Rapid fabrication of highly customizable solid microneedle arrays

皮下注射针头有许多缺点，如插入疼痛、组织创伤和进行注射所需的专业知识。微型制造的微针阵列只穿透皮肤的上部，避免了神经，从而保证了无痛的血液提取和药物输注。固体微针涂有治疗剂，使药物分子在穿透皮肤屏障后溶解到周围组织中。剂量取决于微针面积，因此产率是有限的。微制造方法是制造固体微针阵列的理想方法，因为这些材料具有生物相容性，坚固耐用，并且设计用于与其他微制造工艺大规模集成。我们展示了一种制造固体微针阵列的新方法。这种概念验证的手工制造方法繁琐、不可靠，并且极大地阻碍了创新周期，当需要数百个微针时，制造一个微针需要大约5分钟。与自动焊丝机供应商合作，我们已经证明，该过程可以减少到每微针约1秒。然而，由供应商制作样品是昂贵的（每个设备数千美元），并且需要长达一个月的时间才能交付。这极大地阻碍了本研究所需的实验调查，其中需要测试和实验验证数百个设备迭代。所要求的自动焊丝机将为我的学生提供专用通道，允许在可重复，可靠，经济高效且非常及时的过程中高效可靠地制造大面积高密度阵列的新设计（设备可以在同一天制造和测试）。这将大大提高我们的研究生产力和保持我们的竞争优势。所要求的自动焊丝机将直接支持我的HQP的培训，他们正在研究通过在固体微针底部附近集成微流体通道来克服固体微针产量问题的方法，部分由我的发现基金支持。如果没有这个设备，我们将无法研究大规模的阵列，将相应数量的液体输送到穿孔皮肤附近的区域。由于我们的微针是金属的，并且可以单独电定位，因此将研究通过电穿孔和离子透入过程增加药物摄取的能力。该粘合剂将被安置在多用户洁净室设施中，由经验丰富的技术人员维护设备，延长其使用寿命并促进HQP培训。该设备将广泛用于当前的研究项目，当闲置时，将提供给其他研究人员，从而提高他们的研究效率。从长远来看，这项研究将从实验室走向床边，通过创造一个坚实的微针系统，可以在没有直接医疗监督的情况下使用，从而减少医疗保健支出。

There are many drawbacks to hypodermic needles, such as insertion pain, tissue trauma, and expertise needed to perform an injection. Microfabricated microneedle arrays promise painless blood extraction and drug infusion by penetrating only the upper part of the skin, avoiding the nerves. Solid microneedles are coated with a therapeutic agent, allowing the drug molecules to dissolve into the surrounding tissue after penetrating the skin barrier. The dosage depends on the microneedle area and therefore the yield is limited. Microfabrication methods are ideal to create solid microneedle arrays, as the materials are biocompatible, robust and designed for large-scale integration with other micro manufacturing processes. We have demonstrated a new method to make solid microneedle arrays. This proof of concept manual fabrication method is tedious, unreliable and greatly impedes the innovation cycle, taking ~5 minutes to make a single microneedle when hundreds are needed. Working with vendors of automated wire bonders, we have shown that the process can be decreased to ~1 second per microneedle. However, having a sample made by a vendor is costly (several thousand dollars per device), and takes up to a month for delivery. This greatly impedes the experimental investigation needed for this research, where hundreds of device iterations need to be tested and experimentally validated. The requested automated wire bonder will provide dedicated access for my students, allowing for efficient and reliable fabrication of new designs of large area, high-density arrays in a repeatable, reliable, cost efficient, and extremely timely process (devices can be made and tested the same day). This will greatly increase our research productivity and maintain our competitive edge. The requested automated wire bonder will directly support the training of my HQP who are investigating methods to overcome the solid microneedle yield issue through integrating microfluidic channels next to the base of the solid microneedles, in part supported by my Discovery Grant. Without this equipment we will not be able to investigate large scale arrays for the delivery of relevant amounts of liquid into the area next to the perforated skin. As our microneedles are metal and individually electrically addressable, the ability to increase the uptake of drugs through the process of electroporation and iontophoresis will be investigated. The bonder will be housed in a multi-user cleanroom facility, with experienced technicians maintaining the equipment, extending its operational lifetime and facilitating HQP training. The equipment will be utilized extensively for the current research program and, when idle, will be available to other researchers thereby increasing their research productivity. Long-term this research will move from the bench to the bedside, by creating a solid microneedle system that can be used without direct medical supervision, thus reducing healthcare expenditure.