特征在于，多巴胺与所述I型胶原的质量比为(0.1-1)：100。
8.根据权利要求5所述的制备方法，其特征在于，所述超声处理的时间为20min-60min。
9.一种如权利要求1-4任一项所述神经鞘管或如权利要求5-8任一项所述制备方法制得的神经鞘管在制备周围神经修复产品中的应用。
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