CN110755174A - 一种生物混合型人工血管及其制备方法 - Google Patents
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Abstract
本发明属于生物工程技术领域,具体涉及一种生物混合型人工血管及其制备方法和Sca‑1+血管干细胞在制备生物混合型人工血管中的应用。所述生物混合型人工血管分为内层和外层,内层主体血管支架采用聚合物材料PCL用静电纺丝制备或采用脱细胞基质法制备,并采用共价结合方式将血管主体肝素化,有利于细胞浸润和血管生成,并减少血栓形成的风险;外层为包封了Sca‑1+血管干细胞的GelMA水凝胶,该水凝胶有良好的细胞粘附性,细胞不易脱落。本发明的人工血管可在血管受损时,帮助血管修复,促进内皮化。在外膜的Sca‑1+血管干细胞通常首先被激活,向内皮细胞分化的Sca‑1+血管干细胞影响血管壁的结构和张力,可参与内皮修复、血管再生、免疫调节等。
Description
技术领域
本发明属于生物工程技术领域,具体涉及一种生物混合型人工血管及其制备方法和Sca-1+血管干细胞在制备生物混合型人工血管中的应用。
背景技术
据《中国心血管病报告2018》最新报告数据可知,中国心血管病患病率及死亡率仍处于上升阶段。心血管病现患病人数高达2.9亿,心血管病死亡率居首位,高于肿瘤及其他疾病,占居民疾病死亡构成的40%以上,特别是农村近几年来的心血管病死亡率持续高于城市。随着患病人数的增加,血管移植物的临床需求在国内日益增大。从外周血管损伤替代、冠状动脉旁路移植,到血液透析动静脉造瘘人工血管移植需求量也逐年增加。从器官移植上来说,现在临床上肝、肾、肺等复杂器官的移植构建以及骨移植或修复等都需要血管化,移植后器官的再血管化是影响器官移植宿主化成功率的关键,因此,人工血管的移植和构建也是一个复杂的关键科学问题之一。
在大多数情况下用于置换受损血管的有自体血管,同种异体血管以及合成的聚合物血管。由于年龄、疾病以及其他一些并发症,自体血管数量十分有限,尽管它是目前临床移植的金标准。人工血管是许多严重狭窄或闭塞性血管的替代品,多是以尼龙、涤纶(Dacron)、聚四氟乙稀(PTFE)等合成材料人工制造的,适用于全身各处的血管转流术,大、中口径人工血管应用于临床已取得良好的效果。为解决合成材料编织的人工血管与生物机体间更好的适应性,在这些高分子材料表面涂上一层生物材料,便可制备生物混合型人工血管。一般采用的人工涂层包括以下几种:白蛋白,可提高人工血管的抗凝血性能;纤维连接蛋白,可促进内膜形成,进而抑制凝血的发生;胶原蛋白,能促进内膜形成,防止凝血发生,还能提高人工血管的顺应性;明胶,有促进细胞黏附和生长的功能,从而在植入后诱导内膜形成,防止凝血。而目前的人工血管在受损后的修复以及免疫调节方面都还存在着短板,因此,有必要研发一种生物相容性好、有利于血管修复和免疫调节的人工血管。
发明内容
本发明的目的之一在于提供一种生物混合型人工血管,该生物混合型人工血管具有良好的血液相容性和生物活性,可以促进内皮化,外层水凝胶加载的血管干细胞可随宿主情况进行适应性调整,不易导致血管内栓塞。
为实现上述目的,本发明采用以下方案:
所述生物混合型人工血管分为内层和外层,内层主体血管支架采用聚合物材料PCL用静电纺丝制备或采用脱细胞基质法制备,外层为包封了血管干细胞的GelMA水凝胶。
近年来,甲基丙烯酸酯明胶(gelatin methacryloyl,GelMA)因其良好的生物相容性和生物活性、易制备、光可控以及可降解的特性,在生物医学工程领域得到广泛应用。GelMA的制备是在明胶内引入了光敏感基团--甲基丙烯酰,在光引发剂作用下,通过紫外照射使得明胶中的赖氨酸和羟赖氨酸中的氨基被酰基化。在合成GelMA的过程中,可以通过调控氨基的取代度、GelMA的浓度及紫外照射时间和强度来方便地控制GelMA的力学性能。在血管组织工程中,具有理想的类似天然细胞外基质(ECM)的移植外层材料不仅能刺激细胞形成具有机械整合性的功能组织,能确保移植物在植入后能快速内皮化加快血流重建,还能达到理想的强度和机械可调性。这些都是GelMA具有的特性。GelMA网络结构易受酶降解,特别是由细胞分泌的基质金属蛋白酶部分降解。由于GelMA的可调性,已在再生神经组织、血管、皮肤、骨、肝、肾等重要组织工程领域中广泛应用,通过各种生物工程改造加工技术能够得到理想化的生物组织工程材料,且GelMA水凝胶有良好的细胞粘附性,细胞不易脱落。
进一步,所述血管干细胞是外膜的Sca-1+血管干细胞。
构建内皮化迅速、促进血管修复和重建的理想化的人工血管重要的一点可以从内皮细胞出发,在血管受损时,内皮细胞可以由血管壁本身存在的血管干细胞(Vascularstem/progenitor cells,VPCs)分化而来。有研究发现,在外膜的Sca-1+(干细胞抗原stemcell antigen-1,Sca-1+)VPCs,通常首先被激活进而影响血管壁的结构和张力,参与内皮修复、血管再生、免疫调节等;血管中膜的多能干细胞,在正常生理条件下处于休眠状态,当血管壁受损时被激活,继而增殖分化为平滑肌细胞,参与颈动脉内皮剥脱损伤后增生内膜的形成和血管重塑,当血管受到一定的影响时,在外膜的Sca-1+内皮祖细胞,通常首先被激活,分化为的内皮细胞进而影响血管壁的结构和张力,促进内皮化,参与内皮功能修复。
因此,本发明创造性的提出了将Sca-1+血管干细胞加载到GelMA水凝胶中并进一步应用于人工血管的制备应用中,且本发明的人工血管可减少机体对异物的免疫排斥,还可以有效调节血管再生,促进内皮修复,是传统加载内皮细胞人工血管之外新的发明,而传统加载内皮细胞的人工血管其内皮化效果不明显,因为血管内皮细胞的再生能力非常有限。而血管干细胞在内皮化过程中分化为内皮细胞,在外膜的Sca-1+血管干细胞,通常首先被激活,参与内皮修复。
本发明的目的之二在于提供一种所述生物混合型人工血管的制备方法,通过该制备方法可稳定得到所述的人工血管。
为实现上述目的,本发明采用以下方案:
所述方法为将Sca-1+血管干细胞加载到GelMA水凝胶中,再采用光交联法将GelMA水凝胶固化于内层主体血管支架外层。
进一步,具体包括以下步骤:
1)内层主体血管支架制备:采用聚合物材料PCL用静电纺丝制备,采用六氟异丙醇配制PCL电纺溶液;或采用脱细胞基质法将猪的心血管进行脱细胞处理后经低渗、冻融和胰酶处理并真空冷冻干燥后保存;
2)内层主体血管支架肝素化:采用共价结合法肝素化内层主体血管支架;有利于细胞浸润和血管生成,并减少血栓形成的风险。
3)GelMA水凝胶制备以及包封血管干细胞:在明胶的基础上,接枝甲基丙烯酸酐,使明胶上的氨酸和羟赖氨酸的氨基被酰基化;再将Sca-1+血管干细胞、光引发剂Irgacure2959和GelMA水凝胶混于PDMS模具中;
4)生物混合型人工血管制备:利用光交联法有效固化步骤3)得到的外层负载有包封了Sca-1+血管干细胞的GelMA水凝胶的人工血管。
具体的,电纺丝纺织法选择的是具有高生物相容性的高分子物质,制备方便高效且性价比高,可根据临床需求纺织任何口径和长度的人工血管;采用脱细胞基质法制备去除抗原的同种或异种血管支架主体,采用有效的低渗,反复冻融和胰酶消化处理获得脱细胞支架,有效去除了DNA、RNA等具有免疫原性的成分,得到的支架保留大部分的胞外基质成分包括胶原、弹力蛋白以及天然血管内部结构。
采用共价结合法肝素化血管支架,共价结合是使肝素的氨基与血管支架主体残留的羧基形成稳定的酰胺键,经肝素固化后的血管支架具有良好的持久的抗凝血性能。可通过能谱分析、甲苯胺蓝染色,血小板粘附实验以及复钙时间测定来验证肝素的接枝率以及肝素化血管的抗凝血能力。
甲基丙烯酸酯明胶(GelMA)是在明胶的基础上,接枝甲基丙烯酸酐,使明胶上的氨基被酰基化,也就是明胶里的赖氨酸和羟赖氨酸,合成的GelMA具有良好的生物相容性和生物活性。采用核磁共振氢谱检测GelMA的合成是否成功,GelMA中双键碳上的氢原子化学位移在5.2~5.6ppm之间有峰,双键碳上的两个氢原子处在不同的化学位移上。可根据核磁共振氢谱结果中的峰值来计算甲基丙烯化程度,主要指标是GelMA中赖氨酸亚甲基的面积和明胶中赖氨酸亚甲基的面积。GelMA水凝胶的合成方便快捷,包封细胞时,直接将消化下来的细胞和GelMA溶胶液混合即可。
进一步,步骤1)所述PCL的浓度为10g/ml。
进一步,步骤3)所述明胶为A型明胶,浓度为10g/ml。
进一步,步骤3)所述光引发剂Irgacure2959的质量体积浓度为1%
进一步,步骤4)所述光交联法采用的光功率为1.65mW/cm2。
更进一步,照射时间为30-40s。
本发明的目的之三在于提供一种Sca-1+血管干细胞在制备生物混合型人工血管中的应用。
本发明将血管干细胞加载到可降解的凝胶中,随着凝胶的降解,细胞溢出后更好地作用于机体,既不存在一般聚合物支架材料上细胞黏附性不好的问题,也不会在手术时导致细胞渗漏。
本发明的有益效果在于:
1)本发明的人工血管负载的Sca-1+血管干细胞可在血管受损时,帮助血管修复,促进内皮化。在血管外膜的Sca-1+血管干细胞,可影响血管壁的结构和张力,参与内皮修复、血管再生、免疫调节等;
2)在人工血管上种植血管干细胞,可以减少机体对异物的免疫排斥,还可以有效调节血管再生,促进内皮修复;
3)随着凝胶的降解,细胞溢出后更好地作用于机体,既不存在在一般聚合物支架材料上细胞黏附性不好的问题,也不会在手术时导致细胞渗漏;
4)加快内皮化进程,为血管移植提供了很好的生物组织工程材料。
附图说明
图1为GelMA核磁氢谱图。
图2为GelMA为傅里叶红外检测。
图3为本发明的人工血管对血管内皮细胞活力的影响。
图4为本发明的人工血管对血管内皮细胞迁移的影响。
具体实施方式
所举实施例是为了更好地对本发明进行说明,但并不是本发明的内容仅局限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1生物混合型人工血管的制备
1.内层主体血管支架制备
1)电纺丝法制备天然高分子聚合物人工血管:用六氟异丙醇配制浓度为10g/ml的PCL电纺溶液,搅拌至完全溶解;实验所用仪器为YFSP-T高压静电纺丝机。将静电纺丝溶液置于10ml注射器中,选择7号针头,设置电压为15KV,注射泵推进速度为1ml/h,接收距离为15cm,滚筒接收装置连接3mm的钢管进行收集,滚筒转速为150r/min,得到的聚合物管状纤维聚合物作为内层主体血管支架;
采用脱细胞基质法制备:
2)制备的异体来源脱细胞基质血管支架来源于猪的心血管,无菌环境下,在无菌PBS中从猪心分离到猪心血管后,立即进行脱细胞处理,将分离好的冠状动脉在无菌蒸馏水中低渗处理24小时,在第4小时的时候取出血管,放入-80℃冰箱冷冻30分钟,然后转移到室温30分钟,所述冻融过程重复两次。24小时后,用0.125%胰酶在37℃摇床上处理1.5小时,再换蒸馏水处理3小时。处理完全的脱细胞血管在真空冷冻干燥之后置于干燥箱里保存。
2.内层主体血管支架肝素化(电纺丝人工血管和脱细胞人工血管肝素固化方法均为共价结合法)
取MES缓冲液(0.05mol/L,pH5.60)50mL,加入0.1917g EDC、0.115gNHS和0.1g肝素,在37℃条件下反应10分钟,将肝素的氨基活化,再加入到血管中,37℃摇床反应24小时,再用PBS中和去除未结合的肝素。3.GelMA水凝胶制备及包封血管干细胞
用PBS配制10g/ml A型明胶(175bloom)溶液,搅拌混匀,将混合液在60℃水浴锅中处理30分钟,直到明胶全部溶解呈透明的颜色。缓慢加入10ml的甲基丙烯酸酐(MA)磁力搅拌1小时,当溶液变得均匀不透明后继续搅拌3小时。反应结束后,在3500g、25℃条件下离心5分钟,以去除未反应的MA单体。将上清液倒入一个大烧杯中,丢弃沉积在离心管底部的MA。将上述溶液转移到透析袋(8000-14000KDa)中,在40℃温水中透析7天,每天至少换一次水。透析完毕后,用1mol/L的NaHCO3溶液将pH调为7.5左右。将GelMA溶液用孔径为0.22μm的滤膜进行真空抽滤。将抽滤后的GelMA溶液分装在50ml离心管中,包好锡箔纸,在-20℃条件下进行冷冻,然后转移至真空冷冻干燥箱中干燥至恒重。从真空冷冻干燥箱取出干燥好的样品保存在-20℃条件下备用,将制备好的GelMA采用核磁氢谱和傅里叶红外检测接枝结果,其结果如图1-2所示,说明GelMA接枝成功。用去离子水配制1%光引发剂Irgacure2959,震荡摇匀后放入80℃烘箱10分钟。拿出后再次震荡,加入GelMA配制4%GelMA溶胶,混匀后在80℃烘箱作用10分钟。将溶液缓慢倒入预先制作好的高200μm、直径6mm聚二甲基硅氧烷(polydimethylsiloxane,PDMS)模具中。将血管干细胞用胰酶消化后,混入GelMA溶胶中,再将将混有光引发剂和1×106个细胞/ml的GelMA溶胶置于PDMS模具中。
4.生物混合型人工血管制备
将制备好的肝素化的人工血管置于含有血管干细胞的GelMA溶胶模具中,利用光交联法,在1.65mW/cm2的光功率密度下,照射30~40秒,有效固化得到的外层负载有包封了Sca-1+血管干细胞的GelMA水凝胶的人工血管。
实施例2人工血管促进血管内皮细胞生长活力
①对HUVECs培养及浸提液的制备
HUVECs培养在1%的双抗(青霉素/链霉素)和10%FBS血清的RPMI1640中于37℃,5%CO2条件下培养,定期观察细胞状态,进行换液或传代。
将过氧乙酸用无菌PBS稀释到终浓度为0.1%(v/v)。最好现配现用。把制备好的Gelatin、GelMA、PCL材料裁剪为1cm×1cm大小,泡在过氧乙酸中1h。倒掉过氧乙酸,用无菌PBS小心冲洗材料,摇晃洗掉过氧乙酸,洗3次,每次1min。用无菌PBS泡3h,弃去PBS,最后泡在无菌PBS中,4℃保存。根据ISO10993-12:2012(2012),材料的表面积与浸提介质的比值为6cm2/ml,将材料浸泡于0.83ml培养基中,与细胞培养条件一致,培养72h。
②细胞活性检测
细胞长满培养瓶后,用胰酶将细胞消化,用1640培养基吹打重悬细胞并用血细胞计数板细胞进行计数,每个孔以1×105个细胞/ml的密度接种到96孔板,每孔100ul,每个样品进行五个重复。培养24小时后,去除旧培养基,更换浸提液继续培养24h和72h。然后每孔加10ulMTS。37℃孵育1h。酶标仪检测490nm波长下OD值,计算细胞相对增殖率(relativegrowth rate,RGR):RGR(%)=(各材料组OD均值/阴性对照组OD均值)x100%)。对照组为细胞培养基,阳性对照和阴性对照分别为接种细胞和不接种细胞。,如图3所示,显示了在培养1d、3d后,本发明的人工血管中所用材料(Gelatin、GelMA、PCL)均无细胞毒性,具有良好的细胞活性,可促进血管内皮细生长活力。
实施例3人工血管促进血管内皮细胞的迁移
用划痕法观察Glatin、GelMA、PCL材料对细胞迁移的影响情况。将对数生长期的细胞消化,制成1x105个/ml的细胞悬液,1ml/孔接种12孔板;待孔内HUVECs生长至单层时,换用无血清培养液饥饿细胞4h;随后用10毫升枪头在孔板上划“十”字,加入PBS清洗3次后,加入培养基和浸提液,显微镜下随机选取6个视野拍照,记录为0h的划痕宽度;在37℃,50%COZ培养箱中培养,分别12h,36h拍照,观察细胞的迁移情况。如图4所示,与对照组相比GelMA、PCL组在培养12h和36h后,显著促进了血管内皮细胞的迁移,因此,足以预测到本发明的人工血管置换后血管内皮细胞可很快迁移到置换处,实现快速内皮化。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种生物混合型人工血管,其特征在于,所述生物混合型人工血管分为内层和外层,内层主体血管支架采用聚合物材料PCL用静电纺丝制备或采用脱细胞基质法制备,外层为包封了血管干细胞的GelMA水凝胶。
2.根据权利要求1所述的生物混合型人工血管,其特征在于,所述血管干细胞是外膜的Sca-1+血管干细胞。
3.权利要求1-2任一项所述的生物混合型人工血管的制备方法,其特征在于,将Sca-1+血管干细胞加载到GelMA水凝胶中,再采用光交联法将GelMA水凝胶固化于内层主体血管支架外层。
4.根据权利要求3所述的制备方法,其特征在于,具体包括以下步骤:
1)内层主体血管支架制备:采用聚合物材料PCL用静电纺丝制备,采用六氟异丙醇配制PCL电纺溶液;或采用脱细胞基质法将猪的心血管进行脱细胞处理后经低渗、冻融和胰酶处理并真空冷冻干燥后保存;
2)内层主体血管支架肝素化:采用共价结合法肝素化内层主体血管支架;
3)GelMA水凝胶制备以及包封血管干细胞:在明胶的基础上,接枝甲基丙烯酸酐,使明胶上的氨酸和羟赖氨酸的氨基被酰基化;再将Sca-1+血管干细胞、光引发剂Irgacure2959和GelMA水凝胶混于PDMS模具中;
4)生物混合型人工血管制备:利用光交联法有效固化步骤3)得到的外层负载有包封了Sca-1+血管干细胞的GelMA水凝胶的人工血管。
5.根据权利要求4所述的制备方法,其特征在于,步骤1)所述PCL的浓度为10g/ml。
6.根据权利要求4所述的制备方法,其特征在于,步骤3)所述明胶为A型明胶,浓度为10g/ml。
7.根据权利要求4所述的制备方法,其特征在于,步骤3)所述光引发剂Irgacure2959的质量体积浓度为1%。
8.根据权利要求4所述的制备方法,其特征在于,步骤4)所述光交联法采用的光功率为1.65mW/cm2。
9.根据权利要求7所述的制备方法,其特征在于,照射时间为30-40s。
10.Sca-1+血管干细胞在制备生物混合型人工血管中的应用。
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