SNM: Scalable Nanomanufacturing of Fab Compatible High-Density Nanowire Arrays for High-Throughput Drug Screening

活体动物的细胞非常小，但测量和操纵它们对于产生新的医学疗法至关重要。 有一些令人鼓舞的新方法可以一次了解和控制一个细胞，但现在还没有技术可以单独测量和控制治疗所需的数千或数百万个细胞。迫切需要使用多个纳米级设备单独测量和控制细胞的新方法。 该奖项将研究一种同时控制和测量许多细胞的方法。 基础技术是一个高密度的纳米级电线平台，与培养系统中的细胞相互作用。纳米线器件的可扩展纳米制造将使建造“芯片上纳米实验室”机器成为可能。这种微型“实验室”，结合患者自身的生长细胞，可以创造低成本、预测性的药物筛选平台，以加速药物发现和个性化治疗。该项目为本科生，高中生和代表性不足的少数民族学生提供材料科学，工程和医学跨学科研究的培训机会。它增强和改进了课程设置，并促进了与行业合作伙伴的强有力的翻译交流。该项目旨在克服开发基于纳米线阵列的系统的障碍，该系统能够在3D网络中实现多用途，非破坏性，高灵敏度的测量，而这些测量是膜片钳，自动贴片或微电极阵列技术无法实现的。人源性神经元和心肌细胞，这是高度相关的药物筛选的人类模型，进行了研究。该项目探讨了纳米压印光刻作为一种可扩展的纳米制造方法，以开发一个晶圆级纳米线神经生理学平台，可扩展到8000个同时数据点的250个威尔斯井，每个32个纳米线电极。这种可扩展的制造方法使得能够在集成系统中以高密度和大量集成纳米线，该集成系统包括芯片上采集和数字化电子器件以及微流体药物干预通道和威尔斯。此外，设计了多高度纳米线的新架构，用于从3D神经元和心肌细胞网络中筛选药物的作用，并将读出电子器件与纳米线传感器完全集成。最后，可扩展到1820个威尔斯孔和115，840个同时测量点的单个低成本平台上的所有组件都是单片集成的，并且该平台在Sanford Burnham Prebys医学发现研究所和UC San Diego用一组药物进行了验证。这些技术创新应该能够实现跨组织深度的非破坏性细胞内电位测量。

Cells from living animals are very small, and yet measuring them and manipulating them are critical for producing new medical therapies. There are encouraging new methods to understand and control cells one at a time, but there really isn't now the technology to measure and control individually the thousands or millions of cells needed for a therapy. New approaches to individually measure and control cells using multiple nanoscopic devices are sorely needed. This award will study a method to control and measure many cells simultaneously. The base technology is a high-density platform of nanoscopic wires that interact with the cells in a culture system. The scalable nanomanufacturing of nanowire devices will make it possible to build "nanolab-on-a-chip" machines. Such tiny "laboratories", combined with a patient's own growing cells could create low-cost, predictive drug-screening platforms to accelerate drug discovery and personalized treatments. The project provides training opportunities for undergraduate, high school, and under-represented minority students in interdisciplinary research in materials science, engineering, and medicine. It augments and improves the course curriculum, and fosters a robust translational exchange with industry partners. The project aims to overcome the barriers in developing a nanowire array-based system that enables multi-use, non-destructive, high-sensitivity measurements in 3D networks that are not possible with patch-clamp, automated patch, or microelectrode array techniques. Human-derived neurons and cardiomyocytes, which are highly relevant human models for drug screening, are studied. The project explores nanoimprint lithography as a scalable nanomanufacturing method to develop a wafer-scale nanowire neurophysiology platform scalable to 8000 simultaneous data points for 250 wells with 32 nanowire electrodes each. This scalable fabrication method enables the integration of nanowires in high densities and large numbers in integrated systems that comprise on-chip acquisition and digitization electronics and microfluidic drug intervention channels and wells. Furthermore, new architectures of multiple height nanowires are devised for screening the effects of drugs from 3D neuronal and cardiomyocyte networks and fully integrate readout electronics with the nanowire sensors. Finally, all components on a single, low cost platform scalable to 1820 wells and 115,840 simultaneous measurement points are monolithically integrated and the platform validated with a panel of drugs at the Sanford Burnham Prebys Medical Discovery Institute and UC San Diego. These technical innovations should enable non-destructive intracellular potential measurements across the depth of a tissue.