Rapid fabrication of highly customizable solid microneedle arrays

皮下注射针有许多缺点，例如插入疼痛、组织创伤和执行注射所需的专业知识。微制造的微针阵列通过仅穿透皮肤的上部而避免神经，从而保证无痛的血液提取和药物输注。固体微针涂有治疗剂，允许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，因此产量有限。微制造方法是制造固体微针阵列的理想方法，因为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进行大规模集成。我们已经展示了一种新的方法，使固体微针阵列。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，当需要数百根微针时，制造一根微针需要约5分钟。通过与自动焊线机供应商的合作，我们已经证明，该过程可以缩短到每个微针约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交付时间。这极大地阻碍了这项研究所需的实验研究，其中数百个设备迭代需要进行测试和实验验证。所要求的自动焊线机将为我的学生提供专用通道，允许以可重复、可靠、经济高效且非常及时的流程（可在同一天制造和测试器件）高效可靠地制造大面积、高密度阵列的新设计。这将大大提高我们的研究生产力，并保持我们的竞争优势。所要求的自动焊线机将直接支持我的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，部分由我的发现资助。如果没有这种设备，我们将无法研究用于将相关量的液体输送到穿孔皮肤附近区域的大规模阵列。由于我们的微针是金属的，并且可以单独电寻址，因此将研究通过电穿孔和离子电渗法增加药物摄取的能力。焊接机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。这些设备将广泛用于目前的研究计划，闲置时，将提供给其他研究人员，从而提高他们的研究生产力。 从长远来看，这项研究将从实验室走向床边，通过创造一种坚固的微针系统，可以在没有直接医疗监督的情况下使用，从而减少医疗费用。

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.