EAGER: Feasibility of approaches for cell-based sensing on chip

使用生活在集成电路芯片表面的生物细胞进行化学检测是识别气味、疾病和病原体的一种很有前途的方法。例如，主要研究人员之前已经证明，当嗅觉细胞暴露在特定气味中时，可以使用芯片来检测这些细胞从鼻子提取的气味感应细胞产生的电信号。尽管对嗅觉传感器进行了数十年的研究，但我们仍在使用动物，主要是狗来进行气味检测；类似手机的气味检测设备将在整个社会得到广泛应用。该项目旨在开发一种技术，以克服基于细胞传感的设备面临的主要实际挑战：需要为这些设备提供电池。在设备使用之前存储或供应电池一直是一项挑战：在许多情况下，将电池运送到设备位置以便在使用前可以装入其中是不可行的，在电力可能不可用和环境温度变化的情况下保持电池长时间存活也是不可行的。最近，其他人开发了一种可以在实验室培养的可干燥动物细胞系，以及对这些细胞进行基因工程的方法。这项拟议的研究将为使用这种芯片上的细胞进行基于细胞的传感奠定必要的基础，以便这些细胞可以在芯片上存储在停滞状态，然后通过添加水来重新激活。这项研究的长期目标是开发一种芯片上的生物糖，可以用于手持气味识别设备，在安全、爆炸物检测和搜救等应用中取代狗，并为监测食品安全和来源、控制工业过程，甚至诊断疾病开辟新的可能性。这项拟议的工作包括三个方面的努力，以证明在芯片上使用可干燥电池线的可行性。首先，将建立一个与细胞构图和随后的干燥相兼容的凝胶系统。在Bionose应用中，表达不同嗅觉受体的细胞将被图案化到水凝胶基质中的特定传感电极上，然后原位干燥。宿主水凝胶应与细胞培养相适应，在干燥过程中和干燥后保持机械完整性，并支持离子和小分子的快速交换。将研究一系列可以使用生物绘图仪绘制图案的凝胶系统。第二，将集成电路传感芯片与微流体进行封装和集成。这将促进脱水-再水化过程，并促进使用气味的系统测试。我们将对传统的微成型和三维打印进行评估。第三，将通过建模和模拟优化监控气味单元的电活动的片上微电极的设计，以最大限度地检测信号，并将同一芯片上不同细胞群之间的预期串扰降至最低。这些发展不仅为芯片上生物糖的应用奠定了基础，也为其他基于细胞的生物电子传感设备奠定了基础。这项拟议的工作具有挑战性，因为微流体和其他芯片器官方法必须与最先进的电路技术和尖端生物学相结合。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。

Chemical detection using biological cells that live on the surface of an integrated circuit chip is a promising approach to identifying odors, disease, and pathogens. For example, the principal investigators have previously demonstrated that a chip can be used to detect electrical signals generated by odor-sensing cells taken from the nose when those cells are exposed to particular odors. Despite decades of research into olfactory sensors, we are still using animals, primarily dogs for odor detection; a cell-phone like device for odor detection would have widespread applications throughout society. This project aims to develop technology that overcomes the main practical challenge for devices based on cell-based sensing: the need to supply cells to these devices. Storage or supply of cells prior to device use has been challenging: shipping cells to the device location so that they can be loaded into it just prior to use is infeasible in many scenarios, as is keeping the cells alive for long periods of time during which power may be unavailable and environmental temperatures are varying. A dryable animal cell line that can be cultured in the lab and methods for genetically engineering these cells has recently been developed by others. The proposed research will lay the necessary groundwork for using such cells on chip for cell-based sensing, so that the cells can be stored in stasis on chip and later re-animated by the addition of water. The long term goal of the research is to develop a bionose-on-a-chip that can be used in a hand-held device for odor identification, replacing dogs in applications such as security, explosives detection, and search and rescue, and opening new possibilities for monitoring food safety and origin, controlling industrial processes, and even diagnosing disease. The proposed work comprises three efforts to demonstrate the feasibility of using dryable cell lines on chip. First, a gel system will be established that is compatible with cell patterning and subsequent dessication. In the bionose application, cells expressing distinct olfactory receptors will be patterned onto particular sensing electrodes within a hydrogel host matrix, then dried in situ. The host hydrogel should be compatible with culture of cells, maintain mechanical integrity during and after drying, and support rapid exchange of ions and small molecules. A range of gel systems that can be patterned using a bioplotter will be studied. Second, the integrated circuit sensing chip will be packaged and integrated with microfluidics. This will facilitate the dehydration-rehydration process and promote testing of the system with odorants. Both conventional micro-molding and 3-dimensional printing will be evaluated. Third, the design of the on-chip micro-electrodes that monitor the electrical activity of the odorant cells will be optimized through modeling and simulation to maximize detection of the signals and to minimize anticipated crosstalk between different cell populations on the same chip. These developments will lay the groundwork not only for the bionose-on-a-chip application, but also other cell-based bioelectronic sensing devices. The proposed work is challenging because microfluidics and other organ on a chip approaches must be coupled with state of the art circuit technologies and cutting edge biology.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.