Heart conduction system sensor based on van der Waals heterostructures

心脏从不休息--一个典型的人的一生大约是30亿次心跳。每一次心跳都是由心脏中少数特殊细胞--起搏细胞--的电刺激启动的。简而言之，电兴奋是由于各种离子（K+，Na+，Ca 2+）流入和流出起搏细胞而产生的跨膜电压差。离子的流动是通过打开和关闭离子通道来精确控制的，而离子通道又是由细胞膜上的电压差决定的。在心跳过程中，20 - 30亿个心肌细胞中的每一个都以一种协调的方式收缩和放松，由起搏细胞传播的电兴奋所协调。然而，电兴奋的产生和传播的机制仍然知之甚少，特别是在亚细胞水平。这就不可避免地阻碍了心电活动异常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占英国所有死亡人数的四分之一，每三分钟就有一人死于心血管疾病。在本研究中，我们的目标是发展一种及时的传感技术，在亚细胞水平上探测起搏细胞中的电兴奋。所提出的传感器将由纳米尺寸的“像素”的一维阵列制成。该阵列将连接到外部电子设备，以获取与传感器紧密接触的起搏器细胞的电活动的快照。为了实现超高灵敏度，并允许未来与柔性电子产品的潜在集成，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。石墨烯本身已经可以超越最好的固态传感器，因为它具有低载流子密度和非常高的迁移率。货车德瓦耳斯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，允许以原子精度构造复杂电路。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夹在hBN之间的单层石墨烯来构建。这种看似简单的封装实际上可以显着提高传感器的质量，使我们的传感器对细胞活动诱导的离子电流非常敏感。毫不奇怪，随着货车德瓦尔斯异质结构领域的蓬勃发展，现在可以使用外延生长在晶圆级扩大规模，突出了我们的传感器在更广泛领域的潜在应用。我们到底该怎么办？首先，我们将使用二维材料的货车德瓦尔斯技术构建传感器“像素”，该技术能够探测和解析亚微米电气特征。同时，将开发一个专用的实验平台，使我们的传感器能够在生理条件下运行。换句话说，确保我们的测量是生物相容的。一旦开发出来，我们将向前迈进，拍摄真实的心脏细胞的“快照”，记录为反映细胞活动的电信号，如细胞内运输，或单个起搏细胞的动作电位。在亚细胞尺度上心脏细胞的这些特征将有助于建立一个更清晰的诊断和治疗心脏病的途径，并作为理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.