Heart disease has been the "number one killer" for the past 20 years, with 16% of all deaths. Recently, researchers at the University of California, San Diego, have developed an array of flexible electronic sensors that can monitor the conduction of electrical signals within and between cardiomyocytes, which is expected to achieve intracellular signal detection, study signaling between different organelles in cells, or can be used to test how new drugs affect heart cells and tissues. The findings were published in Nature Nanotechnology on December 23, 2021.
This tiny "pop-up" sensor enters the cell without damaging it and directly measures the conduction and velocity of electrical signals within a single heart cell, and can also obtain high-resolution pictures within the heart.
Sensor | under a light microscope Courtesy of Xu Sheng
The fruit shell editing team contacted the researchers for the first time, and the first author of the article, Gu Yue, told the fruit shell: "'High resolution' means that the same device can arrange multiple sensors on the unit area of myocardial tissue to obtain more detailed information in a limited space; 'picture' refers to the path map of electrical signals conducted between cells and within cells, according to which we can see which cells are malfunctioning, where activities are out of sync with other places, and accurately point out signal weaknesses." ”
Xu Sheng, a professor of nanomaterials at the University of California' Jacobs School of Engineering in San Diego, said: "The information provided by the sensors can help clinicians better diagnose. ”
How does the device work?
The sensor consists of a three-dimensional array of miniature field-effect transistors, or FETs, shaped like a pointed tip. These tiny field-effect transistors can penetrate but not damage cell membranes and are so sensitive that they detect very weak electrical signals directly within the cell.
Sensor topography under scanning electron microscopy | Courtesy of Xu Sheng
The surface of fets modifies the phospholipid bilayer, and the process of entering the cell is similar to the process by which vesicles or liposomes enter the cell — when the modified FETs approach the cell, the phospholipids on its surface spontaneously fuse with the cell membrane. This avoids being treated as a foreign body by the cell and makes it easier to get into the cell. In addition, FETs can form a close and stable contact with the cell membrane after entering the cell interior, allowing them to test longer and more accurately.
Illustration of the device's interface to heart cells, the sensor can simultaneously monitor the electrical signals of multiple single cells (bottom left) and two positions of one cell (bottom right) | Nature-Nanotechnology[3]
When the device tests cell signals, if the sensors each test different cells, the electrical signals studied are intercellular conduction between these cells. "Another situation is that if two adjacent sensors are monitored at different locations in the same cell, what is obtained is the intracellular conduction of the signal inside the cell." ”
At present, the details of the electrical signal conduction within a single cell are unknown. "That's what makes this device unique," Gu Yue said, "it allows two sensors to penetrate the membrane of the same cell in a minimally invasive way, allowing us to see the direction in which the signal is conducted within the same cell, and how fast it conducts." ”
How do I make a device that enters the cell?
"Studying how electrical signals are conducted between different cells is important for understanding cell function and disease mechanisms." Gu Yue introduced, "For example, if the signal shows abnormalities, it may be a sign of an irregular heart rhythm. If electrical signals cannot be conducted normally, then some parts of the heart cannot receive signals and cannot contract. ”
The two-dimensional form of the device (left) and the scanned image folded into a three-dimensional structure (right) | Nature-Nanotechnology[3]
To build the device, the team first made the field-effect transistor into a two-dimensional sheet, and then transferred the two-dimensional device to a pre-stretched silicone elastomer substrate. When the pre-stretched force is released, the original two-dimensional structure is subjected to an extrusion force, and under the action of this squeezing force, the two-dimensional structure will become a three-dimensional structure.
"This sensor is like a pop-up book." Gu Yue said, "It starts as a two-dimensional structure, which pops up in certain parts under pressure, thus forming a three-dimensional structure. ”
How effective is the monitoring?
The team tested the sensor on both heart muscle cells and heart tissue cultured in vitro. The experiment places cell culture or tissue on the device and then monitors the electrical signal received by the field-effect transistor sensor. By looking at which sensors detect the signal first, and the time it takes for other sensors to detect the signal, the team was able to determine how and how quickly the signal was transmitted, as well as the signal of neighboring cells — the first time in the field that signals within a single cardiomyocyte have been measured.
The traditional patch clamp technique for monitoring cell electrical signals is still the most widely used intracellular electrophysiological signaling technology, but the operation of the device is very difficult, and the invasive measurement method can easily kill the cells to be measured. Using this sensor that modifies the phospholipid bilayer on the surface, it is possible to minimize the invasion of the cells to be tested, thus enabling the test of placing two sensors inside the same cell.
Xu Sheng also introduced: "What is even better is that this is the first time that researchers have been able to measure intracellular signals in three-dimensional tissue structures. "Signal monitoring in such tissues has only been achieved outside the cell membrane, and this sensor can collect signals in cells within the tissue.
A device with a proportionally amplified FET sensor array for measuring electrical signals in a three-dimensional heart tissue structure | Courtesy of Gu Yue[2]
The team also found in the experiment that the signaling within a single cardiomyocyte is nearly 5 times faster than between multiple heart cells. Gu Yue believes that studying these problems can reveal the causes of heart abnormalities at the cellular level. "Assuming that the rate of intracellular signaling is measured and the rate of signaling between two cells, if the measurement shows that the rate of intercellular conduction is much smaller than the rate of intracellular conduction, then it is likely that there is a problem with the connection between cells, such as fibrosis."
What are the prospects for industrialization?
One of the most basic application directions of the device is that it can replace the traditional patch clamp technology for the monitoring of intracellular electrophysiological signals in the future. In addition to the extremely high requirements for operator technology and experience, which makes it impossible to promote it on a larger scale, it is also difficult to apply to recording the signal of multiple cells at the same time, so it is rarely used to study the conduction performance of electrical signals, but the tools introduced in this study have advantages in both aspects.
Next, the team will conduct a study of the electrical signaling activity inside neurons. The researchers plan to use the device to record the electrical activity of real biological tissues in living organisms. Xu sheng envisioned a device that could be implanted on the surface of a beating heart or the surface of the cerebral cortex, but the current device is still far from the stage of this vision.
To achieve this goal, researchers also need to conduct in-depth research on the adjustment of FET sensor layout, the optimization of the size and materials of FET arrays, and the integration of ai-aided signal processing algorithms.
"Industrialization is also an area that we are very interested in." Gu Yue told Guo Hu, "The equipment preparation process introduced in this study is relatively novel, and the new process also needs to formulate corresponding composite industrial production standards. On the other hand, this preparation technique can be customized. For different types of cells or research content, different structures of equipment can be designed. If you want to embark on the road of industrialization, how to develop a set of design standards and guidelines is also a problem that needs to be solved. ”
Thanks
Thanks to Sheng Xu, Assistant Professor of the Department of Nanoengineering at the University of California, San Diego, and Yue Gu, Ph.D., for their review and suggestions for this article.
Author: Crispy Fish
Editor: Jin Xiaoming
Typography: Washing dishes
bibliography
[1]https://www.eurekalert.org/news-releases/938733
[2]https://ucsdnews.ucsd.edu/pressrelease/pop-up-electronic-sensors-could-detect-when-individual-heart-cells-misbehave
[4]https://engineeringcommunity.nature.com/posts/intra-and-inter-cellular-recording-by-a-3d-transistor-array
Xu Sheng's team "Fu Linmen" | Courtesy of Xu Sheng
Thesis information
Published the magazine Nature Nanotechnology
Published on December 23, 2021
Thesis title
Three-dimensional transistor arrays for intra- and inter-cellular recording
Articles on nanomaterials in medicine and bioengineering
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