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

1066531 Wang智力优势：在信号处理方面的最新进展，包括实现逻辑门（如AND、OR等）的酶促反应级联，以及在将这些门联网和将所得系统耦合到信号响应电极以用于输出读出方面的进展，已经开启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模式，数字操作的生物传感器逻辑处理多个生化信号，通过布尔逻辑网络组成的生物分子系统，产生的是/否响应的最终输出信号。因此，与常见的单个或并联感测装置相比，这种活动将导致高保真度的生物感测。我们将开发用于新型生物传感器概念的生化信号处理系统，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，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。这些实验的发展将促进理论建模和设计的新的低噪声，可扩展的，多级信号处理网络与数字逻辑门，以及非布尔网络元素进行生化反应。我们将开发一种全面的方法来优化生物传感网络，将模拟/数字误差抑制组件纳入大型网络。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的作用，例如，filters.我们的研究的一个重要组成部分将是在接口的生物传感逻辑系统与电化学换能器和化学致动器，对实用的逻辑门生物传感器和反馈回路系统的发展。将开展旨在应对与新生物传感范式相关的独特挑战的基础研究。将特别注意的生物分子的“机械”组件的表面限制，系统的可扩展性的作用，并有效的输出信号的转导。我们还将直接将新的生化信号处理组件与信号响应化学致动器连接，以产生“智能”反馈回路系统，对来自生化环境的输入做出可逆响应。这项研究是变革性的，因为对新的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“感测/行动”系统。我们的合作，跨学科计划将需要在两个机构的协调努力，并将利用最先进的生物电子学和生物纳米技术的进步，最近开发的参与团队。我们提供必要的互补专业知识和既定的业绩记录，以及成功的持续合作，证明了联合高质量的出版物和专利申请。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，有利于从环境和健康监测到国防和食品安全的广泛应用。甚至中等复杂性的逻辑生物传感器系统将允许实现用于安全或生物医学应用的闭环（“感测/动作/治疗”）组件，例如，为病人量身定制的治疗我们的计划将有助于教育和确保先进科学技术的国家领导地位。这些影响将通过培训下一代科学家，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。为高中和本科生提供科学职业是我们推广的一个关键因素。因此，这两所大学的K-12外联活动将包括广泛的大学前辅导和社群活动。

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.