CN114796622B - 一种含聚乳酸生物医用植入膜的制备方法 - Google Patents

一种含聚乳酸生物医用植入膜的制备方法 Download PDF

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CN114796622B
CN114796622B CN202210449281.3A CN202210449281A CN114796622B CN 114796622 B CN114796622 B CN 114796622B CN 202210449281 A CN202210449281 A CN 202210449281A CN 114796622 B CN114796622 B CN 114796622B
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polymer material
polylactic acid
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CN114796622A (zh
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杨义浒
陈锐
刘浦
湛露
林峰
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Shenzhen Jusheng Biotechnology Co ltd
Shenzhen Esun Industrial Co ltd
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Abstract

本发明公开了一种含聚乳酸生物医用植入膜的制备方法，包括以下步骤：取生物可吸收高分子材料层作为底膜片平铺；将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；取另外的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；对所有膜片进行均匀碾压，使之贴合均匀、平整；所述生物可吸收高分子材料层的厚度控制在100‑1000nm；所述生物活性体层的厚度控制在1‑20μm；所述生物活性体层是羟基磷灰石涂层、含氟羟基磷灰石涂层、磷酸三钙涂层、磷酸八钙涂层、生物玻璃涂层或氧化钛涂层。本发明所制得的植入膜不仅满足修复材料应具备的基本特点，而且可以诱导组织生长，具有防黏连效果，个体化给药，实现有针对性的治疗目的。

Description

一种含聚乳酸生物医用植入膜的制备方法
技术领域
本发明属于医用材料技术领域，特别是涉及一种含聚乳酸生物医用植入膜的制备方法。
背景技术
聚乳酸羟基乙酸(PLGA)是聚乳酸(PLA)的一种衍生物，与PLA一样， PLGA是一种无毒无刺激性的生物高分子材料，生物相容性和生物可吸收性良好，具有较好的可加工性能和机械强度；且作为一种生物医用高分子材料，目前PLGA在医学领域得到了广泛的应用，例如：外科手术用防黏连膜、组织工程支架材料、药物载体等，且与PLA相比，PLGA最大的优点在与可以通过调节乳酸与羟基乙酸的比例来调节PLGA的降解时间以适应不同的手术部位。但是，PLGA与PLA具有相同的缺点，即强度较高，单韧性较差，这严重影响了 PLGA在临床的应用范围，因而在对PLGA韧性要求较高的场合，则须对PLGA 进行增韧。
聚己内酯(PCL)也是一种医用较多的生物高分子材料，且其优点是韧性较好，且同样具有较好的生物相容性和生物可降解性。因而将PLGA与PCL进行复合能够有效的解决PLGA韧性较差的问题。本发明将PLGA和PCL交替进行静电纺丝得到的复合膜，既具有较高的强度，同时又具有良好的韧性，同时在PLGA和PCL静电纺丝层上开有规则的空洞，能达到防止组织黏连的目的，又有一定的透气和透液性，有利于伤口的愈合，这拓宽了PLGA的应用范围。
目前，含聚乳酸及其各种衍生物的医用植入材料已经得到了开发，甚至有些已经投入生产/应用，但是现有相关技术普遍存在以下问题：
采用常规原料制备的植入膜材料的透过性不佳，材料植入后对生物体影响过大；采用常规方法制备的植入膜材料由于其表面性质(包括膜材料本身的特性与生物组织接触面积较大)导致容易黏连，这基本上直接阻止了材料在重要组织位置的应用；生物材料的降解时间不稳定，受到影响较大，降解时间不可控，对后续恢复和治疗非常不利。要解决上述问题，本领域的研究人员普遍把目光集中在开发新的聚乳酸衍生物方面，但这种研究方向是进展缓慢且成本很高的，并且开发出新的衍生物后，其临床应用效果也需要很长的时间来验证。
发明内容
为解决上述问题，我们主要想使用目前已有的材料，尤其是已经得到实验室或临床广泛开发或应用的材料，配合创新的步骤参数等手段，制备内部、表面结构独特的膜材料，这样制备的膜材料往往能够表现出多种不同特性，应用于不同领域，并且由于基础材料已经经过实验室或临床验证的无生物毒性或其他有害作用，避免了这一风险，可以快速投入应用，且原材料可以直接采购或通过多种可选方法制备，也能够大大降低研发和生产成本。
在上述初衷的指导下，我们开发出了多种独特的含聚乳酸或其衍生物的医用植入材料(包括膜材料)，本发明提供其中的一种：
本发明主要解决的技术问题是提供一种含聚乳酸生物医用植入膜的制备方法，所制得的植入膜不仅满足修复材料应具备的基本特点，而且可以诱导组织生长，具有防黏连效果，个体化给药，实现有针对性的治疗目的。
为解决上述技术问题，本发明采用的一个技术方案是：一种含聚乳酸生物医用植入膜的制备方法，包括以下步骤：
(1)取生物可吸收高分子材料层，进行预处理；
(2)取预处理后的生物可吸收高分子材料层作为底膜片平铺；
(3)将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；
(4)取另外的预处理后的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；
(5)将所得膜片放入密闭空间中，先抽真空后，再进行空气加压，结束后缓慢减压。
优选地，步骤1所述预处理包括：将生物可吸收高分子材料层(膜)放入高压蒸汽灭菌锅中，高压蒸汽灭菌。
优选地，所述高压蒸汽灭菌，温度为121℃，时间为50-90min。
优选地，所述高压蒸汽灭菌锅，媒介采用本领域常规的水蒸气。
更优选地，所述预处理，还包括，高压蒸汽灭菌结束后取出，自然冷却干燥；或者，高压蒸汽灭菌结束后取出干燥后，快速冷却至低温并且在降温的同时抽真空。
优选地，所述快速冷却至低温，冷却速度大于50℃/min，所述低温，温度为-10～-20℃；所述抽真空，真空度为10-20Pa，抽真空时间为10-15min。
优选地，步骤5所述将所得膜片放入密闭空间中，将底膜片向下，平放在加热板上。
优选地，步骤5所述抽真空为程序抽真空：先保持空气压力在 1.00×102-1.00×103Pa之间，时间1-2min，在保持空气压力在5-80Pa之间，时间 5-10min。
优选地，步骤5所述抽真空期间，加热板温度保持在30-35℃。
优选地，步骤5所述空气加压，可采用空气加压器等仪器。
优选地，步骤5所述空气加压，保持压力在2-4个大气压之间，时间5-10min。
优选地，步骤5所述空气加压期间，加热板温度保持在45-70℃。
所述生物可吸收高分子材料层的厚度控制在100-1000nm；所述生物活性体层的厚度控制在1-20μm。
所述生物活性体层是羟基磷灰石涂层、含氟羟基磷灰石涂层、磷酸三钙涂层、磷酸八钙涂层、生物玻璃涂层或氧化钛涂层。
所述生物活性体层中的生物功能活性物质分别选自羟基磷灰石、磷酸三钙、壳聚糖、青藤碱、骨形态发生蛋白中的一种或多种。
进一步地说，所述生物可吸收高分子材料层的厚度控制在300-1000nm；所述生物活性体层的厚度控制在3-15μm。
进一步地说，所述生物可吸收高分子材料层是含有高分子材料的无纺布。
进一步地说，所述生物可吸收高分子材料层中的高分子材料由以下材料中的至少一种制成：聚乳酸、聚羟基乙酸、聚己内酯、聚乙烯醇、聚对二氧环己酮、聚氨基酸衍生碳酸酯、聚原酸酯、聚三亚甲基碳酸酯。
进一步地说，所述生物可吸收高分子材料层中的高分子材料选自左旋聚乳酸、右旋聚乳酸、消旋聚乳酸中的一种或多种。
进一步地说，所述生物活性体层是羟基磷灰石涂层。
进一步地说，所述生物活性体层的生物活性体中加入有抗生素、抗凝血剂和免疫制剂。
进一步地说，所述生物活性体层中掺杂活性组元。
进一步地说，所述活性组元为氮或者钛。
进一步地说，所述生物活性体层中的生物功能活性物质选自壳聚糖和骨形态发生蛋白。
本发明的有益效果：
本发明实施例的医用植入补片包括生物活性体层，以及覆盖于生物活性体层两侧的生物可吸收高分子材料层，通过预处理和后处理，实现了多层结构膜材料表面结构和内部结构的改变，制备的膜材料产品表面结构能够避免黏连，内部结构配合特定的层间关系，能够有效控制降解速度。该医用植入补片不仅满足修复材料应具备的基本特点，而且可以诱导组织生长，具有防黏连效果，其中的生物活性体层中可加入抗菌药和/或抗肿瘤药，根据病人需求进行个体化治疗，达到局部给药有针对性治疗的目的等。
具体实施方式
下面对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。
实施例1一种含聚乳酸生物医用植入膜的制备：
(1)取生物可吸收高分子材料层，进行预处理；
(2)取预处理后的生物可吸收高分子材料层作为底膜片平铺；
(3)将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；
(4)取另外的预处理后的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；
(5)将所得膜片放入密闭空间中，先抽真空后，再进行空气加压，结束后缓慢减压。
步骤1所述预处理包括：将生物可吸收高分子材料层(膜)放入高压蒸汽灭菌锅中，高压蒸汽灭菌。
所述高压蒸汽灭菌，温度为121℃，时间为50min。
所述高压蒸汽灭菌锅，媒介采用本领域常规的水蒸气。
更所述预处理，还包括，高压蒸汽灭菌结束后取出，自然冷却干燥；或者，高压蒸汽灭菌结束后取出干燥后，快速冷却至低温并且在降温的同时抽真空。
所述快速冷却至低温，冷却速度大于50℃/min，所述低温，温度为-10℃；所述抽真空，真空度为10-20Pa，抽真空时间为10min。
步骤5所述将所得膜片放入密闭空间中，将底膜片向下，平放在加热板上。
步骤5所述抽真空为程序抽真空：先保持空气压力在1.00×102-1.00×103Pa 之间，时间1min，在保持空气压力在5-10Pa之间，时间5min。
步骤5所述抽真空期间，加热板温度保持在30-35℃。
步骤5所述空气加压，可采用空气加压器等仪器。
步骤5所述空气加压，保持压力在2-3个大气压之间，时间5min。
步骤5所述空气加压期间，加热板温度保持在45-70℃。
所述生物可吸收高分子材料层的厚度控制在300-500nm；所述生物活性体层的厚度控制在3-5μm。
所述生物可吸收高分子材料层是含有高分子材料的无纺布。
所述生物可吸收高分子材料层中的高分子材料由聚乳酸制成。
所述生物活性体层是羟基磷灰石涂层。
所述生物活性体层的生物活性体中加入有抗生素、抗凝血剂和免疫制剂。
实施例2一种含聚乳酸生物医用植入膜的制备：
(1)取生物可吸收高分子材料层，进行预处理；
(2)取预处理后的生物可吸收高分子材料层作为底膜片平铺；
(3)将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；
(4)取另外的预处理后的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；
(5)将所得膜片放入密闭空间中，先抽真空后，再进行空气加压，结束后缓慢减压。
步骤1所述预处理包括：将生物可吸收高分子材料层(膜)放入高压蒸汽灭菌锅中，高压蒸汽灭菌。
所述高压蒸汽灭菌，温度为121℃，时间为90min。
所述高压蒸汽灭菌锅，媒介采用本领域常规的水蒸气。
更所述预处理，还包括，高压蒸汽灭菌结束后取出，自然冷却干燥；或者，高压蒸汽灭菌结束后取出干燥后，快速冷却至低温并且在降温的同时抽真空。
所述快速冷却至低温，冷却速度大于50℃/min，所述低温，温度为-20℃；所述抽真空，真空度为10-20Pa，抽真空时间为15min。
步骤5所述将所得膜片放入密闭空间中，将底膜片向下，平放在加热板上。
步骤5所述抽真空为程序抽真空：先保持空气压力在1.00×102-1.00×103Pa 之间，时间2min，在保持空气压力在60-80Pa之间，时间10min。
步骤5所述抽真空期间，加热板温度保持在30-35℃。
步骤5所述空气加压，可采用空气加压器等仪器。
步骤5所述空气加压，保持压力在3-4个大气压之间，时间10min。
步骤5所述空气加压期间，加热板温度保持在45-70℃。
所述生物可吸收高分子材料层的厚度控制在800-1000nm；所述生物活性体层的厚度控制在10-15μm。
所述生物可吸收高分子材料层是含有高分子材料的无纺布。
所述生物可吸收高分子材料层中的高分子材料由聚乳酸制成。
所述生物活性体层是羟基磷灰石涂层。
所述生物活性体层的生物活性体中加入有抗生素、抗凝血剂和免疫制剂。
实施例3一种含聚乳酸生物医用植入膜的制备：
(1)取生物可吸收高分子材料层，进行预处理；
(2)取预处理后的生物可吸收高分子材料层作为底膜片平铺；
(3)将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；
(4)取另外的预处理后的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；
(5)将所得膜片放入密闭空间中，先抽真空后，再进行空气加压，结束后缓慢减压。
步骤1所述预处理包括：将生物可吸收高分子材料层(膜)放入高压蒸汽灭菌锅中，高压蒸汽灭菌。
所述高压蒸汽灭菌，温度为121℃，时间为60min。
所述高压蒸汽灭菌锅，媒介采用本领域常规的水蒸气。
更所述预处理，还包括，高压蒸汽灭菌结束后取出，自然冷却干燥；或者，高压蒸汽灭菌结束后取出干燥后，快速冷却至低温并且在降温的同时抽真空。
所述快速冷却至低温，冷却速度大于50℃/min，所述低温，温度为-15℃；所述抽真空，真空度为10-20Pa，抽真空时间为15min。
步骤5所述将所得膜片放入密闭空间中，将底膜片向下，平放在加热板上。
步骤5所述抽真空为程序抽真空：先保持空气压力在1.00×102-1.00×103Pa 之间，时间2min，在保持空气压力在50-70Pa之间，时间10min。
步骤5所述抽真空期间，加热板温度保持在30-35℃。
步骤5所述空气加压，可采用空气加压器等仪器。
步骤5所述空气加压，保持压力在2-3个大气压之间，时间10min。
步骤5所述空气加压期间，加热板温度保持在45-70℃。
所述生物可吸收高分子材料层的厚度控制在500-700nm；所述生物活性体层的厚度控制在5-10μm。
所述生物可吸收高分子材料层是含有高分子材料的无纺布。
所述生物可吸收高分子材料层中的高分子材料由聚乳酸制成。
所述生物活性体层是羟基磷灰石涂层。
所述生物活性体层的生物活性体中加入有抗生素、抗凝血剂和免疫制剂。
对比例1与实施例3的区别在于：未对生物可吸收高分子材料层做预处理。
对比例2与实施例3的区别在于：对生物可吸收高分子材料层做预处理的方法包括：采用干燥加热加压方式，121℃100KPa处理60min。
对比例3与实施例3的区别在于：对生物可吸收高分子材料层做预处理的方法包括：采用干燥加热，121℃处理60min。
对比例4与实施例3的区别在于：对生物可吸收高分子材料层做预处理的方法包括：采用干燥加压方式，100KPa处理60min。
对比例5与实施例3的区别在于：步骤5不做抽真空处理。
对比例6与实施例3的区别在于：步骤5不采用空气加压，而采用上下加热板加热加压，参数不变。
对上述实施例及对比例所得产品进行检测：
首先对力学性能进行检测，本发明实施例1-3所得产品其拉伸强度均高于 5MPa，断裂伸长率均高于110％，这使得本发明所得产品适用于各个部位，包括关节等需运动部位或结构复杂部位，本发明采用的步骤1、5中的操作和参数，对材料整体的力学性能是有贡献的。分别取上述产品置于80℃去离子水中和 37℃PBS缓冲液中保温，分别在第5、6、7……13天称取剩余重量计算重量保留率(剩余重量与原始重量的比值)，我们发现，实施例1-3在PBS缓冲液中第 5天保留率不超过85％，也不低于80％，第8天保留率不超过62％，也不低于58％，且实施例1-3分别在第13天、第11天、第10天保留率达到22.7％、27.1％、 25.6％，并在其后的一天无法继续检测重量保留率(剩余固体物质无法取出)，可见本发明公开的方法，能够有效控制材料在生物环境下的降解过程，不会降解过快也不会过慢，对创口愈合具有积极作用，并且当生物活性体中掺杂药物时，能够有效控制药物缓释。对比例中，除对比例3外，均降解缓慢，在第13 天重量保留率均高于50％。对比例3在第8天即达到保留率24.8％，第10天无法继续检测保留率。可见对比例的降解速度均存在问题，不适用于实际应用。抗黏连试验：选100只健康大鼠作为腹腔损伤试验对象，雌雄各半，体重200g 左右，随机分为10组，每组10只，分别对应实施例1-3、对比例1-6和空白对照组。按照动物试验规程，对大鼠进行禁食、麻醉、脱毛、消毒处理，无菌下取前下腹正中切口约2cm，提出盲肠后，置于纱布上5分钟，使浆膜干燥，用单向锉刀在整个盲肠浆膜上造成点状出血伤口，再滴入适量(1-2滴)无水酒精在创面上，将样品膜置于动物创面局部贴敷，连续缝合关腹，术后青霉素抗炎3 天，观察情况，于术后在1周、2周和8周处死大鼠后解剖，对损伤部位的黏连程度进行观察，本发明实施例1-3、对比例5-6损伤部位修复良好，基本无黏连，第二周后基本无炎症反应，，对比例1、2、4在第1、2周黏连明显，第8周黏连情况有所改善，有轻微的炎症反应；对比例3从始至终黏连严重，且损伤部位未见修复，炎症反应强烈。
Figure BDA0003616645790000091
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效结构变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。

Claims (8)

1.一种含聚乳酸生物医用植入膜的制备方法，其特征在于：包括以下步骤：
(1)取生物可吸收高分子材料层，进行预处理；
(2)取预处理后的生物可吸收高分子材料层作为底膜片平铺；
(3)将生物活性体均匀涂覆于所述底膜片之上，形成生物活性体层；
(4)取另外的预处理后的生物可吸收高分子材料层作为顶膜片覆盖于所述生物活性体层之上；
(5)将所得膜片放入密闭空间中，先抽真空后，再进行空气加压，结束后缓慢减压；
步骤1所述预处理包括：将膜状的生物可吸收高分子材料层放入高压蒸汽灭菌锅中，高压蒸汽灭菌；
所述预处理，还包括，高压蒸汽灭菌结束后取出，自然冷却干燥；或者，高压蒸汽灭菌结束后取出干燥后，快速冷却至-10～-20℃并且在降温的同时抽真空。
2.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：所述高压蒸汽灭菌，温度为121℃，时间为50-90min。
3.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：所述快速冷却至低温，冷却速度大于50℃/min，所述低温，温度为-10～-20℃；所述抽真空，真空度为10-20Pa，抽真空时间为10-15min。
4.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：步骤5所述抽真空为程序抽真空：先保持空气压力在1.00×102-1.00×103Pa之间，时间1-2min，在保持空气压力在5-80Pa之间，时间5-10min。
5.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：步骤5所述抽真空期间，加热板温度保持在30-35℃。
6.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：步骤5所述空气加压，保持压力在2-4个大气压之间，时间5-10min。
7.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：步骤5所述空气加压期间，加热板温度保持在45-70℃。
8.根据权利要求1所述的含聚乳酸生物医用植入膜的制备方法，其特征在于：所述生物可吸收高分子材料层的厚度控制在100-1000nm；所述生物活性体层的厚度控制在1-20μm。
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