Heart conduction system sensor based on van der Waals heterostructures

心脏从不休息——一个典型的人一生大约有30亿次心跳。每一次心跳都是由心脏中少数特殊细胞——起搏器细胞的电刺激引起的。简而言之，电激发是由于各种离子（K+, Na+, Ca2+）进出起搏器细胞而产生的跨膜电压差。离子的流动是通过离子通道的打开和关闭来精确控制的，而离子通道的打开和关闭又由细胞膜上的电压差决定。在心跳过程中，20 - 30亿个心肌细胞中的每一个都以一种很好的协调方式收缩和放松，这是由从起搏器细胞传播出来的电兴奋所协调的。然而，电兴奋的产生和传播机制仍然知之甚少，特别是在亚细胞水平上。这不可避免地阻碍了由异常心电活动引起的疾病的诊断和治疗。根据英国心脏基金会的数据，心脏和循环系统疾病导致了英国四分之一的死亡，准确地说，英国每三分钟就有一个人死于心血管疾病。因此，迫切需要深入了解。在这个项目中，我们的目标是开发一种及时的传感技术，在亚细胞水平上探测起搏器细胞的电兴奋。该传感器将由纳米级“像素”的一维阵列构成。该阵列将连接到外部电子设备，以获取与传感器密切接触的起搏器细胞的电活动快照。为了实现超高灵敏度，并允许未来与柔性电子器件的潜在集成，我们建议使用二维（2D）材料，如石墨烯或六方氮化硼（hBN）及其异质结构，作为传感器像素的构建块。石墨烯本身的性能已经超过了现有最好的固态传感器，因为它具有低载流子密度和非常高的迁移率。范德华异质结构的进步进一步实现了使用简单的冲压和剥离技术的逐原子层工程，允许构建具有原子精度的复杂电路。因此，所提出的传感器将是几个原子层的厚度和几十微米的长度，但功能齐全，包括放大器，互连线，支持和保护层。例如，设想的传感器可以使用单层石墨烯夹在hBN之间。这种看似简单的封装实际上可以极大地提高传感器的质量，使我们的传感器对细胞活动引起的离子电流非常敏感。毫不奇怪，随着范德华异质结构领域的繁荣发展，它们现在可以在晶圆尺度上使用外延生长来扩大规模，这突出了我们的传感器在更广泛领域的潜在应用。我们到底要做什么？首先，我们将使用二维材料的范德华技术构建传感器“像素”，该技术能够探测和解析亚微米电子特征。与此同时，一个专门的实验平台将被开发出来，以允许我们的传感器在生理条件下工作。换句话说，确保我们的测量是生物相容的。一旦开发成功，我们将继续拍摄真实心脏细胞的“快照”，记录为反映细胞活动的电信号，如细胞内运输，或单个起搏器细胞的动作电位。心脏细胞在亚细胞尺度上的这些特征将有助于为心脏病的诊断和治疗建立更清晰的途径，并作为了解许多其他电活性细胞的基础。

The heart never rests - a typical human lifetime is approximately three billion heartbeats. Each of these heartbeats is initiated by an electrical excitation in a handful of special cells in the heart - the pacemaker cells. In a nutshell, electrical excitation is the transmembrane voltage difference generated as a result of various ions (K+, Na+, Ca2+) flowing in and out of pacemaker cells. The flow of ions is precisely controlled by opening and closing ion channels, which, in turn, is determined by the voltage difference across the cell membrane. During heartbeat, each of the 2-3 billion heart muscle cells contracts and relaxes in a well-coordinated manner, orchestrated by electrical excitation spreading out from pacemaker cells. However, mechanisms of the generation and spreading of electrical excitation are still poorly understood, especially at a sub-cellular level. This inevitably hinders the diagnosis and treatment of diseases caused by abnormal cardiac electrical activity. According to British Heart Foundation, heart and circulatory diseases cause one-quarter of all deaths in the UK, to put into perspective, every three minutes someone in the UK dies from cardiovascular disease. A deep understanding is therefore sorely needed.In this project, we aim to develop a timely sensing technique to probe electrical excitation in pacemaker cells at the sub-cellular level. The proposed sensor will be made of a one-dimensional array of nanosized "pixels". This array will be connected to external electronics to acquire snapshots of the electrical activity of a pacemaker cell placed in close contact with the sensor. To achieve ultra-high sensitivity, and to allow potential integration with flexible electronics in the future, we propose to use two-dimensional (2D) materials, such as graphene or hexagonal boron nitride (hBN) and their heterostructures, as the building blocks for the sensor pixels. Graphene itself could already outperform the best available solid-state sensors because it has a low charge carrier density and very high mobility. The advancement in van der Waals heterostructures further enables layer-by-atomic-layer engineering using a simple stamping and peeling technique, allowing the construction of complex circuitry with atomic precision. Consequently, the proposed sensor will be a few atom-layer in thickness and tens of microns in length, but fully functioning including amplifier, interconnect wires, support and protection layers. For example, the envisaged sensor can be built using a single layer of graphene sandwiched between hBN. This seemingly simple encapsulation could, in fact, dramatically improve sensor quality, making our sensor very sensitive to ionic current induced by cell activities. Not surprisingly, with the prosperous development in the field of van der Waals heterostructures, they can now be scaled up using epitaxial growth at wafer-scale, highlighting the potential applications of our sensors in broader fields. What exactly are we going to do? First, we will build the sensor "pixels" using van der Waals technology of 2D materials that are capable of probing and resolving sub-micron electrical features. In parallel, a dedicated experimental platform will be developed to allow our sensors to operate at physiological conditions. In other words, to make sure our measurements are biocompatible. Once developed, we will move forward to take "snapshots" of real heart cells, recorded as electrical signals that reflect cell activities, such as intracellular transport, or the action potential of individual pacemaker cells. These characteristics of heart cells at a sub-cellular scale will help to build a much clearer pathway towards diagnosis and treatment of heart diseases and serve as fundamentals to understand many other electrically active cells in general.