CN112138145B - 一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片及其制备方法和应用 - Google Patents
一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片及其制备方法和应用 Download PDFInfo
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- CN112138145B CN112138145B CN202010798503.3A CN202010798503A CN112138145B CN 112138145 B CN112138145 B CN 112138145B CN 202010798503 A CN202010798503 A CN 202010798503A CN 112138145 B CN112138145 B CN 112138145B
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Abstract
本发明公开了一种基于3D打印技术制备微针阴模，并以此为模板制备一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片，并提供了其制备方法及应用。本发明采用3D打印技术制备了微针的阴模，其能够简化微针模板的制备流程，具有尺寸可控、规模化、精确度高及经济高效等优点。同时，本发明基于3D打印制备的阴模，使用生物相容性好的聚合物作为微针基质，并复合生长因子和抗菌药物，采用离心灌注法构建了分层微针贴片。该微针贴片具有良好的生物相容性及微创无痛等优点，能够刺穿溃疡面并即刻溶解，将装载的治疗药物有效释放到溃疡面深层，实现抑制菌膜形成和促进溃疡愈合的双重目的，并有效缩短溃疡的愈合时间。
Description
技术领域
本发明涉及生物医用材料技术领域，具体涉及一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片及其制备方法和应用。
背景技术
复发性阿弗他溃疡(RAU)是最常见的口腔黏膜溃疡类疾病，患病率高达66％，且复发率较高。由于口腔黏膜中丰富的神经分布，RAU常伴有疼痛，严重影响患者的进食、语言等功能。RAU病因及发病机制尚未完全明确，目前国内外还没有根治的有效方法，临床上的治疗以局部对症治疗为主，治疗以减少复发次数、延长间歇期、减轻疼痛、促进愈合为主要目标，临床局部用药有含漱剂、含片、喷雾剂、凝胶及膜剂等。但由于口腔环境特殊，局部用药会受到不断分泌的唾液及咀嚼肌群运动的影响，药物在口内停留时间短，作用于病变部位的时间不足，局部有效药物浓度低，因而疗效欠佳。研究表明，机体组织通过止血、炎症、增生与重新塑形四个阶段，来实现对损伤刺激的生理反应，以达到伤口愈合的目的。每一个阶段都是紧密联系的，在此过程中各种生长因子、细胞因子和趋化因子等发挥着重要的作用。其中，表皮生长因子(EGF)、碱性成纤维细胞生长因子(bFGF)、白细胞介素2(IL-2)、转化生长因子β1(TGF-β1)等细胞因子在在RAU治疗中具有潜在的价值。此外，将抗菌药物如西吡氯铵(CPC)、复方氯己定、碘甘油、抗菌肽、纳米银等局部应用于溃疡部位直接杀灭或抑制病原菌，也能有效缩短溃疡愈合时间，促进溃疡愈合。
微针具有无痛、微创、药物缓释可控、使用方便等优势，其作为新的透皮药物递送系统出现并受到广泛的关注，在疫苗输送、肿瘤治疗、伤口愈合、糖尿病治疗等方面得到广泛的应用，其具有广阔的市场应用前景，在口腔溃疡的治疗方面具有潜在的应用前景，然而目前鲜有报道。微针的制备方法主要采用模板法，以金属模板为阴模，将微针材料注入到阴模后制备，翻制出微针，因此微针模板的质量将影响微针的制备水平。目前微针模板制备的方法主要有：反应离子刻蚀微加工技术，基于X射线光刻技术的MEMS 加工技术，可控的拉延制造技术，激光刻花技术等，上述制备方法均需要昂贵的设备，复杂的技术流程并且不符合工厂规模化制备的要求。
3D打印技术作为一种新的增材制造技术，具有规模化，集约化，程序化及精确化等技术优点，其被认为人类继19世纪的蒸汽机和20世纪的电气化之后的第三次“革命”。目前按照打印方式可分为：熔融沉积型打印，喷墨打印，立体光刻成型打印(光固化打印)及选择性激光烧结打印等。光固化打印常用的材料是光固化树脂，其在紫外光的照射下，能够固化成型，因此可以在计算机的控制下实现模型的逐层打印，并最终实现整个模型的打印，相较于其他打印方式，该方法具有精度高(20微米)，打印速度快的优点。且通过光固化打印出的模型颜色透明，利于观察微针材料的灌入情况。
发明内容
本发明的目的之一在于为改善现有微针阴模制作方法复杂、成本较高，尺寸固定且难以更改的缺陷，发明了一种基于3D打印技术快速、成本低廉、规模化、个性化制作微针阴模的方法。
为了实现上述目的，本发明提供的技术方案为：一种用于微针阴模制作的3D打印技术，实现了微针阴模的快速、规模化、尺寸可控的制作，该方法具有经济高效、高度可重复性的优点。具体技术方案如下：
(1)根据需要在3DMax软件上制作所需尺寸模型，微针尺寸大小按需任意设计，单位面积上微针数目按需任意设计，微针高度为200微米-3毫米，并导出STL格式用于打印。
(2)采用光固化打印机进行打印，打印所采用的墨水涉及光固化打印机所使用的所有打印材料，但并不仅限于此。
本发明的另一目的就是针对上述现有技术中治疗复发性阿弗他溃疡的效果不佳，提供了一种低成本、高效率、操作简便的用于治疗复发性阿弗他溃疡的可溶性载药微针贴片及其制备方法，该微针贴片具有良好的生物相容性且无体内毒性，能够较快的促进溃疡的愈合，同时能够对溃疡的创面起到一定的保护作用。
为了实现上述目的，本发明提供的技术方案为：一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片，微针贴片由载药针体和微针基板组成，所负载的药物包括生长因子和抗菌剂。是将可溶性聚合物基质溶液与生长因子和抗菌剂混合，置于上述3D打印微针模板上，自然干燥后形成微针贴片。具体技术方案如下：
(1)在水浴和磁力搅拌的条件下，将可溶性聚合物基质溶解于去离子水中，制备微针基板溶液。其中水浴温度为0～90℃，聚合物基质和水的质量比为1～10：10～50；
(2)将上述可溶性聚合物基质溶液与生长因子、抗菌剂混合得到载药针体制作液。其中，聚合物基质涉及所有的天然及部分人工合成的聚合物，如透明质酸、羧甲基纤维素、聚乙烯吡咯烷酮、海藻酸钠、壳聚糖、胶原、明胶、聚乙烯醇等中的一种或几种，生长因子为表皮生长因子、碱性成纤维细胞生长因子、白细胞介素2、转化生长因子β1 中的一种或几种，抗菌剂为西吡氯铵、复方氯己定、碘甘油、抗菌肽、纳米材料抗菌剂中的一种或几种。以重量为基准，生长因子、抗菌剂和聚合物基质溶液的质量比为 (0.05～0.15)×10-5：0.05～0.25：1～10；
(3)将载药的针体制作液平铺到3D打印的微针模板上，并置于10mL离心管中以3000～20000rpm转速离心1-3h，使所述微针模板上的针孔充满针体制作液，获得注液微针模板；
(4)将步骤(3)中的注液微针模板放于真空干燥箱中，将气压调整至0.1～0.5Pa，干燥温度为0℃～37℃，获得干燥微针模板；
(5)将微针基板制作液平铺到步骤(4)中的干燥微针模板上，干燥后获得成型微针贴片；
(6)将步骤(5)中成型微针贴片从微针模板上剥离，获得可溶性载药微针贴片。
本发明具有以下有益效果：本发明采用3D打印技术制作微针阴模，具有精度高、规模化、尺寸可控及经济高效等优点。所提供的可溶性载药微针贴片，采用透明质酸、羧甲基纤维素、聚乙烯吡咯烷酮、海藻酸钠、壳聚糖、胶原、明胶、聚乙烯醇等，其生物安全性高，具有优异的生物相容性、体内可降解性，无潜在的刺激性和免疫原性；所负载药物，是常见的用于治疗复发性阿弗他溃疡的临床药物，能有效地减少菌斑形成并促进溃疡愈合；通过微针技术，可以将上述药物直接注入溃疡基底层，通过针尖在组织液中的快速溶解而释放药物，将药物集中分布在微针针尖，提高局部有效药物浓度且节约用药成本。此外本发明提供的制备方法，制备方法简单明了，制备条件容易满足，易实现批量化生产。
附图说明
下面结合附图对本发明作进一步详细的描述。
图1是本发明采用3D打印技术制备的微针阴模。
图2是本发明提供的可溶性载药透明质酸微针贴片的显微照片。
图3是本发明提供的分别在治疗前、治疗第三天、治疗第五天、治疗第七天空白对照组、透明质酸微针贴片组、重组牛碱性成纤维细胞生长因子-透明质酸微针贴片组、西吡氯铵-透明质酸微针贴片组、可溶性载药透明质酸微针贴片组、常规药物治疗组的大体照片。
图4是本发明提供的分别在治疗前、治疗第三天、治疗第五天、治疗第七天空白对照组、透明质酸微针贴片组、重组牛碱性成纤维细胞生长因子-透明质酸微针贴片组、西吡氯铵-透明质酸微针贴片组、可溶性载药透明质酸微针贴片组、常规药物治疗组的H&E 染色照片。
具体实施方式
下面结合附图，对本发明的具体实施方式作进一步的详细描述。
本发明提供的可溶性载药微针贴片，以重量为基准，生长因子、抗菌剂和聚合物基质溶液的质量比为(0.05～0.15)×10-5：0.05～0.25：1～10。
实施例1：3D打印微针阴模
S1，通过3DMax设计符合本发明要求尺寸的微针阴模模型，用于本发明的微针阴模为直径0.75mm，高3mm的圆锥状微针，以STL格式文件保存。
S2，将STL文件导入光固化3D打印机，并采用3D打印的光固化树脂进行打印，切片厚度为0.05mm。
S3，待打印完成后，使用异丙醇溶液浸泡模型10min，以洗去多余树脂，获得微针阴模。
实施例2可溶性载药透明质酸微针贴片的制备
S1，采用实施例1中的3D打印微针模板；
S2，制备透明质酸基板制作液(10％，w/v)：称取1g透明质酸钠(分子量4万～10万)溶于9mL去离子水中，磁力搅拌下搅拌24h，确保充分溶胀；
S31，将针体制作液重组牛碱性成纤维细胞生长因子、西吡氯铵与透明质酸基板制作液的重量比为(0.08～0.1)×10-5：0.05～0.1：1到步骤S1中的微针模板上，并置于10mL离心管中以3000rpm转速离心1h，使所述微针模板针尖制作液填满针孔；
S32，将步骤S31中的含有针尖制作液的微针模板放于真空干燥箱中，将气压调整至 0.1Pa，干燥温度为37℃，真空干燥24h获得针尖成型的微针模板；
S33，将微针基板制作液平铺到步骤S32中的针尖成型的微针模板上，置于10mL离心管中以3000rpm转速离心45min，获得注液微针模板；
S4，将步骤S33中的注液微针模板放于真空干燥箱中，将气压调整至0.1Pa，干燥温度为37℃，干燥24h获得干燥微针模板；
S5，将微针基板制作液到步骤S4中的干燥微针模板上，干燥后获得成型微针贴片；
S6，将步骤S5中成型微针贴片从微针模板上剥离，获得可溶性载药透明质酸微针贴片。
本实施例中制备的可溶性载药透明质酸微针贴片(见图1)，仅为针尖的部分含有重组牛碱性成纤维细胞生长因子和西吡氯铵，此微针贴片针体和基板材质为能在水中快速溶解的透明质酸钠构成，刺入口腔黏膜后接触到组织液与唾液而快速溶解释放出重组牛碱性成纤维细胞生长因子和西吡氯铵。
实施例3可溶性载药海藻酸钠微针贴片的制备
S1，采用实施例1中的3D打印微针模板；
S2，制备海藻酸钠基板制作液(5％，w/v)：称取0.5g海藻酸钠溶于9.5mL去离子水中，50℃磁力搅拌24h，确保充分溶胀；
S31，将针体制作液重组人表皮生长因子、复方氯己定与海藻酸钠基板制作液的重量比为(0.05～0.15)×10-5：0.05～0.1：1到步骤S1中的微针模板上，并置于10mL离心管中以3000rpm转速离心1h，使所述微针模板针尖制作液填满针孔；
S32，将步骤S31中的含有针尖制作液的微针模板放于真空干燥箱中，将气压调整至 0.1Pa，干燥温度为37℃，真空干燥24h获得针尖成型的微针模板；
S33，将微针基板制作液平铺到步骤S32中的针尖成型的微针模板上，置于10mL离心管中以3000rpm转速离心45min，获得注液微针模板；
S4，将步骤S33中的注液微针模板放于真空干燥箱中，将气压调整至0.1Pa，干燥温度为37℃，干燥24h获得干燥微针模板；
S5，将微针基板制作液到步骤S4中的干燥微针模板上，干燥后获得成型微针贴片；
S6，将步骤S5中成型微针贴片从微针模板上剥离，获得可溶性载药海藻酸钠微针贴片。
实施例4可溶性载药透明质酸微针贴片的制备
该实施例与实施例1相同，不同之处在于：针体制作液为重组牛碱性成纤维细胞生长因子与透明质酸溶液，其重量比为(0.08～0.1)×10-5：1。
实施例5可溶性载药透明质酸微针贴片的制备
该实施例与实施例1相同，不同之处在于：针体制作液为西吡氯铵与透明质酸溶液，其重量比为0.05～0.1：1。
实施例6可溶性透明质酸微针贴片的制备
该实施例与实施例1相同，不同之处在于：针体制作液为质量分数为10％透明质酸溶液。
实验例
对本发明提供的可溶性载药透明质酸微针贴片治疗复发性阿弗他溃疡的疗效评估
受试对象：
雄性SD大鼠，6至8周龄，体重180-220g，购于兰州大学生物医学实验中心，应用冰醋酸化学灼烧法建立大鼠复发性阿弗他溃疡动物模型。
实验分组：将建立的复发性阿弗他溃疡大鼠按治疗方式分为空白对照组(8只)、透明质酸微针贴片组(8只)、重组牛碱性成纤维细胞生长因子-透明质酸微针贴片组(8只)、西吡氯铵-透明质酸微针贴片组(8只)、可溶性载药透明质酸微针贴片组(8只)、常规药物治疗组(8只)，其中除空白对照组与透明质酸微针贴片组外，其余各组中重组牛碱性成纤维细胞生长因子与西吡氯铵的药物浓度分别均为：0.08～0.1μg/mL，5mg/mL。
治疗方案：空白对照组不予任何处理，治疗组分别使用本发明实施例1、例2、例3与例4的微针贴剂和临床常规药物贝复新(重组牛碱性成纤维细胞生长因子外用凝胶)+ 依信(西吡氯铵含漱液)处理，每日1次，治疗周期为7天。
疗效评价：分别于用药后3天、5天、7天观察溃疡愈合情况。7天后处死大鼠，切取溃疡面黏膜组织，放置于4％多聚甲醛内固定,酒精脱水后二甲苯透明石蜡包埋、切片，常规行H&E染色，观察各组大鼠黏膜组织病理变化。
实验结果：
由图3的结果可知，在用药5天后可溶性载药透明质酸微针贴片组黏膜颜色恢复，溃疡面完全消失，溃疡愈合；其余组别用药7天后溃疡局部黏膜颜色发红，黏膜表面仍存在小的溃疡面。
由图4的结果可知，可溶性载药透明质酸微针贴片组全层黏膜愈合，其余组别局部黏膜愈合，并有炎性细胞浸润。
动物实验表明本发明提供的可溶性载药透明质酸微针贴片治疗复发性阿弗他溃疡，使用后口腔溃疡面积明显减小，愈合时间明显缩短，疗效显著。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种用于治疗复发性阿弗他溃疡的可溶性载药微针贴片的制备方法，其特征在于，包括以下步骤：
(1)在水浴和磁力搅拌的条件下，将透明质酸溶解于去离子水中，制备微针基板溶液；其中水浴温度为0～90℃，透明质酸和水的质量比为1～10：10～50；
(2)将上述透明质酸溶液与重组牛碱性成纤维细胞生长因子、西吡氯铵混合得到载药针体制作液，以重量为基准，重组牛碱性成纤维细胞生长因子、西吡氯铵和透明质酸溶液的质量比为(0.05～0.15)×10-5：0.05～0.25：1～10；
(3)将载药的针体制作液平铺到3D打印的微针模板上，并置于10mL离心管中以3000～20000rpm转速离心1-3h，使所述微针模板上的针孔充满针体制作液，获得注液微针模板；
(4)将步骤(3)中的注液微针模板放于真空干燥箱中，将气压调整至0.1～0.5Pa，干燥温度为0℃～37℃，获得干燥微针模板；
(5)将微针基板制作液平铺到步骤(4)中的干燥微针模板上，干燥后获得成型微针贴片；
(6)将步骤(5)中成型微针贴片从微针模板上剥离，获得可溶性载药微针贴片。
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