CN114767939B - 一种可改善粘连的载药修复支架及其制备方法 - Google Patents
一种可改善粘连的载药修复支架及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种可改善粘连的载药修复支架及其制备方法,所述载药修复支架由多股数量的多层包芯纱线构成、并具有三维编织形态;所述多层包芯纱线由内到外的结构依次为增强芯层、载药纳米纤维内包覆层以及纳米纤维外包覆层,其中所述纳米纤维外包覆层的数量至少一层;所述多层包芯纱线的材料为可降解材料;增强芯层采用医用纱线,所述载药纳米纤维内包覆层与所述纳米纤维外包覆层中的纳米纤维是纳米纤维复合材料,具体可以是乳酸‑己内酯共聚物/明胶复合材料,所载药物为消炎药物。采用静电纺丝与三维编织制成编织支架,结构不易松散,且具有较好的强度和韧性,能够显著减慢成纤维细胞的过度增殖,且能缓解炎症,有效预防或减轻肌腱等处的粘连。
Description
技术领域
本发明涉及纤维支架技术领域,具体涉及一种可改善粘连的载药修复支架及其制备方法。
背景技术
作为连接肌肉与骨骼的重要组织,肌腱很容易在体育等运用过程中遭受撕裂或破裂等损伤。肌腱损伤后自然愈合的过程中排列紊乱的胶原纤维容易形成粘连导致肌腱功能丧失,且自然愈合的肌腱生物化学和机械性能差,容易再损伤甚至断裂。因此即使耗费了数周至数月来等待愈合,其通常也难以完全恢复至理想的水平,导致肌腱变弱并增加了再次受伤的风险。
鉴于肌腱低血管的生理微环境,其损伤后自然修复速率较慢,容易形成恶性纤维性修复,给患者带来严重的并发症如局部炎症或病理性瘢痕组织,进而给患者造成痛苦,因此,肌腱损伤后大多需要手术辅助治疗。传统的手术治疗方式采用自体、同种或异种肌腱材料联合肌腱修复和缝合技术等,然而,在治疗中还有很多尚未解决的问题,自体移植供体或供区有限,异体移植存在免疫排斥反应、术后疼痛、肌腱撕裂复发等。
临床手术后因组织炎症或感染通常会在肌腱、腹部等处产生粘连,这是一种会导致两种相邻组织非正常粘合的并发症。粘连产生时,通常会进一步导致慢性疼痛、肠梗阻等疾病,进而需要多次手术进行干预,这增加了临床术后并发症的发病率和术后死亡率。肌腱损伤至修复的过程中,常因为损伤的肌腱与周围组织粘连而造成肌腱手术失败。粘连的产生与很多生理性因素有关,如肌腱手术部位修复过程中成纤维细胞过度增殖,伤口感染导致严重炎症反应,以及手术后残留血凝块淤积等。因此,在防止术后肌腱粘连中,抑制肌腱修复过程中成纤维细胞的过度增殖,防止术后感染和炎症,以及及时清除血凝块极为重要。
发明内容
为了改善肌腱损伤修复产生的粘连问题,而提供一种可改善粘连的载药修复支架及其制备方法。本发明的修复支架为可降解材料,能够显著减慢成纤维细胞的过度增殖,且能缓解炎症,有效预防或减轻肌腱等处的粘连。
为了达到以上目的,本发明通过以下技术方案实现:
一种可改善粘连的载药修复支架,所述载药修复支架由多股数量的多层包芯纱线构成、并具有三维编织形态;所述多层包芯纱线由内到外的结构依次为增强芯层、载药纳米纤维内包覆层以及纳米纤维外包覆层,其中所述纳米纤维外包覆层的数量至少一层;
所述多层包芯纱线的材料均为可降解材料。
进一步地,所述增强芯层的材料为PLA、PCL、PLGA、SF医用纱线中的一种,单根所述医用纱线的直径为100-150μm;所述载药纳米纤维内包覆层与所述纳米纤维外包覆层中的纳米纤维为纳米纤维复合材料。
再进一步地,所述纳米纤维复合材料为可降解聚合物与天然材料的纳米纤维复合材料,其中所述可降解聚合物为PLCL、PLA、PLGA中的一种或多种,所述天然材料为明胶、透明质酸或其盐、海藻酸盐、壳聚糖、丝素蛋白中的一种或多种。
再进一步地,所述纳米纤维复合材料为乳酸-己内酯共聚物/明胶复合材料(PLCL/Gel复合材料);所述载药纳米纤维内包覆层所载药物为消炎药物,例如萘普生钠(NPS)、布洛芬等。
再进一步地,所述乳酸-己内酯共聚物/明胶复合材料中,乳酸-己内酯共聚物与明胶所占重量百分数之比为60-90%:10-40%;所述载药纳米纤维内包覆层的载药量为乳酸-己内酯共聚物与明胶总重量的2.5-10%。
进一步地,所述载药修复支架的编织直径为2-3mm;所述多层包芯纱线的单根直径为150-200μm;所述载药纳米纤维内包覆层的厚度为10-25μm,所述纳米纤维外包覆层的厚度为10-25μm。三维编织的支架尺寸可调节,且支架长度在一定的范围内可裁剪且不易松散变形。
本发明另一方面提供上述载药修复支架的制备方法,包括如下步骤:
(1)配制纺丝液:将可降解聚合物、天然材料、消炎药按照配比溶于溶剂中得到A纺丝液;将可降解聚合物、天然材料按照配比溶于溶剂中得到B纺丝液;
静电纺丝:以微米级医用纱线为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层,再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得至少一层纳米纤维外包覆层,由此获得多层包芯纱线;根据选择的天然材料的不同选择性地对所述多层包芯纱线进行交联;
(2)编织:采用多股数量的多层包芯纱线,利用电脑横机进行三维编织,最终获得可改善粘连的载药修复支架。
进一步地,步骤1中所述溶剂为醇类溶剂,优选为六氟异丙醇(HFIP);所述A纺丝液与所述B纺丝液的浓度为0.05-0.5g/mL。
进一步地,步骤1中所述静电纺丝法采用共轭电纺设备进行制备,设备参数设置:左、右推进器的推进速度0.02-0.05mL/min、接收辊接收纱线速度8-15rpm、缠绕辊的缠绕速度300-450rpm、正电压7-12kV、负电压7-12kV。根据纺丝液浓度、空气湿度、温度等实际情况在以上范围内设定。
进一步地,步骤2利用电脑横机进行三维编织,针织机速为0.1m/s、NP值为8-10(NP值反应编织密度,NP值越大,密度越小,经密纬密也变小,织物越松),结尾利用活扣设计,待编织结束后,裁去废纱,支架不会松散。
有益技术效果
本发明从抗粘连角度出发,联合静电纺丝技术和针织编织技术制备了含消炎药(如萘普生钠)的三维编织形态载药修复支架,用于改善损伤处相邻组织之间的非正常粘连问题。
本发明采用乳酸-己内酯共聚物(PLCL)、明胶(Gel)、萘普生钠(NPS)制成载药纺丝液,通过静电纺丝法在医用纱线外周表面获得载药纳米纤维复合材料,然后再外静电纺丝包覆至少一层不载药的纳米纤维复合材料获得多层包芯纱线。其中,医用纱线作为增强芯提供修复支架一定的力学性能,纳米纤维可模仿细胞外基质,提供肌腱等损伤组织的修复微环境,纤维上所载药物在三维编织形态下发生缓释作用可显著抑制成纤维细胞的增殖,有效减少细胞炎症因子的产生,防止肌腱等组织的粘连,进而促进损伤组织再生;另外本发明三维编织形态的修复支架不仅可以负载细胞,且修复支架的线密度存在一定的空隙,有利于损伤组织对支架的浸润。通过调节双层包芯纱线的股数、编织的参数,支架各股线与线之间的空隙可调,得到的支架不仅可用于肌腱损伤,还可用于韧带损伤、肩袖损伤等修复。本发明修复支架所采用的材料均为可降解材料,且降解产物对移植宿主无毒害作用,此外随着材料降解,组织逐渐替代植入,有助于损伤组织的快速修复。
附图说明
图1为本发明单根双层包芯纱线截面结构的示意图,其中1-增强芯层、2-载药纳米纤维内包覆层、3-纳米纤维外包覆层。
图2为本发明修复支架的三维编织形态电脑生成图。
图3为本发明修复支架的实物图。
图4为实施例1中的单根双层包芯纱线以及最后制得的修复支架的扫描电镜图,其中a为单根双层包芯纱线放大500倍的SEM图,b为修复支架放大70倍的SEM图。
图5为实施例及对比例未编织支架的纱线的应力-应变图,其中a为实施例1-4和对比例1的单根纱线的应力-应变图,b为对比例3纱线的应力应变图。
图6为实施例1-4、对比例2的支架对RAW264.7细胞的毒性实验图。
图7为NIH3t3细胞在实施例1-4、对比例1支架上的增殖图。
图8为实施例1-3、对比例1支架的抗炎效果图,其中a为CCR7、CD206两种因子的抗炎分析图,b为CD80、CD86两种因子的抗炎分析图。
具体实施方式
下面将结合本发明的实施例和附图,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。以下对至少一个示例性实施例的描述实际上仅仅是说明性的,决不作为对本发明及其应用或使用的任何限制。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。
除非另外具体说明,否则在这些实施例中阐述的数值不限制本发明的范围。对于相关领域普通技术人员已知的技术、方法可能不作详细讨论,但在适当情况下,所述技术、方法应当被视为说明书的一部分。在这里示出和讨论的所有示例中,任何具体值应被解释为仅仅是示例性的,而不是作为限制。因此,示例性实施例的其它示例可以具有不同的值。
以下实施例中未注明具体条件的实验方法,通常按照国家标准测定;若没有相应的国家标准,则按照通用的国际标准、或相关企业提出的标准要求进行。除非另有说明,否则所有的份数为重量份,所有的百分比为重量百分比。
以下所用原材料:乳酸-己内酯共聚物(PLCL)的摩尔比LA:CL=75:25,由济南岱罡生物工程有限公司提供;明胶(Gel)S30952由上海源叶生物科技有限公司提供;消炎药萘普生钠(NPS)纯度99wt%,F21356,由上海迈瑞尔化学技术有限公司提供。
实施例1
一种可改善粘连的载药修复支架,所述载药修复支架由三股双层包芯纱线构成、并具有三维编织形态;所述双层包芯纱线截面结构示意图如图1所示,由内到外的结构依次为增强芯层1、载药纳米纤维内包覆层2以及纳米纤维外包覆层3;所述双层包芯纱线的材料均为可降解材料。
上述载药修复支架的制备方法,包括如下步骤:
(1)配制纺丝液:将0.7g PLCL、0.3g Gel、25mg NPS溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到A纺丝液;
将0.7g PLCL、0.3g Gel溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到B纺丝液;
静电纺丝:以医用PLA纱线(直径约135-145μm)为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层(厚度约10-20μm);再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得一层纳米纤维外包覆层(厚度约10-20μm),由此获得双层包芯纱线;
静电纺丝法具体操作是:采用共轭电纺设备,固定医用PLA纱线,取两支含A纺丝液的5mL注射器放置于设备的左右正负电压处,选用20号针头连接注射器,设定左右正负电压8.5kV、左右推进器推进速度0.02mL/min、接收辊接收纱线速度10rpm、缠绕辊缠绕速度400rpm的条件下在医用PLA纱线的外周表面进行静电纺丝,使纺得的载药纳米纤维复合材料粘附于医用PLA纱线表面得到单层包芯纱线;然后再在上述参数下采用B纺丝液在获得的单层包芯纱线基础上进行二次静电纺丝,使纺得的纳米纤维复合材料粘附于单层包芯纱线外周表面,最后制得双层包芯纱线;
将双层包芯纱线置于戊二醛蒸汽中交联40min,然后放置在通风橱吹风3-5天;
(2)将三股双层包芯纱线利用电脑横机进行三维编织,机器参数为:机速0.1m/s,NP值8.5,编织后将废纱去掉,得到可改善粘连的载药修复支架。
本实施例修复支架的三维编织形态电脑生成图如图2所示,修复支架的实物图如图3所示,支架裁剪至不同长短后可见其不易松散,裁剪后结构仍然较为紧密。
本实施例单根双层包芯纱线以及最后制得的修复支架的扫描电镜图如图4所示,其中图4的a为单根双层包芯纱线放大500倍的SEM图,图4的b为修复支架放大70倍的SEM图。如图4可知,本实施例的单根双层包芯纱线的直径约为150-180μm;修复支架的直径约2-3mm,长度可裁剪且不易变形。双层包芯纱线之间编织的较为紧密,但仍留有一定空隙。
本实施例产品记为PG-N2.5。其中PG-N表示纳米纤维纤维复合材料,2.5表示NPS占PLCL与Gel总质量的百分数,即本实施例中载药量为2.5%,实施例2-4中的载药量以此类推。
实施例2
本实施例的产品结构及制备方法与实施例1相同,不同之处在于,A纺丝液中NPS加入了50mg。本实施例产品记为PG-N5。
实施例3
本实施例的产品结构及制备方法与实施例1相同,不同之处在于,A纺丝液中NPS加入了75mg。本实施例产品记为PG-N7.5。
实施例4
本实施例的产品结构及制备方法与实施例1相同,不同之处在于,A纺丝液中NPS加入了100mg。本实施例产品记为PG-N10。
实施例5
一种可改善粘连的载药修复支架,所述载药修复支架由两股双层包芯纱线构成、并具有三维编织形态;所述双层包芯纱线截面结构示意图如图1所示,由内到外的结构依次为增强芯层1、载药纳米纤维内包覆层2以及纳米纤维外包覆层3;所述双层包芯纱线的材料均为可降解材料。
上述载药修复支架的制备方法,包括如下步骤:
(1)配制纺丝液:将0.6g PLCL、0.4g Gel、50mg NPS溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到A纺丝液;
将0.6g PLCL、0.4g Gel溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到B纺丝液;
静电纺丝:以医用PLA纱线(直径约135-145μm)为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层(厚度约8-15μm);再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得一层纳米纤维外包覆层(厚度约8-15μm),由此获得双层包芯纱线;
静电纺丝法具体操作是:采用共轭电纺设备,固定医用PLA纱线,取两支含A纺丝液的5mL注射器放置于设备的左右正负电压处,选用20号针头连接注射器,设定左右正负电压9kV、左右推进器推进速度0.02mL/min、接收辊接收纱线速度12rpm、缠绕辊缠绕速度450rpm的条件下在医用PLA纱线的外周表面进行静电纺丝,使纺得的载药纳米纤维复合材料粘附于医用PLA纱线表面得到单层包芯纱线;然后再在上述参数下采用B纺丝液在获得的单层包芯纱线基础上进行二次静电纺丝,使纺得的纳米纤维复合材料粘附于单层包芯纱线外周表面,最后制得双层包芯纱线;
将双层包芯纱线置于戊二醛蒸汽中交联40min,然后放置在通风橱吹风3-5天;
(2)将三股双层包芯纱线利用电脑横机进行三维编织,机器参数为:机速0.1m/s,NP值9,编织后将废纱去掉,得到可改善粘连的载药修复支架。
本实施例修复支架的三维编织形态电脑生成图如图2所示,修复支架的实物图如图3所示。
本实施例的单根双层包芯纱线的直径约为150-170μm;修复支架的直径约2-3mm。双层包芯纱线之间编织的较为紧密,但空隙较NP值8.5的要多一些。
实施例6
一种可改善粘连的载药修复支架,所述载药修复支架由三股双层包芯纱线构成、并具有三维编织形态;所述双层包芯纱线截面结构示意图如图1所示,由内到外的结构依次为增强芯层1、载药纳米纤维内包覆层2以及纳米纤维外包覆层3;所述双层包芯纱线的材料均为可降解材料。
上述载药修复支架的制备方法,包括如下步骤:
(1)配制纺丝液:将0.8g PLCL、0.2g Gel、50mg NPS溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到A纺丝液;
将0.8g PLCL、0.2g Gel溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到B纺丝液;
静电纺丝:以医用PLA纱线(直径约135-145μm)为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层(厚度约15-25μm);再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得一层纳米纤维外包覆层(厚度约15-25μm),由此获得双层包芯纱线;
静电纺丝法具体操作是:采用共轭电纺设备,固定医用PLA纱线,取两支含A纺丝液的5mL注射器放置于设备的左右正负电压处,选用20号针头连接注射器,设定左右正负电压8kV、左右推进器推进速度0.02mL/min、接收辊接收纱线速度8rpm、缠绕辊缠绕速度350rpm的条件下在医用PLA纱线的外周表面进行静电纺丝,使纺得的载药纳米纤维复合材料粘附于医用PLA纱线表面得到单层包芯纱线;然后再在上述参数下采用B纺丝液在获得的单层包芯纱线基础上进行二次静电纺丝,使纺得的纳米纤维复合材料粘附于单层包芯纱线外周表面,最后制得双层包芯纱线;
将双层包芯纱线置于戊二醛蒸汽中交联40min,然后放置在通风橱吹风3-5天;
(2)将三股双层包芯纱线利用电脑横机进行三维编织,机器参数为:机速0.1m/s,NP值8,编织后将废纱去掉,得到可改善粘连的载药修复支架。
本实施例修复支架的三维编织形态电脑生成图如图2所示,修复支架的实物图如图3所示。
本实施例的单根双层包芯纱线的直径约为160-190μm;修复支架的直径约2-3mm。双层包芯纱线之间编织紧密,但仍留有少量空隙。
实施例7
一种可改善粘连的载药修复支架,所述载药修复支架由三股双层包芯纱线构成、并具有三维编织形态;所述双层包芯纱线截面结构示意图如图1所示,由内到外的结构依次为增强芯层1、载药纳米纤维内包覆层2以及纳米纤维外包覆层3;所述双层包芯纱线的材料均为可降解材料。
上述载药修复支架的制备方法,包括如下步骤:
(1)配制纺丝液:将0.9g PLCL、0.1g Gel、50mg NPS溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到A纺丝液;
将0.9g PLCL、0.1g Gel溶于10mL的HFIP中,室温置于磁力搅拌器上搅拌12h充分溶解得到B纺丝液;
静电纺丝:以医用PLA纱线(直径约135-145μm)为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层(厚度约10-20μm);再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得一层纳米纤维外包覆层(厚度约10-20μm),由此获得双层包芯纱线;
静电纺丝法具体操作是:采用共轭电纺设备,固定医用PLA纱线,取两支含A纺丝液的5mL注射器放置于设备的左右正负电压处,选用20号针头连接注射器,设定左右正负电压10kV、左右推进器推进速度0.02mL/min、接收辊接收纱线速度10rpm、缠绕辊缠绕速度350rpm的条件下在医用PLA纱线的外周表面进行静电纺丝,使纺得的载药纳米纤维复合材料粘附于医用PLA纱线表面得到单层包芯纱线;然后再在上述参数下采用B纺丝液在获得的单层包芯纱线基础上进行二次静电纺丝,使纺得的纳米纤维复合材料粘附于单层包芯纱线外周表面,最后制得双层包芯纱线;
将双层包芯纱线置于戊二醛蒸汽中交联40min,然后放置在通风橱吹风3-5天;
(2)将三股双层包芯纱线利用电脑横机进行三维编织,机器参数为:机速0.1m/s,NP值8,编织后将废纱去掉,得到可改善粘连的载药修复支架。
本实施例修复支架的三维编织形态电脑生成图如图2所示,修复支架的实物图如图3所示。
本实施例的单根双层包芯纱线的直径约为150-180μm;修复支架的直径约2-3mm。双层包芯纱线之间编织紧密,但仍留有少量空隙。
对比例1
本对比例的产品结构及制备方法与实施例2相同,不同之处在于内包覆层未载药,本对比例记为PG。
NIH3t3细胞分别在对比例1的PG支架、实施例1-4的PG-N支架上的生长情况见表1。
表1 NIH3t3细胞在支架上的生长情况(CCK-8法)
支架 | 第一天 | 第四天 | 第七天 | |
对比例1 | PG | 0.240667 | 0.655167 | 1.332333 |
实施例1 | PG-N2.5 | 0.2205 | 0.526833 | 1.224333 |
实施例2 | PG-N5 | 0.189333 | 0.464333 | 0.9125 |
实施例3 | PG-N7.5 | 0.213 | 0.388 | 0.722667 |
实施例4 | PG-N10 | 0.184333 | 0.340167 | 0.578 |
(注:表1中数据来自图7,数据为450nm吸光值)
由表1可知,对比例1的PG支架不能抑制NIH3t3成纤维细胞的迅速增殖。
对比例2
本对比例的产品结构及制备方法与实施例2相同,不同之处在于不存在纳米纤维外包覆层(即未进行B纺丝液的配制,未第二次静电纺丝),本对比例记为D2。
在静电纺丝的过程中,会有一部分药物留在纤维的表面,在应用时,表面的药物会大量突释,为了避免留在纤维表面的药物的快速流失,故采用二次纺丝的方法,使外层纤维膜包裹内层纤维。对比例2没有外层纤维包裹,表面药物的快速流失会在第一天对细胞造成一定毒性,在初期虽会杀死炎症细胞,但从长期看,对其他细胞也会产生不利影响。
对比例3
本对比例的产品结构及制备方法与实施例2相同,不同之处在于不存在增强芯层。
对实施例1-4以及对比例1、对比例3未编织支架的单根纱线测试力学性能,其应力-应变图如图5所示,由图5的a可知,含增强芯的单根双层包芯纱线平均应力73.5±4.36MPa,应变44.11±5.25%,杨氏模量1390.04±86.39MPa,具有较好的强度及韧性;而对比例3不存在增强芯的纱线应力在6-7MPa,力学性能较差。本发明的含增强芯的双层包芯纱线的力学强度及韧性表现优异,应力在60-80MPa,应变超过40%,能满足一般动物肌腱修复模型。
测试RAW264.7细胞在实施例1-4以及对比例2的支架上存活一天的活力情况,以PG无载药组为对照验证NPS是否对细胞产生毒性。具体操作是:紫外照射24h灭菌后的支架材料转移至48孔板中,PBS清洗2遍,每个孔板加入含2万细胞的培养基,然后转移至37℃,5%CO2的培养箱培养24h,24h后取出细胞培养板、弃旧培养基、PBS清洗两遍。每孔加入无血清的培养基270μL和30μL的CCK-8原液,37℃培养箱避光孵育1h。待孵育完成后,将液体转移至96孔板,用酶标仪在450nm波长处检测吸光值,每组选择4个平行样,实验组(实施例1-4载药支架)和对照组(对比例1)的比值作图,细胞毒性百分数以大于75%判定支架材料无毒,细胞毒性百分数以小于75%判定支架材料有毒。结果如图6所示,PG-N2.5、PG-N5对细胞均无毒性,细胞长势优于对照组PG;PG-N7.5细胞毒性约为65.3%,略毒,细胞长势差,但仍有细胞存活;但PG-N10细胞存活率较低。对比例2(D2)虽然能在第一天即可杀死炎症细胞,但毒性过大,会对其他正常细胞及组织也带来伤害,而其他组支架材料,随着药物浓度的增加对细胞的活力产生的影响不同,但比D2活性要好。
测试NIH3t3细胞在对比例1、实施例1-4支架材料上的增殖情况,具体操作是:紫外照射24h灭菌后的支架材料转移至48孔板中,PBS清洗2遍,每个孔板加入含2万细胞的培养基,然后转移至37℃,5%CO2的培养箱培养,每两天换液一次,待达到时间后,取出细胞培养板、弃旧培养基、PBS清洗两遍。每孔加入无血清的培养基270μL和30μL的CCK-8原液,37℃培养箱避光孵育1h。待孵育完成后,将液体转移至96孔板,用酶标仪在450nm波长处检测吸光值。测试结果如表1以及图7所示,NIH3t3细胞在第4天、第7天各组支架之间有明显的差距,各组支架上的细胞均处于增殖状态,第7天细胞平均活力:对比例1PG支架的吸光值为1.33±0.02,实施例1PG-N2.5支架的吸光值为1.22±0.06,实施例2PG-N5支架的吸光值为0.91±0.07,实施例3PG-N7.5支架的吸光值为0.72±0.04,实施例4PG-N10支架的吸光值为0.57±0.08。这证明NPS存在的情况下支架材料可以为细胞的生存提供良好的生存环境,且可以预防成纤维细胞的过度增殖以预防肌腱粘连。
评价实施例1-3、对比例1支架的抗炎效果,具体操作是:(1)细胞种植培养:每组支架称量15mg灭菌、浸泡在培养基中3天,过滤细菌,将培养基装在离心管中标记好备用。将50万RAW264.7细胞种在6孔板中,7℃,5%CO2的培养箱中孵育24h,每孔100ng/mL脂多糖诱导24h(除对照PBS组),弃旧培养基,PBS清洗2遍,用4℃冷PBS吹打每个孔,将细胞从孔板上吹下,转移至离心管离心,倒上清液,加PBS吹打,每个离心管中加入2μL CCR7工作液和2μLCD206工作液,转移至流式管中,在含有冰块的泡沫箱中避光孵育0.5h,最后通过流式细胞仪器检测分析。(2)重复上述细胞种植培养步骤,得到吹打后的细胞后每个离心管中加入2μL CD80工作液和2μL CD86工作液,转移至流式管中,在含有冰块的泡沫箱中避光孵育0.5h,最后通过流式细胞仪器检测分析。结果如图8所示,图8的a为CCR7、CD206两种因子的抗炎分析图,CD206/CCR7的比值分析可见PG-N5支架能有效抵抗CCR7;图8的b为CD80、CD86两种因子的抗炎分析图,具体是CD80、CD86两种促炎因子的流式mean值图,随着NPS药物含量的增多,CD80、CD86两种抗体指数下降,其中CD80指数左移幅度偏少,而CD86指数明显左移。
综上,本发明采用静电纺丝与三维编织制成的编织支架,结构不易松散,且具有较好的强度和韧性,能够显著减慢成纤维细胞的过度增殖,且能缓解炎症,有效预防或减轻肌腱等处的粘连。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (2)
1.一种可改善粘连的载药修复支架,其特征在于,所述载药修复支架由多股数量的双层包芯纱线构成、并具有三维编织形态;所述载药修复支架的直径为2-3mm;
所述双层包芯纱线由内到外的结构依次为增强芯层、一层载药纳米纤维内包覆层以及一层纳米纤维外包覆层;单根所述双层包芯纱线的直径为150-200μm;所述载药纳米纤维内包覆层的厚度为10-25μm,所述纳米纤维外包覆层的厚度为10-25μm;
所述增强芯层的材料为医用PLA纱线,单根所述医用纱线的直径为100-150μm;
所述载药纳米纤维内包覆层与所述纳米纤维外包覆层中的纳米纤维是纳米纤维复合材料,所述纳米纤维复合材料为乳酸-己内酯共聚物/明胶复合材料,所述载药纳米纤维内包覆层所载药物为萘普生钠;
所述乳酸-己内酯共聚物/明胶复合材料中,乳酸-己内酯共聚物与明胶所占重量百分数之比为60-90%:10-40%;所述载药纳米纤维内包覆层的载药量为乳酸-己内酯共聚物与明胶总重量的2.5-5%;
可改善粘连的载药修复支架的制备方法包括如下步骤:
(1)配制纺丝液:将乳酸-己内酯共聚物、明胶、萘普生钠按照配比溶于六氟异丙醇中得到A纺丝液;将乳酸-己内酯共聚物、明胶按照配比溶于六氟异丙醇中得到B纺丝液;
静电纺丝:以微米级医用PLA纱线为增强芯层,先采用所述A纺丝液在所述增强芯层的外周表面以静电纺丝法制得一层载药纳米纤维内包覆层,再采用所述B纺丝液接着在获得的所述载药纳米纤维内包覆层外以静电纺丝法制得一层纳米纤维外包覆层,由此获得双层包芯纱线;对所述双层包芯纱线进行交联;
(2)编织:采用多股数量的双层包芯纱线,利用电脑横机进行三维编织,针织机速为0.1m/s、NP值为8-10,结尾采用活扣设计,最终获得可改善粘连的载药修复支架。
2.根据权利要求1所述的一种可改善粘连的载药修复支架,其特征在于,所述A纺丝液与所述B纺丝液的浓度为0.05-0.5g/mL;
步骤1中所述静电纺丝法采用共轭电纺设备进行制备,设备参数设置:左、右推进器的推进速度0.02-0.05mL/min、接收辊接收纱线速度8-15rpm、缠绕辊的缠绕速度300-450rpm、正电压7-12kV、负电压7-12kV。
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