用光刻胶喷涂和柔性掩制备医用注射用针尖上的微细电极
Summary
指电极的制作方法 (间隙和宽度:20 µm) 在皮下针 (直径: 720 µm) 是使用喷雾涂层和柔性膜掩在光刻过程中演示。
Abstract
我们介绍了一种电子阻抗谱 (EIS)–针 (EIS-on-a 针) 的制作方法, 通过测量和分析不同组织之间电阻阻抗的差异来定位体内的靶组织。本文介绍了用光刻胶喷涂和柔性膜掩在光刻工艺中, 在皮下针尖端指电极 (ide) 的制作方法。采用25µm 壁厚的聚对苯二甲酸乙二醇酯 (PET) 热收缩管作为绝缘和钝化层。与聚 (p-xylylene) 聚合物相比, 它具有更高的机械耐久性, 被广泛用作介质涂层材料。此外, 哈勃望远镜对大多数酸和碱具有良好的耐化学性, 这有利于限制化学物质对永世的损害。对化学/生物材料或使用酸性/碱性化学制品的制造而言, 使用 “永世” 尤其可取。该 ide 的制造间隙和宽度均为20µm, 其总宽度和长度分别为400µm 和860µm。皮下针的制作余量 (皮下注射针头尖端与 ide 起始点之间的距离) 小至680µm, 这表明在组织中可以避免不必要的过度侵入电阻阻抗测量。该方法具有很高的临床应用潜力, 如甲状腺活检和脊髓间隙麻醉药物的传递。此外, 即使在涉及部分切除肿瘤的手术中, 也可以通过检测手术切口 (与肿瘤切除后的正常组织) 之间的正常组织和病变组织。
Introduction
皮下针被广泛用于医院的活检和药物传递, 因为它们价格低廉, 易于使用。他们也有优良的机械性能, 尽管他们的薄直径和锋利的结构适合入侵。在活检中, 靶组织在皮下注射针头的中空取样, 超声引导1。虽然超声检查是没有辐射, 安全的胎儿和孕妇, 并提供 real-time 成像, 很难看到身体深处的器官, 特别是在肥胖患者的情况下, 因为超声波不能穿透空气或脂肪组织2。此外, 外科医生无法从 two-dimensional 超声中获取深度信息, 这是大多数医院常规使用的, 因此, 如果医生缺乏技能或经验, 需要进行多次活检。在给药的脊髓麻醉, 医生确定, 针已达到脊髓的空间, 如果脑脊液 (CSF) 回流到注射器, 而小心插入到病人的背部针。确认脑脊液回流后, 将麻醉药注入脊髓间隙3。然而, 医生的风险穿透或切断神经纤维在脊柱的空间, 造成严重的疼痛病人, 甚至截瘫4,5。因此, 这个过程也需要一个熟练的医生。克服和减轻上述困难的一个解决办法是在皮下注射针头上添加一个导航功能, 以便能够提供关于针头位置的客观信息。这将有助于医生随时进行活检, 药物传递, 甚至手术, 而不依赖于他们的经验判断只。
为了在人体内电定位靶组织, 采用电阻抗谱 (EIS) 传感器的皮下针作为 EIS-on-a 针 (永世)6。EIS 传感器目前用于生物医学工程领域的应用, 如 DNA 检测7,8,9, 细菌/病毒检测10,11,12, 并分析细胞/组织13,14,15,16,17,18,1920,21,22. 在频率域中, 基于电导率和介电常数, 可以区分不同的材料。对磷酸缓冲盐水 (PBS)23、猪脂肪/肌肉组织的6、23、甚至人类肾脏正常/癌症组织的不同浓度水平的鉴别能力进行了验证24 ,25。这一能力的永世预计将大大提高活检的准确性, 通过定位靶组织的基础上的不同, 在电子阻抗的目标病变组织和相邻的正常组织。以类似的方式, 调查药物注射空间 (脊椎或硬膜外间隙) 和周围组织之间的电阻阻抗的差异可以帮助医生在确切的靶位置提供麻醉药物。此外, 可以用来电刺激大脑/肌肉, 以及确定在手术中的最佳手术切口, 涉及部分切除肿瘤, 如部分肾切除, 以保持尽可能多的正常组织可能.
在实现的最大的挑战之一是在皮下针的弯曲表面上的电极制造有一个小半径的曲率。使用传统的光刻工艺的直接金属图案被认为不适合在直径为几毫米或更小的弯曲衬底上制造微米电极。到目前为止, 各种方法, 包括共形印刷26, 柔性干膜光刻胶的27, 微流控方法28, 压光刻29, 和基板旋转光刻30, 已介绍了在曲面上制造金属/聚合物的模式。然而, 由于所要求的, 如所需的基板直径小于1毫米, 总电极长度为20毫米或以上, 宽度和间隙的电极范围在几十微米, 和高批量生产, 仍然有限制。
在本研究中, 提出了采用光刻胶喷涂和柔性膜掩的直接金属模式来实现皮下针曲面上的微米电极。针的直径和720µm (22 口径) 一样小, 广泛用于医院的活检和药物传递。并对所提出的制造方法的产量进行评估, 以确定以可承受的价格批量生产的可行性。
Protocol
Representative Results
Discussion
我们证明, 使用喷涂涂层和胶片掩的光刻是一种可行的方法, 在一个小直径小于1毫米的皮下针的曲面上制造精细的 ide。ide 的宽度和间隙均低至20µm, 而尖端的加工余量则小至680µm。在协议中, 对齐过程 (包括楔形错误删除) 是一个关键步骤。该产品的产量超过 90%, 当该公司通过严格的对准过程单独制造。这表明, 所提出的制造方法有可能发展为散装生产以可承受的价格。
对 PBS, ?…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
这项工作得到了 “生物医学综合技术研究” 项目的支持, 其依据是2017年提供的一项赠款。
Materials
| Heat shrink tube | VENTION MEDICAL, Inc. | 103-0655 | |
| Hypodermic needle (22G) | HWAJIN MEDICAL co. ltd | – | http://www.hwajinmedical.com |
| Heat gun | Weller | WHA600 | http://www.weller-tools.com/en/Home.html |
| Ultrasonic cleaner | HWASHIN INSTRUMENT CO, LTD. | POWERSONIC 620- | http://www.hwashin.net |
| Hotplate | AS ONE Corporation | 006560 | |
| Sputtering | A-Tech System. Ltd. | ATS/SPT/0208F | http://www.atechsystem.co.kr |
| Glass slide | Paul Marienfeld GmbH & Co. KG | 1000412 | |
| Spray coater | LITHOTEK | LSC-200 | |
| Photoresist | AZ electronic materials | GXR 601 | http://www.merck-performance-materials.com/en/index.html |
| Developer (solution) | AZ electronic materials | MIF 300 | http://www.merck-performance-materials.com/en/index.html |
| Aligner | MIDAS SYSTEM CO.,Ltd. | MDA-400M | http://www.midas-system.com |
| Microscope | NIKON Corporation | L200 | http://www.nikonmetrology.com |
| Au wet etchant | TRANSENE COMPANY, Inc. | Au etchant type TFA | http://transene.com |
| Cr wet etchant | KMG Electronic. Chemicals, Inc. | CR-7 | http://kmgchemicals.com |
| Au target | Thin films and Fine Materials | – | http://www.thifine.co.kr |
| Cr target | Thin films and Fine Materials | – | http://www.thifine.co.kr |
| Argon gas (99.999%) | SINIL Gas Co.Ltd | – | http://www.sigas.kr |
| Acetone solution | OCI Company Ltd | – | http://www.ocicorp.co.kr/company/index.asp |
| Impedance analyzer | Gamry Instruments Inc | Reference 600 | https://www.gamry.com |
| Height Controller | Mitutoyo Corporation | 192-613 | |
| Phosphate buffered saline | Life Technologies Corporation | 10010023 |
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