CN110101918A - 一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料及其制备方法和应用 - Google Patents
一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料及其制备方法和应用,所述材料是通过以下方法制备的:将修饰双键的壳聚糖与交联剂BIS、2‑羟基‑4'‑(2‑羟乙氧基)‑2‑甲基苯丙酮及蒸馏水混合获得前驱液,加入或不加入生长因子配置成胶前驱液,置于液氮中冰晶导向,然后在‑20℃下紫外光照引发成胶。本发明材料具有沿材料长轴内径大小不一的导向孔,提供了神经环路重构所需空间结构,方便内源性神经干细胞定向迁移到材料移植区域并形成新生神经元,神经突触沿设计的多级结构生长,构成神经网络,重建损伤区域的神经环路,促进脊髓损伤后运动功能恢复。
Description
技术领域
本发明涉及神经再生修复技术领域,具体地说,涉及一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料及其制备方法和应用。
背景技术
脊髓损伤(spinal cord injury,SCI)通常是指由于外伤等多种原因所造成的脊髓直接损伤,导致损伤平面以下的运动和感觉功能不同程度的缺失,甚至运动和感觉功能完全丧失出现截瘫。SCI具有较高的发病率,除了造成机体四肢瘫痪和半身瘫痪外,还可能产生其他继发性疾病,严重影响患者生活的质量。SCI的治疗和康复一直是基础和临床医学领域的重大难题之一。
脊髓损伤最初往往会导致细胞和组织的不断丢失,组织工程支架可以模拟细胞外基质的生理状态,从而有利于细胞的黏附、迁移、扩增和分化。组织工程修复脊髓损伤着重于三个方面:种子细胞、组织工程支架及材料和细胞因子。用于组织工程支架的材料可分为天然材料和人工合成材料,天然材料通常是提取蛋白或者碳水化合物的聚合物,已被用作组织支架。常见组织工程支架的材料有胶原、壳聚糖、琼脂糖/藻酸盐、纤连蛋白、合成聚合物、聚乳酸、聚羟基乙酸/聚乳酸、聚β羟丁酸、磁性纳米颗粒等。但现有技术多是物理混合,将材料通过物理方法构建相关脊髓修复材料,无内部的精微结构,无法构建神经环路重构的通路。另外有学者利用纺丝结构或多束纤维结构来构建脊髓修复材料,但同样无法满足神经再生与神经环路重建的空间要求。另外现有技术中没有通过空间结构实现相关因子可控释放的体系。例如,专利文献CN109106981A,公开日2019.01.01公开的一种双重修饰的胶原支架,所述双重修饰的胶原支架包括胶原支架材料,以及修饰在所述胶原支架材料上的EGFR抗体和微管稳定分子,所述EGFR抗体和微管稳定分子通过物理吸附的方式均匀分布于所述胶原支架材料的内部和表面。
此外,专利文献CN102727936A,公开日2012.10.17,公开了一种用于修复横断性脊髓损伤的含有干细胞的缓释NT-3明胶海绵圆柱体支架材料,其形貌特征是:圆柱体支架表面包裹着由聚乳酸-聚羟基乙酸共聚物(poly D,L-lactic-co-glycolic acid,PLGA)薄膜构成的薄壁,圆柱体中央填充着负载NT-3/丝素蛋白的明胶海绵;通过负载NT-3/丝素蛋白的明胶海绵吸附种植的干细胞及其分化的细胞,构建成有利于受损伤脊髓神经再生及其功能修复的缓释NT-3明胶海绵圆柱体支架。所述的圆柱体支架是由外表薄层的PLGA管壁和内部的负载NT-3/丝素蛋白的明胶海绵构成,负载NT-3/丝素蛋白的明胶海绵为多孔隙结构。但该支架材料的孔隙是无序的。
目前还未见包含沿材料长轴方向的导向孔,提供神经环路重构所需空间结构,以方便内源性神经干细胞定向迁移的基于壳聚糖的支架材料。
发明内容
本发明的目的是针对现有技术中的不足,提供一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料。
本发明再一的目的是,提供一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料的制备方法。
本发明另一的目的是,提供所述多级孔功能支架材料的用途。
为实现上述第一个目的,本发明采取的技术方案是:
一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料,所述的多级孔功能支架材料是通过以下方法制备的:
a)将甲基丙烯酸缩水甘油酯交联壳聚糖与交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮及蒸馏水以一定比例混合获得前驱液,其中,所述的甲基丙烯酸缩水甘油酯交联壳聚糖、交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮和蒸馏水的质量比为1:(0.5%-2%):(2%-4%):(35-45);
b)加入生长因子,与前驱液配置成胶前驱液;或不加入生长因子,则所述前驱液即为成胶前驱液;
c)所述成胶前驱液置于液氮中进行冰晶导向;
d)然后在-20℃下紫外光照引发成胶,即得。
作为一个优选例,步骤b)和步骤c)之间,还包含步骤:将所述成胶前驱液离心除去气泡。
更优选地,所述的离心条件为:4500-5500r/min,2.5-4min。
作为另一优选例,将所述成胶前驱液注入玻璃管中,再将所述玻璃管匀速置于液氮中进行冷冻导向。
更优选地,置于液氮中的速率为2.5-3.5mm/s。
作为另一优选例,步骤d)中,紫外光照时间为3-18min。
作为另一优选例,所述的生长因子选自脑源性神经营养因子(BDNF)、神经营养因子-3(NT-3)、神经营养素-4(NT-4)、神经生长因子(NGF)、碱性成纤维细胞生长因子(bFGF)、表皮细胞生长因子(EGF)、***(IGF)、转化生长因子(TGF)、血管内皮生长因子(VEGF)、肝细胞生长因子(HGF)、胶质细胞神经营养生长因子(GDNF)、骨骼生长因子(SGF)和血小板源生长因子(PDGF)、干细胞因子(SCF)中的一种或几种,但不限于此。
作为另一优选例,所述的多级孔功能支架材料还种植有种子细胞。
作为另一优选例,所述的种子细胞为神经干细胞、胚胎干细胞、许旺细胞、嗅鞘细胞、骨髓基质细胞、少突胶质细胞等。
为实现上述第二个目的,本发明采取的技术方案是:
一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料的制备方法,包括以下步骤:
a)将甲基丙烯酸缩水甘油酯交联壳聚糖与交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮及蒸馏水以一定比例混合获得前驱液,其中,所述的甲基丙烯酸缩水甘油酯交联壳聚糖、交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮和蒸馏水的质量比为1:(0.5%-2%):(2%-4%):(35-45);
b)加入生长因子,与前驱液配置成胶前驱液;或不加入生长因子,则所述前驱液即为成胶前驱液;
c)所述成胶前驱液置于液氮中进行冰晶导向;
d)然后在-20℃下紫外光照引发成胶,即得。
作为一个优选例,步骤b)和步骤c)之间,还包含步骤:将所述成胶前驱液离心除去气泡。
更优选地,所述的离心条件为:4500-5500r/min,2.5-4min。
作为另一优选例,步骤c)中,将所述成胶前驱液注入玻璃管中,再将所述玻璃管匀速置于液氮中进行冷冻导向。
更优选地,置于液氮中的速率为2.5-3.5mm/s。
作为另一优选例,步骤d)中,紫外光照时间为3-18min。
为实现上述第三个目的,本发明采取的技术方案是:
如上任一所述的多级孔功能支架材料在制备修复脊髓损伤的产品中的应用。
本发明优点在于:
1、本发明提供了一种依照神经元轴突生长多级特征的多级孔材料,该材料经特殊方法制备而成,内部形成沿材料长轴、内径大小不一的导向孔,提供了神经环路重构所需要的空间结构,以方便内源性神经干细胞定向迁移到材料移植区域并形成新生神经元,神经突触沿设计的多级结构生长,形成有效突触联系,构成神经网络,重建损伤区域的神经环路,促进脊髓损伤后运动功能恢复。
2、本发明的多级孔材料具有良好的力学强度,导向孔的孔径适宜,经动物实验表明移植治疗小鼠脊髓损伤,可以显著促进小鼠下肢运动功能恢复。
3、本发明的材料在构建过程中可以负载相关因子,构建成为控释体系,更好地促进再生修复。
4、本发明的材料还可以负载外源性神经干细胞。
5、本发明的材料孔径可调(适应细胞培养)、强度可控(可耐受声磁电物理因素加载)、可3D打印(整合纳米控释体系)、具有生物相容性。
附图说明
附图1:有、无修饰双键的壳聚糖的红外图。
附图2:胶体材料在不同光照时间下的压缩测试图。
附图3:有、无冷冻导向的胶体材料的压汞测试孔径分布图。
附图4:胶体材料的成胶测试图。
附图5:胶体材料的SEM测试图。
附图6:本发明多级孔功能支架材料修复脊髓损伤的示意图。
附图7:用构建的多级孔功能支架移植治疗脊髓损伤。A图为多级孔功能支架的移植示意图,利用前期构建的脊髓损伤全横断模型进行体内实验,将构建的多级孔支架置于损伤区;B图上半部分为移植时大体标本,可见移植后多级孔功能支架完全填充损伤区,下半部分为8周后损伤组与对照组的大体标本对比,可见对照组组织坏死,而移植治疗组有新生组织;C图为小鼠的行为学评分,可见移植治疗组行为学恢复较对照组有明显统计学差异;D图为脊髓损伤小鼠的电生理检测,可见对照组无明显的电生理波形,而移植治疗组出现了明显的波幅;揭示多级孔功能支架促进了脊髓损伤后神经功能恢复。
附图8:多级孔功能支架移植治疗8周后脊髓切片染色结果。在移植治疗区发现了新生神经元,靠近损伤边界神经元较多,而损伤中心区域神经元较少,呈现了一定的趋势梯度效应,而正常组织中无该分布效应,推测多级孔功能支架可能诱导了内源性神经干细胞的定向迁移(白色边界为损伤区与正常组织边界,下半部分为局部放大图像)。
具体实施方式
下面结合附图对本发明提供的具体实施方式作详细说明。
实施例1本发明多级孔功能支架材料的制备(一)
1、壳聚糖接枝双键:
称取2.0g壳聚糖于三颈烧瓶中,加入150ml2%的乙酸水溶液,滴加少量的KOH水溶液,调节pH=3.8。接着缓慢滴加3.51g甲基丙烯酸缩水甘油酯(GMA),持续搅拌,60℃条件下反应6小时。之后将反应混合液倒入丙酮中,得到大量絮状沉淀,再将絮状物倒入乙腈中,得到粉末状沉淀,最后经丙酮洗涤数次后用水溶解,装入分子量为3500的透析袋中透析3天,冷冻干燥,得到原材料Chitosan-GMA,备用。利用红外光谱和H-NMR对接枝双键后的壳聚糖进行表征。
结果:图1为有、无修饰双键的壳聚糖的红外图,修饰双键的壳聚糖对比没有修饰双键的壳聚糖在1710.39处出现双键透射峰,说明双键壳聚糖上成功修饰了双键。
2、材料的制备:
称取50mg(2.5%)Chitosan-GMA于小玻璃瓶中,然后加入100μL BIS(N,N'-亚甲基双丙烯酰胺,10mg/mL)交联剂(单体的2%),再加入1.5mg光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮(单体的3%),最后加入1900μL H2O,于37℃搅拌2h使其溶解,形成前驱液,也即成胶前驱液。
溶解完全后将成胶前驱液进行5000r/min离心3min除去气泡。然后将溶液使用洗耳球注入毛细管中。
将注入溶液的毛细管使用升降机匀速(3.3mm/s)置于液氮中进行冷冻导向。导向结束后将毛细管立刻置于-20℃冰箱中使用冷冻紫外灯(UV Led Curing System,型号UP3-304,购于Mean Well International Co.Ltd)进行冷冻紫外成胶。
通过调节壳聚糖以及交联剂的用量及紫外光照时间对材料的力学强度进行调整。力学性能测试:首先测量圆柱状的胶体材料的直径和高度,将参数输入进万能力学试验机(三思纵横UTM2505)中,然后使用万能力学试验机进行压缩测试,压缩速率为5mm/min。
通过调节升降机的下降速率调整孔径的大小。
利用压汞法对材料的孔径及孔径分布进行表征。
利用流变仪对成胶时间进行测试。
将凝胶经冷冻干燥除去冰晶后,利用扫描电镜观察凝胶的导向结构及孔结构。
结果:
图2为胶体材料在不同光照时间下的压缩测试图,在不同的光照时间下,胶体的压缩强度先上升后下降,在光照12min时具有最大的压缩强度。图3为有、无冷冻导向的胶体材料的压汞测试孔径分布图。图4为胶体材料的成胶测试图。图5为胶体材料的SEM测试图。
实施例2本发明多级孔功能支架材料的制备(二)
1、壳聚糖接枝双键:
同实施例1。
2、材料的制备:
称取50mg Chitosan-GMA于小玻璃瓶中,然后加入25μL BIS(N,N'-亚甲基双丙烯酰胺,10mg/mL)交联剂(单体的0.5%),再加入2mg光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮(单体的4%),最后加入1700μL H2O,于37℃搅拌2h使其溶解,形成前驱液,也即成胶前驱液。
溶解完全后将成胶前驱液进行4500r/min离心4min除去气泡。然后将溶液使用洗耳球注入毛细管中。
将注入溶液的毛细管使用升降机匀速(2.5mm/s)置于液氮中进行冷冻导向。导向结束后将毛细管立刻置于-20℃冰箱中使用冷冻紫外灯(UV Led Curing System,型号UP3-304,购于Mean Well International Co.Ltd)进行冷冻紫外成胶,紫外光照时间为15min。
实施例3本发明多级孔功能支架材料的制备(三)
1、壳聚糖接枝双键:
同实施例1。
2、材料的制备:
称取50mg Chitosan-GMA于小玻璃瓶中,然后加入50μL BIS(N,N'-亚甲基双丙烯酰胺,10mg/mL)交联剂(单体的1%),再加入1mg光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮(单体的2%),最后加入2200μL H2O,于37℃搅拌2h使其溶解,形成前驱液,也即成胶前驱液。
溶解完全后将成胶前驱液进行4500r/min离心4min除去气泡。然后将溶液使用洗耳球注入毛细管中。
将注入溶液的毛细管使用升降机匀速(3.5mm/s)置于液氮中进行冷冻导向。导向结束后将毛细管立刻置于-20℃冰箱中使用冷冻紫外灯(UV Led Curing System,型号UP3-304,购于Mean Well International Co.Ltd)进行冷冻紫外成胶,紫外光照时间为3min。
实施例4本发明多级孔功能支架材料的制备(四)
1、壳聚糖接枝双键:
同实施例1。
2、材料的制备:
称取50mg Chitosan-GMA于小玻璃瓶中,然后加入25μL BIS(N,N'-亚甲基双丙烯酰胺,10mg/mL)交联剂(单体的0.5%),再加入1.5mg光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮(单体的3%),最后加入1950μL H2O,于37℃搅拌2h使其溶解,形成前驱液。在前驱液加入相关因子与前驱液配置成胶前驱液,加入的相关因子是BDNF、NT-3、NT-4、NGF、bFGF、EGF、IGF、TGF、VEGF、HGF、GDNF、SGF和PDGF、SCF中的一种或几种。
溶解完全后将成胶前驱液进行5500r/min离心2.5min除去气泡。然后将溶液使用洗耳球注入毛细管中。
将注入溶液的毛细管使用升降机匀速(3.0mm/s)置于液氮中进行冷冻导向。导向结束后将毛细管立刻置于-20℃冰箱中使用冷冻紫外灯(UV Led Curing System,型号UP3-304,购于Mean Well International Co.Ltd)进行冷冻紫外成胶,紫外光照时间为3min。
实施例5本发明多级孔功能支架材料的制备(五)
1、壳聚糖接枝双键:
同实施例1。
2、材料的制备:
称取50mg Chitosan-GMA于小玻璃瓶中,然后加入100μL BIS(N,N'-亚甲基双丙烯酰胺,10mg/mL)交联剂(单体的2%),再加入2mg光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮(单体的4%),最后加入1950μL H2O,于37℃搅拌2h使其溶解,形成前驱液。在前驱液加入相关因子与前驱液配置成胶前驱液,加入的相关因子是BDNF、NT-3、NT-4、NGF、bFGF、EGF、IGF、TGF、VEGF、HGF、GDNF、SGF和PDGF、SCF中的一种或几种。
溶解完全后将成胶前驱液进行5000r/min离心4min除去气泡。然后将溶液使用洗耳球注入毛细管中。
将注入溶液的毛细管使用升降机匀速(3.0mm/s)置于液氮中进行冷冻导向。导向结束后将毛细管立刻置于-20℃冰箱中使用冷冻紫外灯(UV Led Curing System,型号UP3-304,购于Mean Well International Co.Ltd)进行冷冻紫外成胶,紫外光照时间为18min。
实施例6
请参见图6,图6是本发明多级孔功能支架材料修复脊髓损伤的示意图,在损伤脊髓缺损处移植本发明多级孔功能支架材料,由于该材料有沿材料长轴内径大小一不的导向孔,能方便内源性神经干细胞定向迁移到材料移植区域并形成新生神经元,神经突触沿设计的多级结构生长,构成神经网络重建损伤区域的神经环路,促进脊髓损伤后运动功能恢复。在材料构建过程中可以负载相关因子,构建成为控释体系,更好地促进再生修复。
通过动物实验验证本发明多级孔功能支架材料在促进内源性神经干细胞重构脊髓损伤区神经环路,修复脊髓损伤中的作用。
利用实施例1所构建的多级孔功能支架材料移植治疗小鼠脊髓损伤,与空白对照组对比发现多级孔功能材料移植可以有效促进小鼠下肢运动功能恢复,行为学评分较对照组显著升高,电生理检测发现多级孔功能支架材料移植治疗组有明显的电生理活动(图7)。通过免疫组化等技术手段,在移植治疗区发现了新生神经元,靠近损伤边界神经元较多,而损伤中心区域神经元较少,呈现了一定的趋势梯度效应(图8)。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (10)
1.一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料,其特征在于,所述的多级孔功能支架材料是通过以下方法制备的:
a)将甲基丙烯酸缩水甘油酯交联壳聚糖与交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮及蒸馏水以一定比例混合获得前驱液,其中,所述的甲基丙烯酸缩水甘油酯交联壳聚糖、交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮和蒸馏水的质量比为1:(0.5%-2%):(2%-4%):(35-45);
b)加入生长因子,与前驱液配置成胶前驱液;或不加入生长因子,则所述前驱液即为成胶前驱液;
c)所述成胶前驱液置于液氮中进行冰晶导向;
d)然后在-20℃下紫外光照引发成胶,即得。
2.根据权利要求1所述的多级孔功能支架材料,其特征在于,步骤b)和步骤c)之间,还包含步骤:将所述成胶前驱液离心除去气泡。
3.根据权利要求1所述的多级孔功能支架材料,其特征在于,步骤c)中,将所述成胶前驱液注入玻璃管中,再将所述玻璃管匀速置于液氮中进行冷冻导向。
4.根据权利要求1所述的多级孔功能支架材料,其特征在于,步骤d)中,紫外光照时间为3-18min。
5.根据权利要求1所述的多级孔功能支架材料,其特征在于,所述的生长因子选自脑源性神经营养因子、神经营养因子-3、神经营养素-4、神经生长因子、碱性成纤维细胞生长因子、表皮细胞生长因子、***、转化生长因子、血管内皮生长因子、肝细胞生长因子、胶质细胞神经营养生长因子、骨骼生长因子、血小板源生长因子、干细胞因子中的一种或几种。
6.一种动员内源性神经干细胞修复脊髓损伤的多级孔功能支架材料的制备方法,其特征在于,包括以下步骤:
a)将甲基丙烯酸缩水甘油酯交联壳聚糖与交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮及蒸馏水以一定比例混合获得前驱液,其中,所述的甲基丙烯酸缩水甘油酯交联壳聚糖、交联剂N,N'-亚甲基双丙烯酰胺、光引发剂2-羟基-4'-(2-羟乙氧基)-2-甲基苯丙酮和蒸馏水的质量比为1:(0.5%-2%):(2%-4%):(35-45);
b)加入生长因子,与前驱液配置成胶前驱液;或不加入生长因子,则所述前驱液即为成胶前驱液;
c)所述成胶前驱液置于液氮中进行冰晶导向;
d)然后在-20℃下紫外光照引发成胶,即得。
7.根据权利要求6所述的制备方法,其特征在于,步骤b)和步骤c)之间,还包含步骤:将所述成胶前驱液离心除去气泡。
8.根据权利要求1所述的制备方法,其特征在于,步骤c)中,将所述成胶前驱液注入玻璃管中,再将所述玻璃管匀速置于液氮中进行冷冻导向。
9.根据权利要求1所述的制备方法,其特征在于,步骤d)中,紫外光照时间为3-18min。
10.权利要求1-5任一所述的多级孔功能支架材料在制备修复脊髓损伤的产品中的应用。
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