Collaborative Research: Multi-Input Biosensors with Built-in Logic

智力优势：最近在酶促反应级联实现逻辑门（如AND、OR等）的信号处理方面取得的进展，以及在将这些门联网并将所产生的系统耦合到信号响应电极以输出读出方面取得的进展，开辟了新的生物传感机会。拟议的合作研究计划的目标是开发一种新的数字化操作生物传感器范例，通过由生物分子系统组成的布尔逻辑网络逻辑处理多种生化信号，产生最终输出信号作为YES/NO响应。与普通的单一或并行传感设备相比，这种活动将导致高保真的生物传感。我们将为新的生物传感器概念开发生化信号处理系统，通过酶或免疫识别过程处理多个输入信号，并结合输出信号的电化学转导。为了展示数字多信号处理生物传感器的新概念，例如，我们将设计一个模型多酶传感系统，旨在快速识别从健康人到各种病理生理功能障碍的复杂生物标志物变化。这些实验发展将通过理论建模和设计新的低噪声、可扩展、多阶段信号处理网络与数字逻辑门，以及由生化反应进行的非布尔网络元素来促进。我们将开发一种综合的方法来优化生物传感网络，包括用于大型网络的模拟/数字误差抑制的组件。具体来说，对于多输入系统，我们将提出一种新的策略，包括模块化网络分析，详细的网络表示和相关组件活动的调整，网络中关键门的门函数优化，以及探索非布尔网络元素（如过滤器）的作用。我们研究的一个重要组成部分将是生物传感逻辑系统与电化学换能器和化学致动器的接口，朝着实用逻辑门生物传感器和反馈回路系统的发展。旨在解决与新的生物传感范式相关的独特挑战的基础研究将进行。将特别注意生物分子“机械”组件的表面限制，系统可扩展性的作用，以及输出信号的有效转导。我们还将直接连接新的生化信号处理组件与信号响应化学致动器，以产生“智能”反馈回路系统，对来自生化环境的输入作出可逆响应。这项研究具有变革性，因为对新型生物分子逻辑系统的理解的提高将导致强大的多分析物传感设备和智能“感知/行动”系统。我们的合作、跨学科项目将需要两个机构的协调努力，并将利用参与团队最近开发的最先进的生物电子学和生物纳米技术。我们提供必要的互补专业知识和既定的业绩记录，以及通过联合高质量的出版物和专利申请证明的成功的持续合作。更广泛的影响和推广：具有内置逻辑的新型生物传感器系统具有巨大的前景，可以从环境和健康监测到国防和食品安全等广泛应用。即使是中等复杂性的逻辑生物传感器系统也将允许实现闭环（“感知/行动/治疗”）组件，用于安全或生物医学应用，例如，针对患者的治疗。我们的计划将有助于教育和确保国家在先进科学和技术方面的领导地位。这些影响将通过培养下一代科学家、研究生和博士后，以及引入新的纳米生物电子学和纳米生物技术课程来实现。激励高中生和本科生从事科学事业是我们拓展的一个关键因素。因此，两所大学的拓展K-12活动将包括广泛的大学前辅导和社区活动。

1066531WangIntellectual Merits: Recent advances in signal processing with cascades of enzymatic reactions realizing logic gates, such as AND, OR, etc., as well as progress in networking these gates and coupling of the resulting systems to signal-responsive electrodes for output readout, have opened new biosensing opportunities. The goal of the proposed collaborative research program is to develop a new paradigm of digitally operating biosensors logically processing multiple biochemical signals through Boolean logic networks composed of biomolecular systems, yielding the final output signal as YES/NO responses. This activity will thus lead to high-fidelity biosensing compared to common single or parallel sensing devices. We will develop biochemical signal processing systems for novel biosensor concepts, with multiple input signals being processed via enzymatic or immune-recognition processes, in combination with electrochemical transduction of the output signal. To demonstrate the new concept of digital multi-signal processing biosensors, we will, for instance, design a model multi-enzyme sensing system aimed at rapid identification of the complex biomarker changes from a healthy person to the conditions of various pathophysiological dysfunctions. These experimental developments will be facilitated by theoretical modeling and design of new low-noise, scalable, multi-stage signal processing networks with digital logic gates, as well as non-Boolean network elements carried out by biochemical reactions. We will develop a comprehensive approach for optimization of networks for biosensing, incorporating components for analog/digital error suppression for larger networks. Specifically, for multiinput systems we will advance a novel strategy including modular network analysis, detailed network representation and adjustment of relative component activities, gate function optimization for the key gates in the network, and exploration of the role of non-Boolean network elements, e.g., filters. An important component of our research will be in interfacing of the biosensing logic systems with electrochemical transducers and chemical actuators, towards the development of practical logic gate biosensors and feedback-loop systems. Fundamental studies aimed at addressing the distinct challenges associated with the new biosensing paradigm will be carried out. Particular attention will be given to the surface confinement of the biomolecular "machinery" components, to the role of the system scalability, and to the efficient transduction of the output signals. We will also interface directly the new biochemical signal-processing assemblies with signal-responsive chemical actuators to yield "smart" feedback-loop systems, responding reversibly to inputs from the biochemical environment. This research is transformative since the improved understanding of the novel biomolecular logic systems will lead to powerful multi-analyte sensing devices and intelligent "Sense/Act" systems. Our collaborative, interdisciplinary program will require a coordinated effort at two institutions, and will utilize the state-ofthe-art bioelectronics and bionanotechnology advances recently developed by the participating teams. We offer the necessary complementary expertise and an established track record, as well as successful ongoing collaboration evidenced by joint high-quality publications and patent applications.Broader Impacts and Outreach: Novel biosensor systems with built-in logic hold great promise to benefit a wide range of applications ranging from environmental and health monitoring to national defense and food safety. Logic biosensor systems of even moderate complexity will allow realizations of closed-loop ("Sense/Act/Treat") assemblies for security or biomedical applications, e.g., patient-tailored therapy. Our program will contribute to education and to ensuring national leadership in advanced science and technology. These impacts will be realized through training of the next generation of scientists, graduate students, and postdocs, and the introduction of new Nanobioelectronics and Nanobiotechnology classes. Inspiring high school and undergraduate students for scientific careers is a key element of our outreach. Outreach K-12 activities in both universities will thus include extensive pre-college mentorships and community activities.