CN110404123A - 一种载药小口径血管支架及其制备方法 - Google Patents
一种载药小口径血管支架及其制备方法 Download PDFInfo
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- Materials For Medical Uses (AREA)
Abstract
本发明涉及一种载药小口径血管支架及其制备方法，所述支架为双层结构；其中，外层为载药静电纺纳米纤维，内层为脱细胞血管层。本发明内部的脱细胞血管层消除了抗原性的同时，也保留了原有血管的天然多孔微结构，其能够提供适宜的微环境，进而促进细胞增殖和迁移；外部的载药纳米纤维层能够显著提高脱细胞血管所损失的力学强度，并具有局部药物缓释功能，同时将药物的全身副作用限制到最低限度。
Description
技术领域
本发明属于组织工程支架领域，特别涉及一种载药小口径血管支架及其制备方法。
背景技术
小管径动脉疾病，尤其是冠状动脉闭塞，在世界范围内有着很高的发病率和死亡率。冠状动脉旁路移植术(CABG)和经皮冠状动脉介入治疗(PCI)是治疗冠状动脉疾病的常规治疗策略。传统的大隐静脉桥血管在CABG术后容易发生内膜增生，进而导致桥血管的粥样硬化和闭塞；同时PCI术后支架内再狭窄和血栓形成也是影响介入治疗预后的主要原因。在冠状动脉疾病、肾动脉狭窄以及其他外周血管疾病的外科治疗领域，始终存在着对小直径(内径<6mm)血管移植物的显著需求。但是自身血管的来源有限，并且经常由于发生严重的病变(如粥样硬化等)而无法使用，故作为传统自身血管的替代产物，近年来，小管径组织工程血管的研究得到了越来越多的重视。现阶段的小管径组织工程血管的制作方法多样，但是仍面临植入后的血管衰败，其主要原因为血栓形成、内膜增生、炎症反应以及动脉粥样硬化等。
理想的小口径血管支架材料应具备良好的力学性能、物理稳定性、抗凝血性、生物相容性及抗感染性等。非降解材料的血管支架内皮细胞难以黏附和生长，容易引发血小板聚集造成急性血栓、吻合口内膜增生和感染等。天然血管经脱细胞处理后很好地去除了抗原性，完全由天然细胞外基质(extracellular matrix,ECM)组成，具有理想的血管支架结构和形状，与聚合物材料相比，移植后与受体细胞有具有良好的生物相容性。然而有研究表明,生物材料脱细胞方法对血管的力学性能有很大的影响,造成弹性蛋白变形降解，降低生物材料在体内的存在时间,导致血管移植物的扩张膨胀甚至形成动脉瘤。
静电纺丝(Electrospinning，ES)是一种特殊的纤维制造工艺，使聚合物溶液或熔体在高压静电场中喷射出纳米级纤维纺丝。静电纺丝在制造过程中能够负载生长因子诱导细胞黏附、增殖和分化，高细胞结合位点的丰度，促进细胞外基质的形成，高人工血管的支架的力学性能、厚度及结构可控性。而人体大多数组织、器官在形式和结构上与纳米纤维类似，故纳米纤维可以模拟天然细胞外基质的结构和生物功能。我们首先使用天然大鼠脱细胞主动脉作为组织工程小血管生物支架，并在脱细胞血管支架外覆以纳米PCL静电纺丝外膜以提高生物支架的机械性能，在血管支架内膜进行肝素化涂层，从而制备一种复合型组织工程血管HTEV(Hybrid Tissue engineered blood vessels)。
然而，HTEV的组织学检测结果提示管腔内可见内膜增生，这可能会影响人造血管的长期通畅率。因此，有必要开发具有生物活性的小管径组织工程血管，使其不仅能为血管壁提供必要的力学支持，而且还能够释放药物以抑制内膜增生。雷帕霉素(Rapamycin,RM)作为FDA批准的一种药物，除了抗增殖活性外，RM还被证明具有额外的治疗潜力，包括抗真菌，抗肿瘤和免疫抑制活性等。此外，在冠状动脉疾病的治疗领域，具有RM或其类似物依维莫司涂层的药物洗脱支架具有改善支架内再狭窄和预防支架血栓形成的能力。然而，RM的药物有效性受到血脑屏障的限制；此外，高剂量的RM全身性给药可导致某些副作用，例如食物摄入减少和伴随的体重减轻等。近期的研究中，研究者利用药物的缓释技术，制备了含有RM纳米颗粒的血管贴片和释放RM的血管周围鞘等，使得RM在特定位点缓慢释放，以避免脱靶全身效应，并且在治疗血管损伤后的内膜增生方面取得了良好的效果。
PCL作为一种热塑性材料，具有良好的机械性能，表现为高刚度、强度和韧性，并且与各种水不溶性药物具有良好的相容性，大约2-3年的长期降解时间也使得PCL适合作为载体以持续释放药物。这都使PCL成为FDA批准的医疗器械的理想原料，包括“Monocryl”缝合线和“SynBiosys”药物释放系统。而RM是一种脂溶性药物，这也确保其在静电纺丝过程中可以稳定均匀地加载到PCL纳米纤维中。
发明内容
本发明所要解决的技术问题是提供一种载药小口径血管支架及其制备方法，该支架外部的载药纳米纤维层具有充分的力学强度，并具有局部药物缓释功能，同时将药物的全身副作用限制到最低限度；内部的脱细胞血管层消除了抗原性的同时，也保留了原有血管的天然多孔微结构，其能够提供适宜的微环境，进而促进细胞增殖和迁移。
本发明提供了一种载药小口径血管支架，所述支架为双层结构；其中，外层为载药静电纺纳米纤维，内层为脱细胞血管层。
所述静电纺纳米纤维为PCL纳米纤维、PLGA纳米纤维、PLLA纳米纤维或者其他生物材料的静电纺纳米纤维。
本发明还提供了一种载药小口径血管支架的制备方法，包括：
(1)取大鼠腹主动脉进行脱细胞处理，得到脱细胞血管；
(2)以上述脱细胞血管为接收装置，将生物材料以及药物配制成纺丝溶液进行静电纺丝，纳米纤维吸附并包绕在脱细胞血管外壁上，即得载药小口径血管支架。
所述步骤(1)中采用的脱细胞液为含0.5％Triton-X100、0.5％去氧胆酸钠和0.5％十二烷基磺酸SDS的PBS溶液及含20μg/ml RNAse、200μg/ml DNAse的PBS溶液。
所述步骤(2)中的生物材料为PCL、PLGA、PLLA或者其他可电纺的生物材料。
所述步骤(2)中的药物为心血管药物或者活性因子。
所述步骤(2)中的药物相对于生物材料的负载比例为0.1～30％w/w。
所述步骤(2)中的静电纺丝工艺参数为：针头20～22G，推进速率0.5～1毫升/小时，电压10KV～12KV，接收距离10～20cm，转速500～1000rpm。
有益效果
本发明外部的载药纳米纤维层具有充分的力学强度，并具有局部药物缓释功能，同时将药物的全身副作用限制到最低限度；内部的脱细胞血管层消除了抗原性的同时，也保留了原有血管的天然多孔微结构，其能够提供适宜的微环境，进而促进细胞增殖和迁移；制备方法简单、快捷、适用于多种生物材料和药物的缓释，具有良好的应用前景。
附图说明
图1为本发明的设计原理图；
图2为本发明大鼠主动脉脱细胞前后组织学光镜检测(A-F)和DNA含量检测(G)；
图3大鼠主动脉脱细胞前(A、C、E)后(B、D、F)扫描电镜观察；
图4为复合小口径血管的电镜图(A-E)和实物图(F)；
图5为载药复合小血管的实物图(a)、电镜图(b-f)、红外吸收光谱图(g)和接触角曲线(h)；
图6为天然腹主动脉、脱细胞腹主动脉、复合小血管以及载药复合小血管的径向拉伸力学性能；包括拉伸断裂曲线(a)、杨氏模量(b)、断裂强度(c)和断裂伸长率(d)。
图7为RM-HTEV的药物缓释曲线；
图8为HTEV以及RM-HTEV的大鼠腹主动脉植入吻合后的照片(a、c)及6周后的超声检测图像(b、d)及血流速度(e)和血管直径(f)的半定量分析；
图9为DRA、HTEV以及RM-HTEV的体内植入12周后的免疫组化分析(a-k)和免疫荧光分析(i-s)。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
1.大鼠腹主动脉的脱细处理及表征
(1)SD大鼠(8周鼠龄)予以2％戊巴比妥40mg/kg(0.2ml/100g)腹腔麻醉后，完整取下胸主动脉至髂动脉分叉以上水平降主动脉，置入无菌生理盐水中反复冲洗，去除主动脉内血凝块，并去除血管外脂肪及结缔组织，获得天然未脱细胞大鼠主动脉(Native rataortas,NRA)。
(2)将NRA置脱细胞液中处理，脱细胞液为：含0.5％Triton-X100、0.5％去氧胆酸钠(SD)以及0.5％十二烷基磺酸钠(SDS)的PBS溶液及含20μg/ml RNAse、200μg/ml DNAse的PBS溶液。最后将脱细胞主动脉置于含1×青-链霉素双抗溶液的PBS溶液中冲洗震荡获得脱细胞大鼠主动脉(Decellularized rat aortas,DRA)。
分别取对照组和脱细胞组血管(n＝3)，在胸主动脉近端部位取小块组织10％甲醛固定，石蜡包埋进行HE染色、Masson染色及Verhoff-von Gieson染色观察大鼠血管组织形态学变化。取NRA和DRA研磨形成干粉，采用dsDNA定量分析试剂盒检测各组样品的DNA含量。接着通过扫描电镜(Scanning electron microscope,SEM)检测，进一步明确脱细胞过程对血管内膜、中层和细胞外基质的情况。
如图2和图3所示，未脱细胞大鼠主动脉的总DNA含量为301.7±15.6ng/mg，脱细胞后显著下降，为89.7±11.6ng/mg，脱细胞较为完全。血管基本结构得以保存，可作为组织工程生物血管支架，但对于胶原纤维以及弹力纤维造成了一定程度的损伤。
2.复合组织工程血管(HTEV)及载药复合组织工程血管(RM-HTEV)的制备
(1)将脱细胞大鼠主动脉用一个匹配血管内径的不锈钢接收轴穿入血管腔，经过真空冷冻干燥以保持血管的管腔结构和管壁多孔结构，使干燥后的脱细胞血管轻微地附着接收轴上，可以在后续过程中可被轻易取下，并避免血管因自然风干后的结构塌陷和与接收轴粘接过紧。
(2)使用环形铜圈作为电极，所产生的电场使纳米纤维更多的喷射到针头轴向的收集装置上，避免纤维之间的斥力影响而分散到其他位置，以提高纳米纤维的纺丝效率。采用可旋转的圆柱状电纺丝收集装置，可调节转动速率和更换不同尺寸的接受轴，以便形成均匀包覆的静电纺纤维层。
(3)将配置好的以六氟异丙醇为溶剂、浓度为12.5％(w/v)聚己内酯(Mn为80,000g/mol)溶液抽入注射器，接上21G的针头并排尽气泡后安装在微量注射泵上，连接环形电极和高压电源；调节注射泵以0.8毫升/小时的推进速率挤出聚己内酯溶液，调节高压电源，加以10KV的高压开始纺丝。将之前准备好的穿有干燥血管的接受轴固定在收集器上，放置在距离平嘴针头15厘米处，调节使其以500rpm的速率匀速转动，纳米纤维吸附并包绕在脱细胞血管外壁上。静电纺丝过程持续进行30分钟，可以在血管外壁形成一层约100μm厚的纳米纤维层。从而获得复合组织工程血管(HTEV)。将纺丝液当中按照PCL：雷帕霉素比例为19：1加入药物并溶解，按照同样的方法制备载药复合组织工程血管(RM-HTEV)。
3.复合组织工程血管(HTEV)及载药复合组织工程血管(RM-HTEV)的表征和测试
用扫描电镜对HTEV支架的形态和尺寸进行表征。如图4所示，脱细胞血管外部纳米PCL层呈均匀的纤维形态，同天然血管类似，而纳米纤维结构更加紧密。此外，ES-PCL层和DRA紧紧附连到彼此，没有明显的分层现象，而脱细胞血管本身分层明显，结构疏松。HTEV支架的内径为1.5～2毫米，纳米PCL纤维的壁厚为约100～150μm。如图5所示，RM-HTEV支架具有和HTEV同样的双层结构，从红外吸收光谱曲线可以看到雷帕霉素的吸收峰，证明药物被有效的载入。从接触角测试可以看出脱细胞血管具有良好的亲水性，HTEV外层的PCL纳米纤维表现出疏水效果，但随着药物的载入，亲水性增加。
将天然腹主动脉、脱细胞腹主动脉、复合小血管以及载药复合小血管进行力学测试，如图6所示，脱细胞处理使得血管的径向拉伸强度和杨氏模量显著下降，而聚己内酯静电纺丝改善了支架的机械强度，RM-HTEV与HTEV的力学特征相似，复合血管支架的拉伸性能能够满足人工血管移植要求。总体而言,该复合组织工程血管支架表现出优越的机械性能，弥补了脱细胞处理对血管的力学损伤。
如图7所示，载有RM的电纺PCL纳米纤维的体外缓释实验结果表明，RM呈现为受控且持续的药物释放方式。在最初的7天内，约30％的RM被释放，表现为轻微的突释。随后，RM从PCL纳米纤维中持续释放，8周后其释放速率明显变慢。70天后，总计约60％的RM从电纺PCL纳米纤维中释放出来。
4.复合组织工程血管(HTEV)及载药复合组织工程血管(RM-HTEV)的体内移植及测试
将复合组织工程血管移植于动物体内进行功能验证。建立同种异体的大鼠腹主动脉移植模型，术后6周应用超声和小动物CT检测移植血管的血流速度和血管形态、结构的变化，术后12周应用组织学以及免疫荧光染色观察移植物细胞重构及血管炎症等。
如图8所示，在与自体腹主动脉(AAA)吻合后，DRA显著扩张，而RM-HTEV和HTEV与AAA均能够充分匹配。整个研究过程中，DRA组一只大鼠术后3小时死于出血，其余17只大鼠在研究过程中存活而没有发生感染或脓肿。组织工程血管植入后6周，进行超声检测以评估组织工程血管的通畅性，结果提示所有血管均通畅。然而，定量分析提示，DRA组的最大血流速度显著低于其他组。相应地，DRA组血管直径显著大于其他组。
如图9所示，尽管在植入后6周超声检测未显示血管闭塞，但在术后12周时进行的组织学评估显示，DRA组中的所有植入血管都发生了血管闭塞。然而，HTEV和RM-HTEV组的H&E和Masson染色均未显示出血栓形成或狭窄形成的迹象。因此，DRA组的整体通畅率为0％(0个通畅血管/6个总植入血管)，HTEV组为100％(6/6)，RM-HTEV组为100％(6/6)。
RM-HTEV组的血管直径显著大于HTEV组。通过分析H&E染色切片，RM-HTEV组的内膜增生程度相比HTEV组要显著抑制。同时，RM-HTEV组的管腔面积明显大于HTEV组。通过vonKossa染色评估血管的钙化情况，结果显示在各组组织工程血管中的脱细胞层均可见钙化区域，但在新生内膜和血管壁的其他层面均未观察到钙化区域。另外，EVG染色显示各组组织工程血管中的脱细胞层具有完整环绕的弹性纤维，其可恰当地模拟天然血管中的纤维取向。
对αSMA的免疫荧光染色结果显示，HTEV和RM-HTEV组在血管壁中均具有平滑肌层。然而，在HTEV组的血管壁中存在大量αSMA阳性细胞，其组成了显著增厚的平滑肌层。相反，在RM-HTEV组中发现较少αSMA染色阳性的细胞，并且在DRA组中仅观察到散在分布的αSMA阳性细胞。通过对Calponin(成熟平滑肌细胞的特异性标记物)的免疫荧光染色进一步证实了上述结果。对血管内皮细胞CD31免疫荧光染色证明，新生的内皮细胞存在于HTEV和RM-HTEV组中。此外，CD68染色表明植入血管中均有巨噬细胞的浸润，CD163染色提示植入血管中同时具有M2巨噬细胞的浸润。对CD163阳性细胞和CD68阳性细胞定量分析表明，HTEV和RM-HTEV组之间没有显著差异，而DRA组的CD163阳性细胞明显少于其余两组，而CD68阳性细胞明显多于其余两组，表明植入血管中存在着大量非M2型巨噬细胞。对M1巨噬细胞标记物iNOS的进一步免疫组织化学分析显示，RM-HTEV和HTEV组中的iNOS阳性区域明显低于DRA组。
5.总结
本实施例将大鼠主动脉血管经过联合去污剂、DNA酶和RNA酶脱细胞处理后,细胞成分能被完整去除，血管支架结构得以保存，可作为组织工程生物血管支架，但对胶原纤维以及弹力纤维造成一定程度的损伤。利用静电纺丝技术将纳米聚己内酯纺丝(ES-PCL)包覆于脱细胞大鼠主动脉外壁形成人工血管外膜，可以构建生物高分子材料和脱细胞血管相结合的、贴合紧密、厚度合适的复合型小口径组织工程血管支架。去细胞过程显著降低了脱细胞血管支架的径向和轴向拉伸应力，而ES-PCL包覆改造大鼠脱细胞主动脉具有良好的生物力学性能，并显示出良好的生物力学顺应性。体内植入研究表明HTEV和RM-HTEV血管通畅性良好，纳米PCL纤维和RM/PCL纳米纤维包覆能防止脱细胞主动脉的扩张和动脉瘤形成。负载雷帕霉素的小血管具有稳定长效的药物缓释功能，且能够诱导平滑肌细胞生长并阻止血管外炎症细胞浸润，进而减轻管腔内膜增生。本实施例为构建基于生物血管支架和外膜覆被、药物缓释的组织工程人工小血管供了新的理论基础，新型复合型组织工程血管具有良好的临床应用前景。
Claims (8)
1.一种载药小口径血管支架，其特征在于：所述支架为双层结构；其中，外层为载药静电纺纳米纤维，内层为脱细胞血管层。
2.根据权利要求1所述的一种载药小口径血管支架，其特征在于：所述静电纺纳米纤维为PCL纳米纤维、PLGA纳米纤维、PLLA纳米纤维或者其他生物材料的静电纺纳米纤维。
3.一种载药小口径血管支架的制备方法，包括：
(1)取大鼠腹主动脉进行脱细胞处理，得到脱细胞血管；
(2)以上述脱细胞血管为接收装置，将生物材料以及药物配制成纺丝溶液进行静电纺丝，纳米纤维吸附并包绕在脱细胞血管外壁上，即得载药小口径血管支架。
4.根据权利要求3所述的制备方法，其特征在于：所述步骤(1)中采用的脱细胞液为含0.5％Triton-X100、0.5％去氧胆酸钠和0.5％十二烷基磺酸SDS的PBS溶液及含20μg/mlRNAse、200μg/ml DNAse的PBS溶液。
5.根据权利要求3所述的制备方法，其特征在于：所述步骤(2)中的生物材料为PCL、PLGA、PLLA或者其他可电纺的生物材料。
6.根据权利要求3所述的制备方法，其特征在于：所述步骤(2)中的药物为心血管药物或者活性因子。
7.根据权利要求3所述的制备方法，其特征在于：所述步骤(2)中的药物相对于生物材料的负载比例为0.1～30％w/w。
8.根据权利要求3所述的制备方法，其特征在于：所述步骤(2)中的静电纺丝工艺参数为：针头20～22G，推进速率0.5～1毫升/小时，电压10KV～12KV，接收距离10～20cm，转速500～1000rpm。
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