CN114886603B - 一种抗弯折神经导管及其制备方法和应用 - Google Patents
一种抗弯折神经导管及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种抗弯折神经导管及其制备方法和应用,涉及组织工程材料技术领域。本发明导管由内层、中层和外层构成,各层原料为生物可降解高分子;其中,内层由光滑层、定向微通道或者纤维的致密薄层构成,由于内层结构光滑或具有定向引导结构会加速神经生长,可以延长其修复距离,致密的内层也能够提供轴向的力学支持;中层由具有一定角度排布的微米纤维缠绕而成,其主要作用是赋予导管抗打折和柔性功能,同时能够提供径向力学支持;外层由聚合物纤维随机缠绕而成并与中层紧密粘接在一起,主要是起到防止周围组织细胞长入妨碍神经生长的作用。本发明导管具有优异的抗弯折性能和神经修复效果。
Description
技术领域
本发明涉及组织工程材料技术领域,特别是涉及一种抗弯折神经导管及其制备方法和应用。
背景技术
创伤、疾病或外科手术等多种原因都会对人体外周神经造成不同程度的损伤,导致感觉和运动功能丧失甚至永久性肌肉运动障碍。全世界外周神经损伤人数约9600万人,在我国,外周神经损伤后仍存在功能障碍的患者有近2000万人,且每年以200万人数的速度递增,这会给患者、家庭和社会造成严重的负担。目前在临床上,对于小尺寸(<5mm)神经缺损,会优先采用端端缝合的方式。然而,对较长距离的神经缺损,通常会采用自体移植或同种异体移植的手段治疗。但自体移植需要二次手术,会对人体造成二次损伤,导致供区神经功能受损或外伤性神经瘤形成,也存在取材神经尺寸不匹配的问题。而同种异体移植来源有限,极大地限制了其临床应用。组织工程神经导管的开发为外周神经修复带来新的选择,可替代自体移植物和同种异体移植物来桥接神经损伤部位,为轴突再生提供仿生微环境。
目前,科学家们已经开发出十余种神经导管产品用于临床神经缺损的修复,并且能够起到促进神经功能恢复的效果。但根据临床外科医生反馈和一些报道显示,有些天然材料产品如胶原神经导管机械强度不足,在植入到肌肉环境中会受到肌肉压缩而管腔体积变小,进而妨碍神经生长。另外,用于修复人体关节部位神经缺损时,由于大部分产品不具有抗弯折性能,在关节弯曲过程中也会导致导管内部体积压缩变形从而妨碍神经生长。关节的弯曲也会导致缝线拔出会诱发神经二次损伤。临床上常用的治疗方式是固定关节部位以防止其运动。在神经修复阶段,如果长时间固定容易引起关节部位术后僵硬、组织粘连、肌肉萎缩等一系列问题。所以理想的神经导管在满足具有良好生物相容性、提供适合神经生长微环境的同时,还应该能够抗肌肉挤压,具有良好的柔性和抗弯折能力。因此,亟需开发能够抗挤压和抗弯折的神经导管产品用于解决肌肉环境和跨关节部位神经缺损问题。
发明内容
本发明的目的是提供一种抗弯折神经导管及其制备方法和应用,以解决上述现有技术存在的问题,使导管具有优异的抗弯折性能和神经修复效果。
为实现上述目的,本发明提供了如下方案:
本发明目的之一是提供一种抗弯折神经导管,由内层、中层和外层构成;所述内层、中层和外层的原料为生物可降解高分子;
所述内层为光滑表面内层、定向微通道内层或纤维内层;
所述中层为具有交叉角度的纤维中层;所述交叉角度为0-90°,不为0°;
所述外层为随机分布的纤维外层。
进一步地,所述抗弯折神经导管的管腔直径为1-100mm,管壁厚度为50-1000um。
进一步地,所述光滑表面内层厚度为1-100um;所述定向微通道内层由反向模板法制备得到,厚度为1-200um,定向微通道的凹槽深度为1-100um;所述纤维内层由磁场辅助静电纺丝制备得到,纤维直径为0.1-200um,厚度为0.1-200um。
进一步地,所述具有交叉角度的纤维中层由湿法纺丝或熔融纺丝制备得到。
进一步地,湿法纺丝制备的纤维直径为5-300um,中层厚度为20-450um;熔融纺丝制备的纤维直径为1-100um,中层厚度为20-500um。
进一步地,所述纤维外层的纤维直径为0.01-200um,外层厚度为10-400um。
进一步地,所述生物可降解高分子包括合成可降解聚合物或天然高分子材料中的一种或几种。
进一步地,所述合成可降解聚合物包括聚乳酸(PLA)、聚己内酯(PCL)、聚L-丙交酯-己内酯(PLCL)、聚羟基脂肪酸酯(PHA)、聚乳酸-聚羟基乙酸共聚物(PLGA)、聚二噁烷酮(PDS)或聚氨酯(PU);所述天然高分子材料包括胶原、明胶、丝素蛋白、纤维蛋白、壳聚糖、甲壳素、纤维素、淀粉、海藻酸或透明质酸。
本发明目的之二是提供上述抗弯折神经导管的制备方法,采用模板法或磁场辅助静电纺丝法制备所述内层;采用湿法纺丝法或熔融纺丝法制备所述中层;采用静电纺丝法制备所述外层。
本发明目的之三是提供上述抗弯折神经导管在制备神经修复材料中的应用。
具体的,该抗弯折神经导管可用于神经、血管、淋巴管、尿道、泪管或肠组织修复。
近年来,针对临床上对于抗挤压和抗弯折神经导管产品的实际需求,研究者们开展了一些类似导管设计与制备工作,但数量较少。在临床应用的产品中,在现有国内外上市产品中,只有美国史赛克(Stryker)公司生产的NeuroflexTM具备抗弯折特点,其抗弯曲角度为60°。为了解决现有产品抗压缩和抗弯折能力差,神经修复距离短、效果差的问题,本发明设计并制备了由内层、中层和外层组成的内层结构光滑或具有引导结构、抗弯折的三层结构导管。
本发明导管内层由光滑层、定向微通道或者纤维的致密薄层构成,由于内层结构光滑或具有定向引导结构会加速神经生长,可以延长其修复距离,致密的内层也能够提供轴向的力学支持。中层由具有一定角度排布的微米纤维缠绕而成,其主要作用是赋予导管抗打折和柔性功能,同时能够提供径向力学支持。外层由聚合物纤维随机缠绕而成并与中层紧密粘接在一起,主要是起到防止周围组织细胞长入妨碍神经生长的作用。管腔直径为1-100mm;管壁厚度为50-1000um。
本发明公开了以下技术效果:
本发明为内层、中层和外层组成的三层结构导管,导管内层为光滑内层或具有定向微通道、定向纤维的内层,能够引导细胞定向迁移;导管中层为具有交叉角度(0-90°)的纤维结构,赋予导管柔性、抗打折、抗肌肉挤压性能,可以防止导管打折导致堵塞;随机纤维外层可以妨碍周围细胞迁移。
本发明导管制备工艺可控性强,可调控内层厚度、光滑度、微通道和纤维直径,中层纤维直径以及纤维之间的角度和粘接程度,外层纤维的粗细和厚度;同时也可以控制导管的直径和厚度。本发明导管可用于神经,血管,淋巴管,尿道,泪管和肠组织修复。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为对照品静电纺丝导管及实施例1-3三层导管的抗弯折性能;
图2为对照品静电纺丝导管及实施例1-3三层导管的微观结构图;
图3为对照品静电纺丝导管及实施例1-3三层导管的径向力学测试图;其中,图A为径向力学测试示意图,图B为径向力学测试结果;
图4为透射电镜显示对照品静电纺丝导管及实施例1-3三层导管用于外周神经修复再生髓鞘的形态。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
本发明三层结构抗弯折神经导管制备包括以下三步:
第一步是制备导管内层,利用反向模板法制备导管内层的定向微通道内层(光滑内层通过光滑金属接收棒接收制备得到);利用磁场辅助静电纺丝制备纤维内层。
定向微通道内层制备方法是:以化学纯试剂(包括乙酸,水,四氢呋喃、二氯甲烷、三氯甲烷、乙酸、丙酮、三氟乙醇、六氟异丙醇等)为溶剂,配制一定浓度(质量/体积分数为1%-60%)的可降解聚合物(包括聚己内酯(PCL)、聚丙交酯(PLA)、聚(丙交酯-乙醇酸)共聚物(PLGA)、聚乙醇酸(PGA)、聚羟基脂肪酸酯(PHA)、聚(丙交酯-己内酯)共聚物(PLCL)、聚对二氧六环己酮(PDS)等)或天然材料(包括丝素蛋白、壳聚糖、明胶、胶原等)溶液,溶解完全后,将溶解的聚合物材料溶液装入注射器中,利用微量注射泵将注射器中的聚合物溶液打印到位于针头下方具有定向微槽接收棒上,接收棒直径为1-100mm,微槽宽度为0.1-50um,高度为0.1-50um。溶液流速为0.1-50ml/h,注射器针头与下方接收棒距离为0.1-5cm,接收棒的转速为1-500rpm,移动速度为1mm-50mm/sec,挤出的聚合物溶液中的溶剂成分挥发,固化后形成内层具有定向微通道的薄膜,可以通过调节聚合物浓度、流速、接受棒直径、转动速度和移动速度等参数从而制备厚度可控(1-200um)的定向微通道内层。
纤维内层制备的方法是:以化学纯试剂(包括乙酸,甲酸,水,四氢呋喃、二氯甲烷、三氯甲烷、乙酸、丙酮、三氟乙醇、六氟异丙醇等)为溶剂,配制一定浓度(质量/体积分数为1%-60%)的可降解聚合物包括聚己内酯(PCL)、聚丙交酯(PLA)、聚(丙交酯-乙醇酸)共聚物(PLGA)、聚乙醇酸(PGA)、聚羟基脂肪酸酯(PHA)、聚(丙交酯-己内酯)共聚物(PLCL)、聚对二氧六环己酮(PDS)等)或天然材料(包括丝素蛋白、壳聚糖、明胶、胶原等)溶液,溶解完全后,将溶解的合成或天然材料溶液装入注射器中,将接收棒安装在磁场辅助静电纺丝仪上,将聚合物溶液吸入注射器中安装在注射泵上,将注射器针头置于接收棒上方1-20cm位置处位置。设定电压为:0.1-100KV,注射泵速度为0.1-40ml/h,接收棒转速为1-1000rpm,移动速度为1-1000mm/sec,纺丝时间为1-100min,完成纺丝后备用。可以通过调节聚合物或天然材料浓度、流速、接受棒转动速度和移动速度等参数从而制备纤维直径(0.1-200um)可控且沿轴向定向排布的内层,厚度为0.1-200um。
第二步是构建具有交叉角度的微米纤维导管中层。具体可用湿法纺丝或熔融纺丝加工而成,将第一步所制备的带有定向微通道或定向纤维或光滑内层的接收棒安装在湿法纺丝仪器上,将一定浓度聚合物或天然材料溶液加入到注射器里,将注射器安装在注射泵上,调整注射泵推进速度、接收棒转速和移动速度等参数来调控中层微米纤维的直径以及纤维之间的角度从而制得直径为5-300um,厚度为20-450um的圆周取向纤维中层。同时也可以将第一步所制备的带有定向微通道或定向纤维或光滑内层的接收棒安装在熔融纺丝仪上,将聚合物添加到恒温加热料筒里,升温使聚合物融化后,通过调节料筒推进活塞速度、针头粗细、接收棒转速和横向移动速度等参数来调控中层微米纤维直径、以及纤维之间的交叉角度从而制得直径为1-100um,厚度为20-500um交缠纤维的导管中层。
第三步是随机分布纤维导管外层的制备。外层随机纤维制备的方法是:以化学纯试剂(包括四氢呋喃、二氯甲烷、三氯甲烷、乙酸、丙酮、三氟乙醇、六氟异丙醇等)为溶剂,配制一定浓度(质量/体积分数为1%-60%)的可降解聚合物(包括聚己内酯(PCL)、聚丙交酯(PLA)、聚(丙交酯-乙醇酸)共聚物(PLGA)、聚乙醇酸(PGA)、聚羟基脂肪酸酯(PHA)、聚(丙交酯-己内酯)共聚物(PLCL)、聚对二氧六环己酮(PDS)等)或天然材料(包括丝素蛋白、壳聚糖、明胶、胶原等)溶液,溶解完全后,将溶解的合成或天然材料溶液装入注射器中安装在注射泵上,将第二步制备得到的载有导管内层和中层的接收棒放置在静电纺仪上,将注射器针头置于接收棒上方1-40cm处位置。设定电压为:0.1-100KV,注射泵速度为0.1-40ml/h,接收棒转速为1-1000rpm,移动速度为1-1000mm/sec,纺丝时间为1-100min,完成后抽真空除去有机溶剂。可以调节聚合物浓度、流速、接受棒转动速度和移动速度等参数从而制备直径可控为0.01-200um,厚度为10-400um随机排布纤维外层。
实施例1聚己内酯(PCL)三层导管的制备
本实施例采用的聚己内酯(PCL)数均分子量为60000;采用的PCL溶液均为PCL氯仿溶液(以质量/体积浓度表示PCL含量)。
制备过程具体如下:
(1)导管内层制备:称取2.0gPCL加入到10ml氯仿中,室温搅拌溶解过夜,制得浓度分数为20%(质量/体积)的PCL溶液。在室温通风橱中利用墨水打印将溶液均匀打印,制备导管内层。将直径为2.0mm带有微槽的不锈钢接收棒安装在打印机上。将PCL溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离不锈钢接收棒上方1mm的位置。设定注射泵推进速度为2ml/h,接收棒转速为100rpm,横向移动速度为0.2mm/sec,打印时间为10min,制备完成后将带有厚度为50um内层、微通道凹槽深度为20um的接收棒真空干燥。
(2)导管中层制备:在室温通风橱中利用湿法纺丝制备导管中层。具体是将带有内层的接收棒安装在湿法纺丝仪上,将15%PCL纺丝溶液吸入注射器中,将注射器安装在注射泵上,将注射器针头置于纺丝凝固浴中距离接收棒2cm位置处。设定注射泵速度为2ml/h,接收棒转速为500rpm,移动速度为1mm/sec,纺丝时间为30min,完成后除去凝固浴和纺丝液溶剂。制得纤维直径为89um、厚度为400um的中层(纤维交叉角度为15°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将10%PCL溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方20cm处位置,进行静电纺丝,设定电压为:13KV,注射泵速度为1ml/h,接收棒转速为500rpm,移动速度为0.5mm/sec,纺丝时间为10min,完成后抽真空除去有机溶剂。制得纤维直径为100um、厚度为30um外层。完成外层纺丝后将三层导管(总厚度为480um,内径为2.0mm)取下表征备用。
实施例2聚L-丙交酯-己内酯(PLCL)三层导管制备
本实施例采用的聚L-丙交酯-己内酯(PLCL)数均分子量为100000;采用的PLCL溶液均为PLCL乙酸溶液(以质量/体积浓度表示PLCL含量)。
(1)导管内层制备:称取1.0g PLCL加入到10ml乙酸中,室温搅拌溶解过夜,制得浓度分数为10%(质量/体积)的PLCL溶液。在室温通风橱中利用磁场辅助静电纺丝仪器来制备导管内层。将直径为3.0mm聚四氟乙烯接收棒安装在纺丝机上。将PLCL溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离聚四氟乙烯上方20mm的位置(制备过程的磁场强度为0.1T)。设定注射泵推进速度为3ml/h,接收棒转速为20rpm,横向移动速度为1mm/sec,纺丝时间为12min,制备完成后将带有40um厚度内层(纤维直径为5um)的接收棒真空干燥。
(2)导管中层制备:在室温通风橱中利用熔融纺丝制备导管中层。将带有内层的接收棒安装在熔融纺丝仪上,将10.0gPLCL添加到恒温加热料筒里,升温到150℃使PLCL融化后,设定料筒推进活塞速度为0.5ml/h,接收棒转速为100rpm,移动速度0.5mm/sec,时间为30min。制得纤维直径为100um、厚度为450um的中层(纤维交叉角度为20°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将12%PLCL溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方30cm处位置,进行静电纺丝,设定电压为:20KV,注射泵速度为3ml/h,接收棒转速为800rpm,移动速度为5mm/sec,纺丝时间为13min,完成后抽真空除去有机溶剂。制得纤维直径为1um、厚度为50um外层。完成外层纺丝后将三层导管(总厚度为540um,内径为3.0mm)取下备用。
实施例3聚(丙交酯-乙醇酸)共聚物(PLGA)三层导管制备
本实施例采用的聚(丙交酯-乙醇酸)共聚物(PLGA)数均分子量为40000;采用的PLGA溶液均为PLGA丙酮溶液(以质量/体积浓度表示PLGA含量)。
(1)导管内层制备:称取1.2g PLGA加入到10ml丙酮中,室温搅拌溶解过夜,制得浓度分数为12%(质量/体积)的PLGA溶液。在室温通风橱中利用墨水打印将溶液均匀打印,制备导管内层。将直径为5.0mm光滑的不锈钢接收棒安装在打印机上。将PLGA溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离不锈钢接收棒上方5mm的位置。设定注射泵推进速度为1.5ml/h,接收棒转速为500rpm,横向移动速度为5mm/sec,打印时间为30min,制备完成后将厚度为60um内层的接收棒真空干燥。
(2)导管中层制备:在室温通风橱中利用熔融纺丝制备导管中层。将带有内层的接收棒安装在熔融纺丝仪上,将30.0gPLGA添加到恒温加热料筒里,升温到130℃使PLGA融化后,设定料筒推进活塞速度为2ml/h,接收棒转速为500rpm,移动速度1mm/sec,时间为25min。制得纤维直径为43um、厚度为500um的中层(纤维交叉角度为35°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将12%的PLGA溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方13cm处位置,进行静电纺丝,设定电压为:12KV,注射泵速度为1.2ml/h,接收棒转速为300rpm,移动速度为10mm/sec,纺丝时间为6min,完成后抽真空除去有机溶剂。制得纤维直径为0.5um、厚度为30um外层。完成外层纺丝后将三层导管(总厚度为590um,内径为5.0mm)取下备用。
以单独采用静电纺丝法制备的纤维直径为5um、厚度为480um的单层静电纺丝导管(以10%质量体积浓度的PCL氯仿溶液为纺丝溶液)作为对照,对实施例1-3制备的三层导管进行相关性能验证:
对实施例1-3制备的三层导管进行抗弯折性能验证,结果如图1所示。由图1可以看出,对照品静电纺丝导管弯折180°后打死折,本发明实施例1-3制备的三层导管弯折180°后无死折形成。图1中:A为对照品静电纺丝导管,B-D分别为实施例1-3制备的三层导管。
对照品静电纺丝导管和实施例1-3制备的三层导管的微观结构图见图2。图2中:A为对照品静电纺丝导管,B-D分别为实施例1-3制备的三层导管。
对实施例1-3制备的三层导管进行径向力学测试,结果如图3所示,其中图A为径向力学测试示意图,图B为径向力学测试结果(图中****表示显著性差异P值<0.0001)。径向力学测试结构显示,本发明三层结构导管径向力学显著高于对照品静电纺丝导管。
将不同结构导管植入到大鼠坐骨神经缺损部分3个月后,取材进行超薄切片观察,发现本发明三层结构导管引导的神经再生髓鞘厚度显著高于对照品静电纺丝导管(结果见图4)。
实施例4胶原蛋白(Col)三层导管的制备
本实施例采用的胶原蛋白(Col)溶液均为胶原蛋白(Col)醋酸溶液(以质量/体积浓度表示胶原蛋白含量)。
(1)导管内层制备:称取1.0克胶原蛋白溶于50ml 0.5%的醋酸溶液中,搅拌过夜获得浓度分数为2%(质量/体积)的胶原溶液。在室温通风橱中利用墨水打印将溶液均匀打印,制备导管内层。将直径为2.0mm光滑不锈钢接收棒安装在打印机上。将胶原溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离不锈钢接收棒上方0.5mm的位置。设定注射泵推进速度为0.5ml/h,接收棒转速为50rpm,横向移动速度为0.3mm/sec,打印时间为15min,制备完成后带有厚度为60um内层的接收棒室温真空干燥。
(2)导管中层制备:在室温通风橱中利用湿法纺丝制备导管中层。具体是将带有内层的接收棒安装在湿法纺丝仪上,将2%胶原纺丝溶液吸入注射器中,将注射器安装在注射泵上,将注射器针头置于纺丝凝固浴中距离接收棒1cm位置处。设定注射泵速度为1ml/h,接收棒转速为400rpm,移动速度为2mm/sec,纺丝时间为50min,完成后除去凝固浴和纺丝液溶剂。制得纤维直径为40um、厚度为370um的中层(纤维交叉角度为20°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将1%胶原溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方20cm处位置,进行静电纺丝,设定电压为:18KV,注射泵速度为1.5ml/h,接收棒转速为1000rpm,移动速度为10mm/sec,纺丝时间为50min,完成后室温真空干燥。制得纤维直径为50um、厚度为70um外层。完成外层纺丝后将三层导管(总厚度为500um,内径为2.0mm)取下备用。
实施例5丝素蛋白三层导管的制备
本实施例采用的丝素蛋白溶液均为丝素蛋白水溶液(以质量/体积浓度表示丝素蛋白含量)。
(1)导管内层制备:称取2.0克已脱胶的丝素蛋白溶于10ml的水溶液中,搅拌过夜获得浓度分数为20%(质量/体积)的丝素蛋白溶液。在室温通风橱中利用墨水打印将溶液均匀打印,制备导管内层。将直径为3.0mm光滑不锈钢接收棒安装在打印机上。将丝素蛋白溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离不锈钢接收棒上方0.3mm的位置。设定注射泵推进速度为0.6ml/h,接收棒转速为30rpm,横向移动速度为0.6mm/sec,打印时间为20min,制备完成后带有厚度为30um内层的接收棒室温真空干燥。
(2)导管中层制备:在室温通风橱中利用湿法纺丝制备导管中层。具体是将带有内层的接收棒安装在湿法纺丝仪上,将20%丝素蛋白纺丝溶液吸入注射器中,将注射器安装在注射泵上,将注射器针头置于纺丝凝固浴中距离接收棒1.2cm位置处。设定注射泵速度为1.5ml/h,接收棒转速为3050rpm,移动速度为1mm/sec,纺丝时间为60min,完成后除去凝固浴和纺丝液溶剂。制得纤维直径为120um、厚度为390um的中层(纤维交叉角度为90°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将20%丝素蛋白溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方10cm处位置,进行静电纺丝,设定电压为:20KV,注射泵速度为1.4ml/h,接收棒转速为900rpm,移动速度为112mm/sec,纺丝时间为30min,完成后室温真空干燥。制得纤维直径为100um、厚度为67um外层。完成外层纺丝后将三层导管(总厚度为487um,内径为3.0mm)取下备用。
实施例6壳聚糖三层导管的制备
本实施例采用的壳聚糖溶液均为壳聚糖乙酸溶液(以质量/体积浓度表示壳聚糖含量)。
(1)导管内层制备:称取0.3克壳聚糖粉末溶于10ml的5%乙酸溶液(质量/体积)中,搅拌过夜获得浓度分数为3%(质量/体积)的壳聚糖溶液。在室温通风橱中利用墨水打印将溶液均匀打印,制备导管内层。将直径为5.0mm光滑不锈钢接收棒安装在打印机上。将壳聚糖溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于距离不锈钢接收棒上方0.1mm的位置。设定注射泵推进速度为0.8ml/h,接收棒转速为100rpm,横向移动速度为1.6mm/sec,打印时间为22min,制备完成后带有厚度为100um内层的接收棒室温真空干燥。
(2)导管中层制备:在室温通风橱中利用湿法纺丝制备导管中层。具体是将带有内层的接收棒安装在湿法纺丝仪上,将3%壳聚糖纺丝溶液吸入注射器中,将注射器安装在注射泵上,将注射器针头置于纺丝凝固浴中距离接收棒上方0.2cm位置处。设定注射泵速度为0.5ml/h,接收棒转速为2000rpm,移动速度为2mm/sec,纺丝时间为27min,完成后除去凝固浴和纺丝液溶剂。制得纤维直径为50um、厚度为320um的中层(纤维交叉角度为70°)。
(3)导管外层制备:利用静电纺丝法制备导管外层。具体是将前两步制备的带有内层和中层的接收棒安装在静电纺丝仪上,将3%壳聚糖溶液吸入到注射器中,将注射器安装在注射泵上,将注射器针头置于接收棒上方12cm处位置,进行静电纺丝,设定电压为:20KV,注射泵速度为1.7ml/h,接收棒转速为600rpm,移动速度为15mm/sec,纺丝时间为25min,完成后室温真空干燥。制得纤维直径为1um、厚度为140um外层。完成外层纺丝后将三层导管(总厚度为560um,内径为5.0mm)取下备用。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (7)
1.一种抗弯折神经导管,其特征在于,由内层、中层和外层构成;所述内层、中层和外层的原料为生物可降解高分子;
所述内层为光滑表面内层、定向微通道内层或纤维内层;
所述中层为具有交叉角度的纤维中层;
所述外层为随机分布的纤维外层;
所述光滑表面内层厚度为1-100um;所述定向微通道内层厚度为1-200um;所述纤维内层的纤维直径为0.1-200um,厚度为0.1-200um;
所述具有交叉角度的纤维中层由湿法纺丝或熔融纺丝制备得到;
所述纤维外层的纤维直径为0.01-200um,外层厚度为10-400um;
所述抗弯折神经导管弯折180°后无死折形成。
2.根据权利要求1所述的抗弯折神经导管,其特征在于,所述抗弯折神经导管的管腔直径为1-100mm,管壁厚度为50-1000um。
3.根据权利要求1所述的抗弯折神经导管,其特征在于,湿法纺丝制备的纤维直径为5-300um,中层厚度为20-450um;熔融纺丝制备的纤维直径为1-100um,中层厚度为20-500um。
4.根据权利要求1所述的抗弯折神经导管,其特征在于,所述生物可降解高分子包括合成可降解聚合物或天然高分子材料中的一种或几种。
5.根据权利要求4所述的抗弯折神经导管,其特征在于,所述合成可降解聚合物包括聚乳酸、聚己内酯、聚L-丙交酯-己内酯、聚羟基脂肪酸酯、聚乳酸-聚羟基乙酸共聚物、聚二噁烷酮或聚氨酯;所述天然高分子材料包括胶原、明胶、丝素蛋白、纤维蛋白、壳聚糖、甲壳素、纤维素、淀粉、海藻酸或透明质酸。
6.如权利要求1-5任一项所述抗弯折神经导管的制备方法,其特征在于:采用模板法或磁场辅助静电纺丝法制备所述内层;采用湿法纺丝法或熔融纺丝法制备所述中层;采用静电纺丝法制备所述外层。
7.如权利要求1-5任一项所述抗弯折神经导管在制备神经修复材料中的应用。
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