CN111910343A - 一种生物基的可生物降解/吸收纳米纤维膜的制备及其在医学领域中的应用 - Google Patents
一种生物基的可生物降解/吸收纳米纤维膜的制备及其在医学领域中的应用 Download PDFInfo
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Abstract
本发明公布了一种生物基的可生物降解/吸收纳米纤维膜的制备方法及其膜片在医学领域中的应用，属于生物医学材料技术领域。本发明以可生物降解/可吸收的聚酯材料作为原料，通过静电纺丝技术制备能用于医学领域的纤维制品。主要技术包括：静电纺丝得到聚酯薄膜，对制备的纺丝薄膜进行退火处理，进而得到生物可降解/吸收的医用手术纳米纤维膜。本发明通过调控聚酯材料的溶液配比，结合静电纺丝的接受距离、电压参数以及退火温度和时间，调节纤维的直径及厚度，从而获得力学性能、生物性能都符合要求的纤维膜。本发明所述制备方法简单，得到的成纤维膜力学性能和生物学性能良好，可用于脑膜修复、组织工程支架材料、药物释放膜、创伤修复等。
Description
技术领域
本发明涉及生物医学材料技术领域，特别涉及一种生物基的生物可降解/可吸收的医用纳米纤维膜的制备方法及其性能分析和在医学领域中的应用。
背景技术
静电纺丝技术是一种制备聚合物超细纤维的简单而有效的加工工艺。该方法的原理是将聚合物流体带上几千至上万伏高压静电，带电的聚合物液滴在电场力的作用下形成Taylor锥，并在锥顶点被加速，当电场强度足够大时聚合物液滴克服表面张力形成喷射细流，喷射细流在空中形成多种形式的不稳定流动并最终落在接地的接收装置上，可根据接收装置的不同，形成类似非织造布状或者有序排列的超细纤维状的聚合物纤维膜。
电纺纤维膜具有很大的比表面积及较高的孔隙率，因此赋予材料很强的吸附力以及良好的过滤性、阻隔性、黏合性和保温性等。纤维材料质轻柔软，便于手术操作，少量聚合物即能纺出所需面积的纤维膜，因此也降低了植入体内材料多而引起的副作用。纳米纤维构成的几何空间模拟细胞外基质结构具有仿生材料的性能。而通过纤维直径的可控性能够实现其降解速度的调控。因此电纺纳米纤维材料在生物膜、伤口包覆、组织工程、脑膜修复、药物释放以及术后防粘连等方面具有很广阔的应用。
目前超过100多种高分子通过电纺技术成功制备出超细纤维材料，其中包括合成的可生物降解的聚合物，如聚乳酸、聚乙交酯、聚己内酯及其共聚物等，天然高分子如蚕丝蛋白、纤维蛋白、胶原蛋白、壳聚糖、透明质酸、DNA等。天然高分子在生物相容性和降解性方面比合成高分子更有优势，更适合生物方面的应用，但由于天然高分子的加工性能普遍不好，所以到目前为止，仅有少数天然高分子实现了电纺。因此只要解决合成高分子生物相容性及降解性方面的问题，合成高分子材料又有本身加工性能好等优势，利用合成高分子材料进行电纺加工将逐渐成为研究的热门。
聚羟基丁酸酯是一种聚羟基脂肪酸酯(PHA)，一种聚酯类聚合物，于1925年，法国微生物学家Maurice Lemoigne首次分离取得。因其生物可降解、可生物合成，属于环境友好型材料逐渐被大众广泛研究，目前已超过90多种不同结构和不同性质的PHA被发现，但由于其脆性大、断裂伸长率低、热稳定性差，不易加工，一直未受到重视。但随着科技的发展，第四代PHA生物塑料被逐渐开发出来，此种材料成本更低，韧性更好而且是生物基材料。如本实验所用的聚-4-羟基丁酸酯是微生物在合适条件下在胞内积累的一种高分子聚合物，具有生物可降解性和生物相容性。可用于制作心脏瓣膜、血管等组织工程材料，也可用于制作支架、手术缝合线、骨板等医用植入材料。因此本实验将其与静电纺丝技术结合起来，制备实验所需的静电纺丝薄膜，进而发现其潜在的应用性能，使材料得到进一步的使用。
发明内容
本发明的其一目的是提供一种生物基的可生物降解/可生物吸收纳米纤维膜的制备方法。
本发明的其二目的是提供一种生物基的可生物降解/可吸收的纳米纤维膜。
本发明的第三个目的是提供一种生物基的可生物降解及吸收的纳米纤维膜的性能分析方法。
本发明的第四个目的是提供一种生物基的可生物降解及吸收的纳米纤维膜的应用。
本发明的第五个目的是提供含治疗药物的纳米成纤维膜及其制备方法。
本发明的可生物降解及吸收的聚合物纳米纤维膜材料的制备方法按以下步骤进行:
(1)高分子电纺丝溶液的配制:将聚酯材料溶解于有机溶剂中，将其于磁力搅拌器上搅拌均匀得到透明的高分子溶液，搅拌时间为5-24h，高分子溶液的浓度为5-30g/ml，进行药物释放用膜在高分子溶液中加入所需药物，加入药物量是高分子溶液的1/1000-1/100；
(2)静电纺丝工艺：将步骤(1)所配的高分子溶液装入静电纺丝设备的储液装置中，储液装置的活塞与注射器泵相连，且储液装置与喷丝头相连，调整溶液的供料速率为5-100ul/min,优选为5～30μl/min，喷丝头与接地的收集器之间的距离为5-30cm，优选为7～20cm；环境温度为10～60℃，优选为15-45℃；环境的空气流速为0-15m2/min，优选为0-10m2/min；开启高压电源，电压为5-30Kv，优选为10-20Kv；开启注射器泵，通过电流作用将喷射流喷射到收集器上，收集器表面覆有锡箔纸，便于收集薄膜，控制喷射时间进而得到不同厚度的可生物降解及可生物吸收的高分子纤维膜；其中收集器的温度范围10-60℃，优选的温度为15-45℃；喷丝的时间为8-24h，得到的纤维膜厚度为20μm-1000μm。
(3)退火灭菌处理：将步骤(2)得到的静电纺丝薄膜小心取下，于75％的酒精中冲洗浸泡1-15min，于紫外灯下通风晾干，然后将其放于真空干燥箱中30-45℃退火干燥12-60h，优选为12-24h，进而得到可以用于生物性能检测的生物可降解成纤维膜。
本实验所述的纤维膜厚度为20μm-1000μm，纤维直径为10nm-1000nm。
本实验所述的静电纺丝过程中，诸多参数影响静电纺丝过程的稳定性、连续性及电纺丝膜的质量等，如高分子溶液的浓度、溶剂的种类、流体的电荷密度、环境温度、环境中的空气流动速度、静电压、喷头的进料速度、收集器的接收距离、喷丝的时间等。
本发明是以氯仿、甲醇、六氟异丙醇中的一种或两种易挥发的有机溶剂制备电纺纤维膜，待膜成型后，通过退火干燥等处理使膜中残留的有机溶剂挥发干净，进而得到纯的聚酯纤维膜。
本实验所用的嵌入药物选自杀菌剂、生物酶、细胞生长因子，具体选自：AgNO3、纳米银，天然抗菌剂如黄连素、壳聚糖等，有机抗菌剂如有机酸、双胍类等，磺胺类药物如磺胺嘧啶等，喹诺酮类抗生素如诺氟沙星、环丙沙星等，胰岛素、头孢类、消炎药、抗生素、抗菌剂等药剂中的一种或一种以上的共混物。根据实际需求适当添加药物的含量，以不影响纺丝性能为准，亦可通过先制备纤维膜后浸泡的方法以在纤维膜中载入更多的药物。
本实验制备电纺丝成纤维膜所用的电纺设备简单主要包括：高压电源、储料容器、进料泵、喷丝头、收集装置、环境温度控制设备(红外灯)等。高压电源采用正负直流高压输出电源，输出的最大电压在30-50 kV，供料泵的输出方式采用多种输出频率的输出泵给料，一般最大输出范围在100-200ul/min，喷丝头材料选用不锈钢作为导体，喷丝头直径在1mm以下，收集装置为不锈钢良导体平板收集，电纺丝环境温度控制采用红外灯加热方式，一般最高温度不高于60℃。
所制备的电纺丝纤维膜在30-45℃真空干燥箱中真空干燥3-60小时。
本发明的可生物降解及可吸收的高分子电纺纤维膜中的纤维呈无序排列的结构。
将所制备的电纺丝纤维膜经过退火处理后，进行性能分析实验，包括热力学分析、力学性能测试、表观性能分析以及生物性能分析。其中热力学分析如DSC测试、TGA测试；力学性能如拉伸测试、溶胀实验；表观性能分析如SEM、接触角测试；生物性能分析如细胞毒性分析、细胞增殖实验、细胞在材料上的生长状态分析、大鼠皮下植入实验、热源分析、药物释放实验等。
本发明的可生物降解及可吸收的纳米电纺纤维膜材料可用于医用组织工程支架、脑膜修复、人造血管、药物释放膜、创伤修复、生物膜、术后防粘连材料及美容材料等。
本发明的特点：提供了一种可生物降解及可吸收的医用纳米纤维膜的制备方法，此方法简单可行，又提供了有效的性能分析方法以及该材料在医学领域中的应用，得到的成纤维膜力学性能以及生物性能都很好，满足生物医学材料的基本要求。
附图说明
图1为实施例制备的纳米纤维膜的扫描电镜图
图2为实施例制备的含药剂的纳米纤维膜药剂释放速率曲线图
图3为实施例制备的纳米纤维膜的力学性能图
图4为实施例制备的纳米纤维膜的接触角示意图
图5为实施例制备的纳米纤维膜的溶胀曲线图
图6为实施例制备的纳米纤维膜的DSC曲线图
图7为实施例制备的成纤维膜的TGA曲线图
图8为实施例制备的纳米纤维膜上细胞贴壁和活力检测结果示意图
图9为实施例制备的纳米纤维膜上细胞增殖示意图
图10为实施例制备的纳米纤维膜上细胞增殖数量曲线图
图11为实施例制备的纳米纤维膜上细胞存活/死亡对比图
图12为实施例制备的纳米纤维膜不同浓度浸提液对细胞存活影响图
图13为实施例制备的纳米纤维膜不同浓度浸提液对细胞毒性检测结果
图14为实施例制备的纳米纤维膜皮下植入切片结果示意图
图15为实施例制备的纳米纤维膜骨膜植入实验过程示意图
图16为静电纺丝装置的示意图
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。本发明制备生物可降解的医用成纤维膜的具体方法及其性能分析具体实施例包括如下几个方面：首先将聚酯材料溶解于有机溶剂中，得到高分子溶液；将所述的高分子溶液进行静电纺丝处理，得到静电纺丝薄膜；将静电纺丝薄膜进行退火和杀菌处理得到用于性能检测的静电纺丝纤维膜；静电纺丝过程中通过调控聚酯的种类和分子量，并结合静电纺丝的喷丝口大小、接收距离、电压参数、喷丝时间等，调节纤维的直径及厚度，制备不同分子量的聚酯纤维薄膜，并从扫描电镜形貌、热性能、力学性能、降解行为、亲水性、细胞毒性及防粘连效果等多方面进行比较，进而获得了综合性能优异的医用成纤维膜。
具体实施例如下，且本发明的保护范围不受以下实施例的限制。
实施例1
膜的制备如下：室温下将聚酯材料溶于三氯甲烷中，得到20wt％的聚酯-三氯甲烷高分子混合液，将该混合液于磁力搅拌器上搅拌过夜从而得到均匀透明的高分子溶液；将高分子溶液置于静电纺丝设备的给料注射器内，以10μl/min的进料速度进料；调节注射器针尖与静止接地板之间的距离为20cm；调整纺丝的环境温度为30℃；开启高压电源以及给料注射器泵，调节电压至20kV，调整环境的空气流速为0-5 m2/min，在静止接地板上覆盖锡铂纸，进而得到静电纺丝纤维薄膜，膜厚度为100-300μm。
将静电纺丝纤维薄膜从锡箔纸上小心取下，置于真空烘箱中退火干燥处理并保证有机溶剂彻底挥发，烘箱温度设置为40℃，干燥时间为24小时，得到成纤维膜，膜的SEM图像如图1所示。
实施例2
制备含有药物的电纺丝薄膜，方法与实施例1相似，不同之处在于向配置的高分子溶液中加入一种抗菌素试剂(头孢氨苄)，而且调整施加于电极上的电压。直接称取适量的药品，添加到高分子溶液中，经磁力搅拌器搅拌混匀，添加比例为1:99。调整电压为18kV，得到稳定的喷射流，其余参数皆与实施例1 相同。从而制备含有抗菌剂的薄膜。
药物释放速率的测定方法如下：将薄膜置于磷酸缓冲液(PBS)中，然后用紫外吸收光谱(262nm) 测量在缓冲液中试剂浓度随时间的变化，试剂在PBS中的释放速率曲线如图2所示。
实施例3
为评估电纺丝膜的力学性能、疏水性能、溶胀性能，分别将退火后的薄膜制成长75mm，宽4mm的拉伸条以及1cm2大小的正方形片。将拉伸条置于拉力实验机上进行测试，主要测试其拉伸强度和断裂韧性等，实验结果如图3所示，其中退火后电纺丝膜的拉伸强度大于2.5MPa，断裂韧性接近2MPa/m1/2，完全满足生物医学材料的要求；取3-5个正方形片进行接触角测试，结果如图4所示，测其接触角的大小为 128.73+5.54°，说明该材料为疏水材料；另外区3-5个正方形片，称其质量，然后置于PBS缓冲液中自然溶胀，然后在不同时间点测其浸润后的质量(每次测量前用滤纸吸去膜片表面的水分)，计算各时间点的溶胀比，最中得到膜片在缓冲液中溶胀比随时间的变化如图5所示。为评估电纺丝膜的热稳定性，我们取适量实施例1制备的薄膜，分别对其进行了DSC和TGA检测，实验结果如图6图7所示。
实施例4
为评估电纺丝薄膜的降解性能，我们对其原材料进行了体外生物降解实验，这是一种医药工业常用的方法，实施过程如下：将制备纤维膜的聚酯材料用压膜机压成1mm厚度的薄膜，将薄膜裁剪成1cm2大小的正方形膜片，将膜片浸泡于磷酸缓冲液(PBS)中，恒温于37℃，测量其质量损失随时间的变化。本实验结果显示该材料在体外降解较缓慢，时至1年时间只降解了10％左右。
实施例5
为评估电纺丝膜的生物相容性，我们首先进行了体外细胞实验，首先将退火处理后的薄膜用75％的酒精浸泡5min，然后于真空干燥箱中干燥过夜，再于超净工作台中紫外灭菌2h，将薄膜剪成1cm2大小的正方形膜片，将膜片用灭菌的双面胶贴于24孔板板底，进而分别进行各种细胞实验包括：细胞贴壁和活力检测、细胞增殖实验、细胞毒性检测。细胞贴壁和活力检测实验采用鬼笔环肽染色法对细胞进行染色，检测结果如图8所示，细胞贴壁状态良好，也有细胞进入纤维丝孔隙中生长；细胞增殖实验采用AM染色法，染活细胞呈绿色，如图9所示，细胞增殖明显如图10所示；细胞毒性检测-Live/Dead实验，用AM染活细胞呈现绿色，Ethd染死细胞呈现红色，结果如图11所示。
实施例6
为进一步评估电纺丝膜的生物相容性，我们分别用0.9％的生理盐水以及培养细胞所用的添加了胎牛血清的培养基作为浸提介质对电纺丝膜进行浸提，浸提比例为1:10(g/ml)，将材料全部没入浸提介质中，置于有盖的玻璃瓶中，将玻璃瓶转移至37℃恒温培养箱中静置，持续浸提72h。然后分别利用两种浸提液进行热源检测是试验、细胞毒性试验(MTT/Live/Dead)、溶血试验。热源检测取3只兔子注射前测量两次平均值作为基础肛温，注射0.9％生理盐水浸提液后每隔30min测量一次肛温，共测量6次，每只兔子测量6次的最高值减去基础体温均低于0.6℃，符合药典中对生物医学材料的要求；细胞毒性试验 Live/Dead结果如图12所示，MTT检测结果如图13所示；溶血实验结果显示溶血率为1.3％，符合医用材料的溶血指标(<5％)。
实施例7
为评估电纺丝膜在生物体内的生物相容性，我们将退火后的电纺丝薄膜按实施例5处理后再将其用环氧乙烷气体进行深层杀菌。将膜片密封在一个塑料袋中，放于环氧乙烷灭菌器中灭菌处理。使用300-450g 的SD大鼠，分开饲养，实验前后喂食相同的水和食物。将大鼠注射麻药使其麻醉，将膜片剪成1cm2大小的正方形膜片，将膜片植入大鼠皮下，用缝合针缝合伤口。本次实验分为3组每组3个平行，分别于3d， 7d，30d作为时间点进行取材，取材后对材料及其周围组织进行切片处理，结果如图14所示。
实施例8
为检测电纺丝膜作为脑膜材料的生物相容性和检测其对于脑脊液的防渗效果，我们将退火后的电纺丝薄膜按实施例7完全处理好后，使用2.5-4kg的新西兰兔进行脑膜试验，取3只经过免疫期饲养的兔子，分开饲养，实验前后喂食相同的水和食物。将兔子注射麻药使其麻醉，在其头部纵向划开4cm切口，剥离脑膜，露出头骨，用电钻制作直径1cm的骨窗，露出脑膜，用手术剪剪出合适大小自身骨膜，将脑脊液清除，将替代骨膜的本实验制备的膜片剪成合适大小，覆盖于脑膜上方开口处，用缝合针缝合骨膜和皮肤，消毒创口。将兔子放回笼中继续饲养。分别于1，3，6个月取材，取材后对材料及其周围组织进行切片处理，实验如图15所示。
总之，结果表明本发明制备的成纤维膜不论在力学性能、热稳定性还是生物相容性方面都表现出很好的结果，因此完全可以作为生物医学材料被广泛应用。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例中，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (15)
1.一种生物基的可生物降解/吸收的医用纳米纤维膜的制备方法，其特征在于，包括以下步骤：
(1)将聚酯材料按5wt％-30wt％的配比溶解于有机溶剂中，然后于磁力搅拌器上搅拌均匀得到透明的高分子溶液；
(2)将所述高分子溶液进行静电纺丝处理，得到静电纺丝薄膜。所述静电纺丝的电压为10-20Kv，接收距离为5-30cm，电纺丝溶液的进料速度为5-20μl/min，环境空气流速为0-10m2/min，环境温度为15-45℃。将锡箔纸置于收集器上，开启高压电源，开启注射器泵，将静电纺丝溶液喷射流喷射到锡箔纸上。在锡箔纸上得到聚合物静电纺丝纤维膜层，小心取下即得到静电纺丝成纤维膜；
(3)将所述静电纺丝薄膜在真空干燥箱中30-45℃退火干燥处理，得到生物可降解/可吸收的医用成纤维膜。
2.根据权利要求1所述的制备方法，其特征在于，所述聚酯材料为环境友好型的生物基材料聚羟基丁酸酯及其改性后材料。
3.根据权利要求1所述的制备方法，其特征在于，所述高分子溶液中聚酯材料占5wt％-30wt％。
4.根据权利要求所述的制备方法，其特征在于，所述步骤(1)中，所述有机溶剂为氯仿、甲醇、六氟异丙醇中的一种或两种。
5.根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中，所述静电纺丝制备过程中的温度为15-45℃。
6.根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中，所述静电纺丝时，高分子溶液的给料速度为5-100μl/min。
7.根据权利要求1所述的制备方法，其特征在于，所述步骤(2)中，所述静电纺丝薄膜的厚度为20μm-1000μm。
8.根据权利要求1所述的制备方法，其特征在于，所述步骤(3)中，所述干燥的温度为30-45℃，时间为12-60小时。
9.一种生物基的生物可降解/可吸收的医用纳米纤维材料的电纺纤维丝制成的生物可降解/可吸收的医用成纤维制品包括不同的可生物可降解/可吸收的复合物。
10.根据权利要求9所述的纤维制品，其中不同纤维的复合物是不同直径的纤维。
11.根据权利要求2所述的纤维制品，其中不同直径的纤维包括直径小于和大于1μm的纤维。
12.根据权利要求11所述的纤维制品，其纤维直径在10nm-1000nm之间。
13.根据权利要求9所述的纤维膜制品的退火温度和时间分别为30-45℃，持续12-24小时。
14.根据权利要求13所述的纤维膜制品其力学性能符合要求，拉伸强度大于2.5MPa。
15.一种根据权利要求1-8所述的可生物降解及吸收的纳米纤维膜材料的用途，其特征是：所述的成纤维膜其力学性能优良，包括热力学和拉伸强度，该材料为疏水性材料，该材料的生物学性能良好包括对细胞毒性小，不影响细胞的增殖，细胞可贴附于膜上生长，生物相容性良好，可进行药物输送等，因此其可用于脑膜修复、组织工程支架材料、药物释放膜、创伤修复、生物膜、术后防粘连材料等使用。
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