CN106474556A - 一种多孔软骨修复用支架材料及其制备方法 - Google Patents
一种多孔软骨修复用支架材料及其制备方法 Download PDFInfo
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- CN106474556A CN106474556A CN201611001758.2A CN201611001758A CN106474556A CN 106474556 A CN106474556 A CN 106474556A CN 201611001758 A CN201611001758 A CN 201611001758A CN 106474556 A CN106474556 A CN 106474556A
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- D—TEXTILES; PAPER
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Abstract
本发明公开了一种多孔软骨修复用支架材料及其制备方法,该方法采用生物相容性较好的材料透明质酸钠和魔芋葡甘聚糖作为原材料,通过流延法制成魔芋葡甘聚糖膜,然后采用静电纺丝的方法将透明质酸钠复合于魔芋葡甘聚糖膜的两面,从而制备出“三明治”结构的透明质酸钠/魔芋葡甘聚糖多孔支架材料。该材料具有制备工艺简单、成本低廉、力学性能优良、生物相容性优良等优势,前期细胞实验表明,该支架材料具有优良生物性能,是一种具有应用前景的软骨修复材料。
Description
技术领域
本发明涉及一种多孔软骨修复支架及其制备方法,属于生物医用材料领域。
技术背景
关节软骨一旦遭到破坏便很难得到修复。直到现在,关节软骨缺损的修复一直是临床面临的难题,这主要是因为软骨组织内无血管,且软骨细胞缺乏迁徙能力,不能迅速聚集到创伤部位所致。关节软骨中纤维含量少,只含有少量的胶原纤维,基质的主要化学成分是蛋白质多糖。关节软骨不同于血管化的组织,由于没有血供,且软骨细胞埋于稠厚的细胞外基质中,无法移动到损伤部位参与修复,且缺乏细胞分化所必须的母细胞及细胞迁徙所必须的理想环境,这样就使得即使是极小的软骨缺损也难于自然修复。
目前临床上传统的治疗方法主要有微骨折术、软骨下骨钻孔术、软骨下磨削术、自体软骨移植和自体软骨细胞移植术等,但是,研究结果显示,这些修复方法只能暂时的缓解疼痛等症状,其修复部位主要由纤维软骨填充而不是透明软骨,其最终结局还是修复部位软骨的退化坏死。组织工程技术的兴起和快速发展为软骨缺损的修复提供了崭新的思路。
在骨组织工程的研究中,支架材料、种子细胞和诱导因子及其生物环境起着非常重要的作用。理想的软骨支架材料应具备的基本条件主要有:①能对软骨细胞生长提供力学支持;②对细胞无毒害作用,有较好的生物相容性,不易引起炎性反应,并可以促进种子细胞黏附;③具有良好的生物活性,能够帮助维持软骨细胞的表型表达;④应该具备多孔疏松的三维结构以保存大量细胞,并且有利于营养物质和氧气的进入和细胞代谢产物的排出,从而有利于软骨细胞的新陈代谢;⑤具备很好的生物降解性,利于细胞增殖,并且要求支架材料的降解速率应与细胞的增殖速率相匹配。
现今有多种支架材料被用于软骨组织工程,按其来源不同大体可分为天然的和人工合成的两种。目前用于软骨组织工程的人工合成材料主要有:聚乳酸、聚羟基乙酸、聚乳酸一羟基乙酸、聚乙二醇、丙交酯乙交酯共聚酯、嵌段共聚物,D—磷酸三钙、聚乙烯醇等;天然支架主要有:透明质酸、胶原、几丁质、藻酸、小肠黏膜下层、纤维蛋白原等。人工合成的支架材料因其来源广泛、易加工成所需的形状等优势近年来得到了广泛的发展,相比于天然支架材料,它具有极好的生物力学性能,并且可以根据需要调整其理化特性和生物降解速率,但因其较弱的亲合性和一定程度的细胞毒性作用限制了它的应用。而天然支架材料因其较好的亲合性而有利于细胞的黏附和增殖被视为细胞生长的天然载体。它具有良好的生物可降解性,经过去抗原处理后生物相容性好,还含有生长因子类物质,可以进一步促进细胞的识别、黏附、增殖和保持分化特性。其缺点是力学性能较差,降解速度快、大量制备困难,不同批次质量差异波动较大,且因其来自于天然生物体,处理不当尚有传播疾病的危险。但是目前所研究的各种支架材料各有其优缺点,并没有任何一种支架材料是公认的最佳组织工程软骨支架材料,因此我们仍然要致力于寻找更好的支架材料来为临床应用提供更多更好的选择。
魔芋是一种天南星科魔芋属的草本植物,魔芋葡甘聚糖(Konjacghhcomannan,简称 KGM)是魔芋的主要成分,在干魔芋块茎中的含量高达55%~ 60%。它是由 D-葡萄糖(G)和D-甘露糖(M)按 1:1.6或1:1.69的摩尔比通过β-1,4-吡喃糖苷键结合的复合多糖。KGM 通常带有短支链,并含有少量乙酰基。KGM具有良好的生物相容性、生物可降解性以及凝血性,使得KGM在抗菌消炎、止血、促进伤口愈合等方面得到广泛应用;如固定化载体、外用材料及组织工程支架、药物控释材料等。所以充分利用魔芋葡甘聚糖良好的生物特性开发其在生物材料领域应用具有优良的发展前景。
透明质酸钠,是一种酸性粘多糖,广泛分布于人体的***中,在眼玻璃体、关节腔中几乎以纯态形式存在,以其独特的分子结构和理化性质在机体内显示出多种重要的生理功能,如润滑关节,调节血管壁的通透性,调节蛋白质,水电解质扩散及运转,促进创伤愈合等,同时透明质酸钠作为软骨基质中重要的蛋白多糖,在维持软骨细胞表型、促进软骨机制分泌等方面也发挥着重要的作用。综合分析研究着研究成果表明,软骨支架材料的研究与选取,仍是软骨组织工程学科研究的重点与难点方向。
发明内容
本发明要解决的技术问题是现有软骨修复支架材料性能不理想,成本高等问题。
本发明目的在于提供一种多孔软骨修复用支架材料,所述多孔软骨修复用支架材料依次由透明质酸钠、魔芋葡甘聚糖、透明质酸钠构成三层结构,即类似于“三明治”结构,结构示意图如图4所示。
本发明的另一目的在于提供一种多孔软骨修复支架的制备方法,按如下步骤进行:
(1)按甘油、乳酸、蒸馏水体积比为(0.6~1.2):(1~2):(90~400)的比例将甘油、乳酸、蒸馏水混合均匀,并按10~25g/L的比例将魔芋葡甘聚糖溶解于其中,在常温常压下,搅拌混匀得到混合溶液。
(2)将步骤(1)制得的混合溶液用微波加热2~8min,然后冷却至室温,负压脱泡后在模具中流延成膜,干燥后得到魔芋葡甘聚糖膜。
(3)按二甲基甲酰胺、蒸馏水体积比为(1~5):(0.5~4)的比例将二甲基甲酰胺、蒸馏水混合均匀,并按8~25g/L的比例将透明质酸钠溶解于其中,得到透明质酸钠纺丝液。
(4)将步骤(3)得到的透明质酸纺丝液,通过静电纺丝的方法复合于步骤(2)得到的魔芋葡甘聚糖膜的两面,得到所述多孔软骨修复支架。
优选的,本发明步骤(2)中微波加热的温度为80~120℃。
优选的,本发明步骤(2)中负压脱泡的条件为:在400~760毫米汞柱的负压下脱泡10~20h。
优选的,本发明步骤(2)中干燥温度为40~60℃,时间为10-48小时。
优选的,本发明步骤(4)中静电纺丝条件为:在正电压为8~22Kv,接收距离为10~20cm,进料速度为0.01mm/min~1.00mm/min,纺丝环境温度为50±10℃条件下进行。
本发明中所述软骨修复支架的抗拉强度为40~60MPa,纤维丝的直径分布在60~180μm。
本发明采用生物相容性好的可降解生物材料魔芋葡甘聚糖与透明质酸钠为基本原料,制备出一种用于软骨修复的魔芋葡甘聚糖/透明质酸钠多孔支架,为软骨组织工程领域的发展提供了一种新的极具应用前景的选择,魔芋葡甘聚糖价格较低,能有效降低材料成本,另外流延法制备的魔芋葡甘聚糖膜其操作简单,易于成型,且具有较高的抗拉强度;采用静电纺丝在魔芋葡甘聚糖膜两侧电纺透明质酸钠,为支架材料提供较好的多孔结构。
本发明的有益效果:
(1)支架材料魔芋葡甘聚糖层采用流延法成型,该方法操作简单且容易成型,并且材料的抗拉强度为40~60MPa,有较高的抗拉强度,满足软骨支架条件。
(2)利用静电纺丝在魔芋葡甘聚糖膜的两面复合透明质酸钠纳米纤维,通过改变静电纺丝相关参数,能较好控制其纤维质量及纤维直径分布,且该结构适合营养物质的运输与细胞的长入。
(3)该支架材料制备方法简单,对设备要求低,其原材料价格低廉,可应用与工业化生产。
附图说明
图1为实施例1制备得到的软骨修复支架材料的显微形貌图。
图2为实施例2制备得到的软骨修复支架材料的显微形貌图。
图3为实施例3制备得到的软骨修复支架材料的显微形貌图。
图4为软骨修复支架材料的结构示意图。
具体实施方式
下面通过实施例对本发明方法作进一步详细说明,但本发明保护范围不局限于所述内容。
实施例1
本实施例所述软骨修复支架材料的制备方法,具体内容如下:
(1)将0.6ml甘油、1ml乳酸和100ml蒸馏水混合均匀,并加入1.016g魔芋葡甘聚糖使其溶解于其中,在常温常压下,以300r/min的速度搅拌6h;得到魔芋葡甘聚糖混合溶液。
(2)将步骤(1)制得的混合溶液置于微波炉中高火(100℃,800瓦)加热3.5min,冷却至室温,在400~760毫米汞柱的负压下脱泡16h,然后在直径为150mm,深为3mm的聚四氟乙烯磨具中流延成膜,置于50℃干燥箱干燥12h,得到魔芋葡甘聚糖膜。
(3)将18ml二甲基甲酰胺和25ml蒸馏水混合均匀,并加入0.43g透明质酸钠使其充分溶解于其中,得到透明质酸钠纺丝液。
(4)通过静电纺丝方法,设定正电压为12Kv,接收距离为12cm,进料速度为1.0mm/min,纺丝环境温度为48℃,将步骤(3)得到的透明质酸钠纺丝液复合于步骤(2)得到的魔芋葡甘聚糖膜的两面,得到所述多孔软骨修复支架。
(5)采用本实施例得到的软骨修复支架材料抗拉强度为45MPa,纤维丝的直径分布在70~100μm,细胞毒性为0级,复合标准,其微观形貌如图1所示,由图可以看出纺丝效果较好,丝较为平滑均匀。
实施例2
本实施例所述软骨修复支架材料的制备方法,具体内容如下:
(1)将0.8ml甘油、2ml乳酸和200ml蒸馏水混合均匀,并加入4.056g魔芋葡甘聚糖使其溶解于其中,在常温常压下,以300r/min的速度搅拌7h;得到魔芋葡甘聚糖混合溶液。
(2)将步骤(1)制得的混合溶液置于微波炉中高火(100℃,800瓦)加热5min,冷却至室温,在400~760毫米汞柱的负压下脱泡10h,然后在直径为150mm,深为3mm的聚四氟乙烯磨具中流延成膜,置于45℃干燥箱干燥48h,得到魔芋葡甘聚糖膜。
(3)将22.5ml二甲基甲酰胺和7.5ml蒸馏水混合均匀,并加入0.36g透明质酸钠使其充分溶解于其中,得到透明质酸钠纺丝液。
(4)通过静电纺丝方法,设定正电压为16Kv,接收距离为17cm,进料速度为0.06mm/min,纺丝环境温度为48℃,将步骤(3)得到的透明质酸钠纺丝液复合于步骤(2)得到的魔芋葡甘聚糖膜的两面,得到所述多孔软骨修复支架。
(5)采用本实施例得到的软骨修复支架材料抗拉强度为50MPa,纤维丝的直径分布在80~150μm,细胞毒性为0级,复合标准,其微观形貌如图2所示,由图可以看出纺丝效果较好,丝比较平滑,且少有断丝。
实施例3
本实施例所述软骨修复支架材料的制备方法,具体内容如下:
(1)将1.2ml甘油、2ml乳酸和400ml蒸馏水混合均匀,并加入10.08g魔芋葡甘聚糖使其溶解于其中,在常温常压下,以300r/min的速度搅拌7.5h。得到魔芋葡甘聚糖混合溶液。
(2)将步骤(1)制得的混合溶液置于微波炉中(100℃,800瓦)高火加热8min,冷却至室温,在400~760毫米汞柱的负压下脱泡20h,然后在直径为150mm,深为3mm的聚四氟乙烯磨具中流延成膜,置于60℃干燥箱干燥10h,得到魔芋葡甘聚糖膜。
(3)将16.5ml二甲基甲酰胺和13.5ml蒸馏水混合均匀,并加入0.6g透明质酸钠使其充分溶解于其中,得到透明质酸钠纺丝液。
(4)通过静电纺丝方法,设定正电压为20Kv,接收距离为18cm,进料速度为0.02mm/min,纺丝环境温度为52℃,将步骤(3)得到的透明质酸钠纺丝液复合于步骤(2)得到的魔芋葡甘聚糖膜的两面,得到所述多孔软骨修复支架。
(5)采用本实施例得到的软骨修复支架材料抗拉强度为45MPa,纤维丝的直径分布在65~135μm,细胞毒性为0级,复合标准,其微观形貌如图3所示,由图可以看出纤维均匀性好,并且纤维比较光滑平直。
Claims (6)
1.一种多孔软骨修复用支架材料,其特征在于:所述多孔软骨修复用支架材料依次由透明质酸钠、魔芋葡甘聚糖、透明质酸钠构成三层结构。
2.权利要求1所述多孔软骨修复用支架材料的制备方法,其特征在于,具体包括以下步骤:
(1)按甘油、乳酸、蒸馏水体积比为(0.6~1.2):(1~2):(90~400)的比例将甘油、乳酸、蒸馏水混合均匀,并按10~25g/L的比例将魔芋葡甘聚糖溶解于其中,在常温常压下,搅拌混匀得到混合溶液;
(2)将步骤(1)制得的混合溶液用微波加热2~8min,然后冷却至室温,负压脱泡后在模具中流延成膜,干燥后得到魔芋葡甘聚糖膜;
(3)按二甲基甲酰胺、蒸馏水体积比为(1~5):(0.5~4)的比例将二甲基甲酰胺、蒸馏水混合均匀,并按8~25g/L的比例将透明质酸钠溶解于其中,得到透明质酸钠纺丝液;
(4)将步骤(3)得到的透明质酸纺丝液,通过静电纺丝的方法复合于步骤(2)得到的魔芋葡甘聚糖膜的两面,得到所述多孔软骨修复支架。
3.根据权利要求2所述多孔软骨修复用支架材料的制备方法,其特征在于:步骤(2)中微波加热的温度为80~120℃。
4.根据权利要求2所述多孔软骨修复用支架材料的制备方法,其特征在于:步骤(2)中负压脱泡的条件为:在400~760毫米汞柱的负压下脱泡10~20h。
5.根据权利要求2所述多孔软骨修复用支架材料的制备方法,其特征在于:步骤(2)中干燥温度为40~60℃,时间为10-48小时。
6.根据权利要求2所述多孔软骨修复支架的制备方法,其特征在于:步骤(4)中静电纺丝条件为:在正电压为8~22Kv,接收距离为10~20cm,进料速度为0.01mm/min~1.00mm/min,纺丝环境温度为50±10℃条件下进行。
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