CN113694005A - 一种可溶性微针阵列及其应用 - Google Patents

一种可溶性微针阵列及其应用 Download PDF

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CN113694005A
CN113694005A CN202110525340.6A CN202110525340A CN113694005A CN 113694005 A CN113694005 A CN 113694005A CN 202110525340 A CN202110525340 A CN 202110525340A CN 113694005 A CN113694005 A CN 113694005A
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microneedle array
soluble
skin
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夏登宁
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Shenzhen Xianjian Consulting Management Partnership LP
Shenzhen Lifan Biomedical Technology Co ltd
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Shenzhen Lifan Biomedical Technology Co ltd
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Abstract

本发明涉及生物医用和化妆品材料技术领域，涉及一种含有外泌体的可溶性微针阵列及其在治疗皮肤组织损伤，去除疤痕、色素沉着和皱纹，抗皮肤衰老中的应用。一种可溶性微针阵列，在基板上或基板上形成1根针体以上的微针阵列，且微针和/或基板内含外泌体和水溶性基质。其制备方法为将含外泌体和水溶性基质的溶液灌注于微针模具中，使得可形成微针部分和基板部分；通过干燥，脱模即得。所述的微针阵列可耐受向皮肤表层及/或皮肤角质层刺入的强度、局部不引起疼痛或出血，刺入表皮的含有外泌体的微针部分是可溶解性或生物降解性，作用安全、高效，使用方便，具有实现临床转化的应用前景。

Description

一种可溶性微针阵列及其应用
技术领域
本发明涉及生物医用和化妆品材料技术领域，涉及一种含有外泌体的可溶性微针阵列及其在皮肤组织损伤修复，去除疤痕、色素沉着和皱纹，抗皮肤衰老中的应用。
背景技术
外泌体（Exosome）是指从细胞中分离出来的包含mRNA 和蛋白质的小膜，直径在30-150nm之间。外泌体的功能取决于其所来源的细胞类型，参与机体组织修复、免疫应答、抗原提呈、细胞迁移、细胞分化、肿瘤侵袭等。外泌体在皮肤修复与再生中发挥重要作用，能促进成纤维细胞的增殖和迁移、血管新生、调节皮肤炎症反应、抑制瘢痕形成，可用于组织损伤修复，疤痕，色素沉着和去除皱纹。组织学分析发现，外泌体可以在伤口愈合早期促进胶原的合成来提高修复速度，晚期则抑制胶原的合成来抑制疤痕组织的形成。在皮肤修复领域，已有研究证明干细胞外泌体在创伤修复中主要依靠旁分泌的方式来促进皮肤创伤的修复。相比于直接利用细胞进行组织修复，外泌体具有以下优势：1）安全性好：利用外泌体来进行组织修复，可以避免产生血管阻塞、突变成瘤、免疫排斥反应等风险。2）易储存、稳定性好：外泌体的外膜可以保护其内容物。3）作用快效率高：外泌体可以直接被细胞摄入，影响靶细胞的功能，提高了作用效率。4）无伦理限制：外泌体在应用时没有相关的伦理限制。5）来源广泛：外泌体可以从多种细胞的培养上清、多种体液、血液中提取。在医学上外泌体可用于疾病诊断，组织修复和药物载体，具有广阔的应用前景。
为了使有效成分在皮肤上发挥功效，通常采用含有有效成分的外用制剂，如软膏，乳膏制剂胶带制剂，贴剂，通过局部涂布或贴附，有效成分经皮吸收，在皮下发挥作用。上述制剂存在以下缺点：在使用过程中由于出汗，清洗导致制剂脱落或消失。尤其是由于角质层的阻止作用，有效成分难以透过角质层进入皮肤组织深部；尤其当有效成分为大分子或诸如外泌体的纳米颗粒时更加难以吸收，而发挥期望的作用。
在临床使用的外泌体多为冻干粉，使用之前溶于水。当干细胞外泌体溶液直接涂抹在肌肤表面上，由于表面肌肤的角质层的阻隔作用而难以进入肌肤内层的目标细胞，既表皮层的肌底细胞。冻干粉中的细胞外泌体活性成分在破皮导入才能达到最大的应用效果，如溶解后皮下或皮内注射、采用滚针、激光导入、电光，CO2介导法来在肌肤上产生微小伤口，外泌体成分顺着破皮之后细胞通道直达肌底细胞，发挥作用。上述使用方法，设备昂贵，需要专业的人员操作才能完成，而无法自己完成；此外使用过程中伴随疼痛，出血，甚至感染，而无法接受。
微针(Microneedles，MNs)是一种呈针状的微米级精细阵列结构，微针既可以辅助药物透过角质层进入皮肤，其长度又不足以触及皮下痛觉神经，具有无损伤、无痛感等优势。常见的微针材料主要包括硅、金属以及聚合物材料。其中，无机材料由于生物相容性差、脆性高、易折断于皮肤中而易产生安全性问题。而可溶性聚合物材料能够在皮肤内完全溶解或降解，使用简便，且具有良好的生物相容性而被广泛应用于微针的制备。
为了解决角质层对有效成分的透皮吸收的阻滞作用，近年来将有效成分制备成微针阵列的研究比较多。主要通过将有效成分加入到微针阵列或基板上或二者都含有有效成分。微针阵列能有效刺破胶质层，使有效成分溶于表皮，或基板上的有效成分通过微针阵列在胶质层上形成的微孔扩散进入表皮甚至皮肤深部。由于微针未深入到真皮层，因而不会引起疼痛和出血。
因此研究和开发用于解决皮肤问题（组织损伤，去除疤痕、色素沉着和皱纹，抗皮肤衰老）含有外泌体的可溶性微针阵列是成为目前亟待解决的问题。
发明内容
鉴于现有技术存在的问题，本发明的目的是提供一种含有外泌体的可溶性微针阵列及其应用。本发明提供的微针阵列包括基板和基板上的可溶性微针（至少2根针体），外泌体存在于微针或微针基板和微针，能够有效无痛地给皮肤递送外泌体，能够有效修复组织损伤，去除疤痕和色素沉着、去除皱纹和抗皮肤衰老；使用方便，且生产工艺简单，在临床医学和美容学中具有广阔的应用前景。
为了实现上述目的，本发明提供以下技术发案。
一种可溶性微针阵列，在基板上或基板上形成1根针体以上的微针阵列，且微针和/或基板内含外泌体和水溶性基质。
进一步地，所述的外泌体是来源于人脐带间充质干细胞或骨髓间充质干细胞。
进一步地，所述的外泌体的浓度为103~1010个/g，按蛋白含量计算1ng/mg~0.5mg/mg。
进一步地，所述微针的根部直径为50~1000µm，顶端直径为1µm~100µm，长度为50~5000µm，邻近的微针顶端距离为100~2000µm；微针呈实心圆锥体，且具有足够的机械强度穿透角质层进入皮肤表皮。
进一步地，所述水溶性基质包括水溶性糖类物质和水溶性聚合物。
所述的水溶性糖类物质为蔗糖、麦芽糖、乳糖、海藻糖中的一种或多种。
所述的水溶性聚合物为聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、聚谷氨酸、聚谷氨酸钠、透明质酸、透明质酸钠、胶原蛋白，明胶，羟丙甲基纤维素，海藻酸（钠）中的一种或多种。
所述可溶性微针阵列的制备方法包括以下步骤：（1）将含外泌体和水溶性基质的溶液灌注于微针模具中；（2）通过室温或进行加热或真空干燥蒸发水分；（3）加入基板层成分，进一步通过室温或进行加热或真空干燥蒸发水分；（4）将针尖和基板结合后从模具中剥离。
所述可溶性微针阵列在治疗组织损伤，去除疤痕、色素沉着、皱纹和抗皮肤衰老中的应用。
与现有技术比，本发明的有益效果如下。
本发明提供的可溶性微针阵列可耐受向皮肤表层及/或皮肤角质层刺入的强度、局部不引起疼痛或出血，刺入表皮的含有外泌体的微针部分是可溶解性或生物降解性，作用安全、高效，使用方便，具有实现临床转化的应用前景。
本发明中可溶性微针阵列采用含有外泌体与水溶性基质的溶液作为微针材料，将溶液注入微针模具中，干燥后，得到固态实心可溶性微针阵列及基板。该固态的可溶性微针阵列可在干燥环境中进行常温保存。通过本发明的制备方法得到的可溶性微针阵列为固态，该微针阵列中并不存在活体细胞，因此本发明提供的可溶性微针阵列不会涉及到活体细胞存储的问题，有效避免了现有技术中各种干细胞在应用过程中的难以保存问题。同时人脐带间充质干细胞易于分离培养，且不存在胚胎干细胞所面临的伦理学问题。
本发提供的可溶性微针阵列可应用于临床治疗紫外线导致的组织损伤，去除疤痕、色素沉着、皱纹和抗皮肤衰老，具有实现临床转化的应用前景。
附图说明
图1是本发明提供的可溶性微针阵列一部分模型断面图。
图2是实施例1采用糖制备的含脐带间质干细胞来源的外泌体微针阵列。
图3是猪皮肤使用实例1制备的微针阵列后，用甲紫溶液染色染色后皮肤的形貌。
图4是实施例1制备的微针阵列用于皮肤后，基板的形貌。
图5是实施例2采用水溶性高分子材料透明质酸和胶原蛋白制备的含脐带间质干细胞来源外泌体的微针阵列。
图6是猪皮肤使用实例2制备的微针阵列后，用甲紫溶液染色染色后皮肤的形貌。
图7是实施例2制备的微针阵列用于皮肤后，基板的形貌。
具体实施方式
下面将结合附图和具体实施例，对本发明的技术方案进行清楚、完整地描述，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做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。
外泌体是来源于人脐带间充质干细胞或人骨髓间充质干细胞。
一种可溶性微针阵列，在基板上或基板上形成1根以上的微针阵列，且微针和/或基板内含外泌体和水溶性基质，可溶性微针阵列一部分模型断面图如图1所示。所述的外泌体是来源于人脐带间充质干细胞或骨髓干细胞。所述的外泌体的浓度为103~1010个/g，按蛋白含量计算1ng/mg~0.5mg/mg。所述的外泌体存在于微针或微针基板和微针。所述微针的根部直径为50~1000µm，顶端直径为1µm~100µm，长度为50~5000µm，邻近的微针顶端距离为100~2000µm。通过上述尺寸的优化，微针可耐受向皮肤表层及/或皮肤角质层刺入的强度、局部不引起疼痛或出血，刺入表皮的含有外泌体的微针部分是可溶解性或生物降解性。
所述含有外泌体的微针阵列的制备方法为：将含外泌体和水溶性基质的溶液灌注于微针模具中，使得可形成微针部分和基板部分。通过干燥，从模具中剥离，即得含外泌体的微针阵列。水溶性基质包括水溶性糖类物质和水溶性聚合物。其中，所述的水溶性糖类物质为蔗糖、麦芽糖、乳糖、海藻糖等中的一种或多种。所述的水溶性聚合物为聚乙烯醇（PVA）、聚乙烯比咯烷酮（PVP）、羧甲基纤维素钠（CMC-Na）、聚谷氨酸（γ-PGA）、透明质酸钠、胶原蛋白、明胶、羟丙甲基纤维素、海藻酸（钠）等中的一种或多种。
实施例1 采用糖制备的含脐带间质干细胞来源的外泌体微针阵列。
取来源于脐带间质干细胞提取的外泌体20微升（外泌体溶液中蛋白含量2.1mg/ml；平均粒径为108nm，颗粒数为2.1×109个/mL），蔗糖20mg，羧甲基纤维素钠1mg，加纯水至100微升，配置成含外泌体的微针材料的溶液，倒入微针的模具中，使溶液灌注针孔中。室温干燥，抽真空进一步干燥，加入含同浓度外泌体的基板层成分，进一步通过室温或进行加热或真空干燥蒸发水分；然后用胶布脱模即得微针阵列，如图2所示。
将除毛的离体猪皮肤固定于平板上保持完全延展，将制备好的外泌体微针阵列按压于猪皮肤上20s，置皮肤上20min后撕下微针阵列，在显微下观察微针形态变化。离体皮肤使用甲紫溶液染色5min，用75%乙醇清洗皮肤表面，显微下观察离体皮肤微针处理处染色情况，如图3所示；微针能有效穿透皮肤角质层，针尖部分溶于皮肤内部，只留下微针阵列基板，如图4所示。
实施例2采用水溶性高分子材料透明质酸和胶原蛋白制备的含脐带间质干细胞来源外泌体的微针阵列。
取脐带间质干细胞提取的外泌体10微升（外泌体溶液中蛋白含量2.1mg/ml；平均粒径为108nm，颗粒数为2.1×109个/mL），透明质酸15mg，胶原蛋白10mg，泊洛沙姆4070.5mg加纯水至100微升，配置成含外泌体的微针材料的溶液，导入微针的模具中，抽真空，使溶液灌注针孔中，抽真空进一步干燥，然后用胶布脱模即得微针阵列，如图5所示。
将离体猪皮肤固定于平板上保持完全延展，将制备好的外泌体微针按压于已处理好的猪耳皮肤上20s，置皮肤上20min后撕下微针，显微下观察微针形态变化；离体皮肤使用甲紫溶液染色5min，用75%乙醇清洗皮肤表面，显微下观察离体皮肤微针处理处染色情况，如图6所示。微针能有效穿透皮肤，针尖部分溶于皮肤内部，如图7所示。

Claims (13)

1.一种可溶性微针阵列，其特征在于，在基板上或基板上形成1根针体以上的微针阵列，且微针和/或基板内含外泌体和水溶性基质。
2.如权利要求1所述的可溶性微针阵列，其特征在于，所述的外泌体是来源于人源间充质干细胞。
3.如权利要求1所述的可溶性微针阵列，其特征在于，所述的外泌体的浓度为103~1010个/g，按蛋白含量计算1ng/mg~0.5mg/mg；外泌体存在于微针和/或基板内。
4.如权利要求1所述的可溶性微针阵列，其特征在于，所述微针的根部直径为50~1000µm，顶端直径为1µm~100µm，长度为50~5000µm，邻近的微针顶端距离为100~2000µm。
5.如权利要求1所述的可溶性微针阵列，其中针尖为圆锥状实心针。
6.如权利要求1所述的可溶性微针阵列，其特征在于，针尖能具有足够的机械强度穿透皮肤角质层进入皮肤表皮。
7.如权利要求1所述的可溶性微针阵列，其特征在于，基板层内的物质能通过针尖在皮肤角质层形成的孔道扩散进入表皮和真皮层。
8.如权利要求1所述的可溶性微针阵列，其特征在于，针尖进入皮肤后能溶解于皮肤。
9.如权利要求1所述的可溶性微针阵列，其特征在于，所述水溶性基质包括水溶性糖类物质和/或水溶性聚合物。
10.如权利要求9所述的可溶性微针阵列，其特征在于，所述的水溶性糖类物质为蔗糖、麦芽糖、乳糖、海藻糖中的一种或多种。
11.如权利要求9所述的可溶性微针阵列，其特征在于，所述的水溶性聚合物为聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、聚谷氨酸、聚谷氨酸钠、透明质酸、透明质酸钠、胶原蛋白，明胶，羟丙甲基纤维素，海藻酸（钠）中的一种或多种。
12.如权利要求1所述的可溶性微针阵列的制备方法，为注模法，其特征在于，将含外泌体和水溶性基质的溶液灌注于微针模具中，使得形成微针部分和基板部分；通过干燥，脱模即得微针阵列。
13.如权利要求1所述的可溶性微针阵列在皮肤组织损伤修复，去除疤痕/色素沉着/皱纹或抗皮肤衰老中的应用。
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