Bio-Based "Molectronic" Devices for Bidirectional Molecular-to-Electronic Signal Transduction

最近的发现将人类胃肠道微生物群与疾病、行为甚至心理健康联系在一起。然而，很少有方法能够研究这些联系，特别是分子、细胞和组织之间的分子信号过程，更不用说它们与行为的联系了。人类和动物研究既昂贵又耗时，而且通常不能提供分子水平的信息。重要的是，正是在这个层面上需要信息。在微型微流控设备上培养人类细胞和组织以模拟人体实际系统被认为是人类或动物研究最有前途的替代方案之一。虽然这些设备具有潜在的变革性，但它们可能很复杂，因为它们有时包括营养供应器、细胞、执行器、泵、阀门，甚至包括探测器系统。为了简化，首席调查员(PI)提出了一种由优化设计的子系统组成的模块化方法。他们的方法还将为操纵这些细胞和了解它们对分子信号的反应提供新的有效途径。微电极将被集成并直接连接到细胞和组织，以刺激和询问细胞反应。由于生物系统被连接到电极上，这就实现了编程的功能和高度准确的反应评估。此前，PI的团队已经开发出电子驱动和记录人类胃肠道细菌和上皮细胞之间的信号过程的方法。生物学中的信息处理是通过分子的分泌和感知来完成的，而电子设备中的信息处理是使用电子来完成的。他们开发的方法在信息内容从分子流动到电子再回来的过程中相互转换。为了做到这一点，他们使用合成生物学和薄膜微制造方法来组装生物系统和微电子设备之间的“智能”接口。他们的方法基于基于氧化还原的信号，这种信号独特地跨越了通信模式。拟议的工作有三个具体目标。在目标1中，PI将开发将电输入转换到分子信号分子的致动器设备，特别是调节行为的细菌群体感应自动诱导器。在目标2中，他们将开发反向通信的传感器设备--生物分子信息将被转换为电子输出。研究人员将通过电子手段直接测定分子浓度，并借助整合到设备中的酶和工程细胞进行测定。在AIM 3中，这些传感器/执行器模块将集成到一个完整的“芯片上的动物”系统中。使用这种模块化的方法，将降低现有系统的复杂性，增加这些设备的吞吐量，并显著提高整个过程的效率。PI们预计这些研究将极大地提高我们理解沟通的能力。在人体内的分子、细胞和组织之间。最重要的是，这项拟议的工作为在与生物学功能相关的长度和时间尺度上询问生物学创造了一个新的有利条件。同样重要的是，由于这些系统融合了多个学科的技术和方法，而且对社会的益处是如此之大，它们吸引了精力充沛、才华横溢的学生，他们将成为未来的创新者和领导者。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Recent revelations have linked the human microbiome of the gastrointestinal tract to disease, behavior, and even mental health. Yet, there are few methodologies that enable study of these linkages, particularly the molecular signaling processes between the molecules, cells, and tissues involved, let alone their connection to behavior. Human and animal studies are expensive and time consuming, and they typically do not provide information at the molecular level. Importantly, it is at this level that information is needed. Culturing human cells and tissues on miniature microfluidic devices to mimic actual systems in the human body has been considered as one of the most promising alternatives to human or animal studies. While potentially transformative, these devices can be complex, as they sometimes include nutrient supplies, cells, actuators, pumps, valves, and even detector systems. To simplify, the principal investigator (PI) proposes a modular approach comprised of optimally designed subsystems. Their approach will also provide new efficient avenues for manipulating these cells and understanding their responses to molecular signals. Microelectrodes will be integrated and directly connected to cells and tissues for stimulating and interrogating cellular responses. Because the biological systems are "wired" to electrodes, this enables "programmed" function and highly accurate assessment of responses.Previously the PI's group has developed methods to electronically actuate and record signaling processes among bacteria and epithelial cells of human GI tract. While information processing in biology is accomplished by the secretion and perception of molecules, information processing within electronic devices is accomplished using electrons. The methodologies they have developed interconvert information content as it flows from molecules to electrons and back. To do this, they use synthetic biology and thin film microfabrication methodologies to assemble "smart" interfaces between biological systems and microelectronic devices. They base their methods on redox-based signals that uniquely span communication modalities. There are three specific aims in the proposed work. In Aim 1, the PIs will develop actuator devices that transduce electrical inputs to molecular signaling molecules, specifically bacterial quorum sensing autoinducers that regulate behavior. In Aim 2, they will develop sensor devices that communicate in the opposite direction - biomolecular information will be converted to electrical outputs. The researchers will determine molecular concentrations electronically, both directly and with the aid of enzymes and engineered cells that are incorporated into the devices. In Aim 3, these sensor/actuator modules will be integrated into a complete "animal-on-a-chip" system. Using this modular approach, the complexity of the current systems will be reduced, the throughput of these devices will be increased, and the efficiency of the entire process will be dramatically enhanced. The PIs expect these studies will vastly improve our ability to understand the ?communication? between molecules, cells, and tissues in the human body. Most importantly, the proposed work creates a new vantage point for interrogating biology at the length and time scales associated with its function. Equally importantly, because these systems incorporate techniques and methods from several disciplines, and because the perceived benefits to society are so great, they attract energetic and talented students who will become the innovators and leaders of the future.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.