Rapid fabrication of highly customizable solid microneedle arrays

皮下注射针有许多缺点，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承诺无痛抽血和药物输注，只穿透皮肤的上部，避开神经。固体微针被涂有治疗剂，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，因此产量有限。微制造方法是制造实心微针阵列的理想方法，因为材料具有生物兼容性、坚固耐用，并且设计用于与其他微制造工艺的大规模集成。我们展示了一种制作固体微针阵列的新方法。这种概念验证的手工制作方法繁琐、不可靠，并且极大地阻碍了创新周期，当需要数百个微针时，只需要大约5分钟就可以制作一根微针。通过与自动引线键合机供应商的合作，我们已经证明，该过程可以减少到每微针~1秒。然而，由供应商制作样品的成本很高(每个设备需要数千美元)，而且需要长达一个月的送货时间。这极大地阻碍了这项研究所需的实验研究，其中需要测试和实验验证数百次设备迭代。所要求的自动引线键合机将为我的学生提供专用通道，允许以可重复、可靠、成本效益和非常及时的工艺高效可靠地制造大面积、高密度阵列的新设计(器件可以在同一天制造和测试)。这将极大地提高我们的研究生产率，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，他们正在研究通过集成实心微针底部旁边的微流控通道来克服实心微针产量问题的方法，这部分由我的发现资助提供支持。如果没有这种设备，我们将不能调查大规模的阵列，以便将相关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，并且可单独电寻址，因此将研究通过电穿孔和离子导入过程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。这些设备将被广泛用于当前的研究计划，当空闲时，将供其他研究人员使用，从而提高他们的研究生产率。从长远来看，这项研究将从工作台转移到床边，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.