Enabling study of electrically transduced information from biomolecules with a low-cost, versatile measurement (Versametrics) system

摘要 大多数研究或检测生物分子的方法都依赖于光谱技术。虽然进步很大 已经使用光谱法制成，通过电可以获取大量信息和功能 测量。例如，几十年来人们一直清楚，理想的生物医学诊断设备将 与光传导相比，利用电传导可实现体积更小的测量系统， 以及其他优点，例如高灵敏度、易于多路复用和低成本。然而实际发展 电转换生物传感技术的发展仍然缓慢且基本上无效。一个专业 造成这种发展缓慢的因素是许多经验丰富的生物医学领域的进入壁垒很高 研究人员致力于电子技术的研究。正确研究生物分子的电刺激方面 或可兴奋细胞——无论是为了提高对生物分子/细胞功能的理解还是选择性检测 用于诊断——需要数万至数十万美元的研究基础设施和先进的 培训，通常是电气工程方面的培训，使许多最有经验的生物医学研究人员无法 做出贡献。此外，表征过程缓慢且繁琐，适应性有限 不同的测试条件——总的来说，减缓了该领域的整体进展。需要的是一个更 易于使用、价格实惠且多功能的电子表征系统，以促进电气研究 转导与生物分子相关的信息。 在第一阶段 STTR 中，我们建议建立多功能电子测量平台的技术可行性 （Versametrics Dart）能够实现并加速电转换生物分子的研究 信息。目标是开发 Dart 系统来表征电子生物芯片 几乎任何基材（例如玻璃、纸张、硅）和各种受控环境（例如液体、气体） 无需电极引线键合，并由直观的软件控制平台支持。我们的 初步结果证明了 Dart 系统在电气监测响应方面的实用性 使用定制的原子力显微镜尖端主动询问生物传感器，这可以是 以无数的方式功能化用于生物分子研究。根据研究收集的反馈 关于原型 Dart 系统的社区（请参阅支持信），我们将追求三个具体目标 解决所需的系统功能。具体目标 1 是为 Dart 开发两个模块：引线键合- 用于快速设备安装/拆卸的免费模块，几乎与任何生物设备基板兼容，其次， 液体环境测量模块。具体目标 2 是扩大电气测量能力 Dart 到三个分辨率为 0.1 pA 的可路由电压源，以实现多路复用的表征 具有独立门控的生物装置配置。具体目标 3 是建立 Dart 控制软件 对于执行电气、电化学和其他定制生物分析具有指导性和直观性 测量。这些目标的成功将产生一个多功能的表征平台，该平台克服了 研究和开发电转生物分子信号技术的长期障碍。

ABSTRACT Most approaches to studying or detecting biomolecules rely on spectroscopic techniques. While much progress has been made using spectroscopy, there is a wealth of information and capabilities available via electrical measurements. For instance, it has been clear for decades that the ideal biomedical diagnostic device would utilize electrical transduction to allow for a less bulky measurement system compared to optical transduction, along with other benefits such as high sensitivity, ease of multiplexing, and low cost. Yet, the actual development of electrically transduced biosensing technologies remains slow and has been largely ineffective. One major contributing factor to this sluggish development is the high barrier to entry for many experienced biomedical researchers to work on electronic technologies. To properly study electrically stimulated aspects of biomolecules or excitable cells – whether for improving understanding of biomolecular/cellular function or selective detection for diagnostics – requires tens to hundreds of thousands of dollars in research infrastructure and advanced training, typically in electrical engineering, leaving many of the most experienced biomedical researchers unable to contribute. In addition, the characterization process is slow and cumbersome, with limited adaptability to different testing conditions – altogether, slowing the overall progress in the field. What is needed is a more accessible, affordable, and versatile electronic characterization system to spur the research of electrically transduced information related to biomolecules. In this Phase I STTR, we propose to establish technical feasibility for a versatile electronic measurement platform (the Versametrics Dart) capable of enabling and accelerating research of electrically transduced biomolecular information. The objective is to develop the Dart system for characterizing electronic biochips fabricated on virtually any substrate (e.g., glass, paper, silicon) and in a variety of controlled environments (e.g., liquid, gas) without the need for electrode wire-bonding and supported by an intuitive software control platform. Our preliminary results demonstrate the utility of the Dart system for electrically monitoring the response of a biosensor while under active interrogation with a customized atomic force microscopy tip, which could be functionalized for biomolecular studies in countless ways. Based on feedback gathered from the research community regarding a prototype Dart system (see Letters of Support), we will pursue three specific aims to address needed system capabilities. Specific aim 1 will be to develop two modules for the Dart: a wire bonding- free module for rapid device installation/removal compatible with virtually any biodevice substrate and, secondly, a liquid environment measurement module. Specific aim 2 will be to expand the electrical measurement capacity of Dart to three routable voltage sources with 0.1 pA resolution to enable characterization of multiplexed biodevice configurations with independent gating. Specific aim 3 will be to establish Dart control software that is instructive and intuitive for performing electrical, electrochemical, and other custom bioanalytical measurements. Success in these aims will yield a versatile characterization platform that overcomes longstanding hurdles to studying, and developing technologies from, electrically transduced biomolecular signals.