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.

Technical Abstract:
Cardiovascular diseases (CVDs) are responsible for one-third of all deaths worldwide, according to the World Health Organization and many other sources. More than half of CVDs are heart related. Heritable and acquired arrhythmias and excitability insufficiencies e.g., caused by infarction due to coronary arterial disease, are essentially blockages and disruptions of cardiac electrical activity and integrity. So far, our understanding of cardiac electrical activities is still very limited due to the complex nature of normal heart function that has evolved over millions of years, thus the cruel fact that precise early diagnostics of cardiovascular diseases is still far from achievable.

We propose to probe the electrical activity of heart cells, and even tissues, down to the subcellular level. A better fundamental understanding of the electrical activity of healthy heart cells will help to reveal the causes of dysfunctional cells and potentially guide us towards better treatment. To realise the proposed sensors with a sub-micron resolution, we will use the state-of-the-art van der Waals technology, which allows precise engineering of sensor structures at the atomic scale. A representative of van der Waals material - graphene, has demonstrated itself as an ideal sensor with high electronic mobility, chemical inertness, biocompatibility, optical transparency, mechanical flexibility, and robustness. Graphene's capabilities can be further enhanced once encapsulated, for example, between layers of hexagonal boron nitride. With such a high-quality sensor, imaging cell electrical activity at the sub-cellular level will finally become viable for us to map, for example, the action potentials in individual pacemaker cells. Our methodology is also transferable to other electrically active cells, e.g., neurons. This project introduces a much-needed interdisciplinary approach towards a big goal of improving health and better diagnostics and treatment of medical conditions.