Engineers at the University of California at San Diego have developed a powerful new tool that monitors electrical activity within the heart’s cells, using tiny “pop-up” sensors that penetrate cells without damaging them. The device directly measures the movement and speed of electrical signals that travel within a single heart cell, the first, as well as between multiple heart cells. It is also the first to measure these signals within 3D tissue cells.
The device, published December 23 in the magazine Nature Nanotechnologyit could allow scientists to obtain more detailed information on heart ailments and diseases such as arrhythmia (abnormal heart rhythm), heart attack and cardiac fibrosis (stiffening or thickening of heart tissue).
“Studying how an electrical signal propagates between different cells is important for understanding the mechanism of cell function and disease,” said lead author Yue Gu, who recently earned his Ph.D. in materials science and engineering from UC San Diego. “Irregularities in this signal can be a sign of arrhythmia, for example. If the signal cannot propagate properly from one part of the heart to the other, then one part of the heart cannot receive the signal, so it cannot contract.
“With this device, we can zoom in on the cellular level and get a very high resolution image of what is happening in the heart; we can see which cells are malfunctioning, which parts are out of sync with each other and pinpoint where the signal is weak, “said senior author Sheng Xu, professor of nanoengineering at UC San Diego Jacobs School of Engineering.” This information they could be used to help inform doctors and enable them to make better diagnoses. “
The device consists of a 3D array of microscopic field effect transistors, or FETs, which are shaped like sharp tips. These tiny FETs puncture cell membranes without damaging them and are sensitive enough to detect even very weak electrical signals directly inside cells. To avoid being seen as a foreign substance and staying inside cells for long periods of time, FETs are coated with a double layer of phospholipids. FETs can monitor signals from multiple cells at the same time. They can even monitor signals at two different sites within the same cell.
“This is what makes this device unique,” said Gu. “It can have two FET sensors that penetrate inside a cell, with minimal invasiveness, and allow us to see how a signal propagates and how fast it goes. Until now, this detailed information on signal transport within a single cell was unknown. “
To build the device, the team first fabricated the FETs as 2D shapes, then glued selected points of these shapes onto a pre-stretched elastomer sheet. The researchers then loosened the elastomer sheet, folding the device and folding the FETs into a 3D structure so that they could penetrate inside the cells.
“It’s like a pop-up book,” Gu said. “It starts out as a 2D structure and with the compression force it opens up in parts and becomes a 3D structure.”
The team tested the device on heart muscle cell cultures and heart tissue designed in the laboratory. The experiments involved placing the cell culture or tissue over the device and then monitoring the electrical signals detected by the FET sensors. By seeing which sensors first detected a signal and then measuring the time it took the other sensors to detect the signal, the team could determine which direction the signal was traveling and its speed. The researchers were able to do this for signals traveling between neighboring cells and, for the first time, for signals traveling within a single heart muscle cell.
What makes this even more exciting, Xu said, is that this is the first time that scientists have been able to measure intracellular signals in 3D tissue constructs. “So far, only extracellular signals, ie signals that lie outside the cell membrane, have been measured in these types of tissues. Now, we can actually pick up signals within cells that are embedded in 3D tissue or the organoid, “she said.
The team’s experiments led to an interesting observation: Signals within individual heart cells travel nearly five times faster than signals between multiple heart cells. Studying this kind of detail could reveal insights into cardiac abnormalities at the cellular level, Gu said. “Let’s say you are measuring the speed of the signal in a cell and the speed of the signal between two cells. If there is a very large difference between these two velocities, i.e. if the intercellular velocity is much, much smaller than the intracellular velocity, then it is likely that something is wrong with the junction between the cells, possibly due to fibrosis, “he explained. .
Biologists could also use this device to study signal transport between different organelles in a cell, Gu added. A device like this could also be used to test new drugs and see how they affect the cells and tissues of the heart.
The device would also be useful for studying electrical activity within neurons. This is a direction the team is looking to explore next. In the future, the researchers plan to use their device to record electrical activity in real biological tissue in vivo. Xu envisions an implantable device that can be placed on the surface of a beating heart or on the surface of the cortex. But the device is still far from that stage. To get there, the researchers have more work to do, including fine-tuning the layout of the FET sensors, optimizing the size and materials of the FET array, and integrating AI-assisted signal processing algorithms into the device. .
Paper: “Three-dimensional transistor arrays for intra and intercellular recording”. Co-authors include Chunfeng Wang, Namheon Kim, Jingxin Zhang, Tsui Min Wang, Jennifer Stowe, Jing Mu, Muyang Lin, Weixin Li, Chonghe Wang, Hua Gong, Yimu Chen, Yusheng Lei, Hongjie Hu, Yang Li, Lin Zhang, Zhenlong Huang, Pooja Banik, Liangfang Zhang and Andrew D. McCulloch, UC San Diego; Rohollah Nasiri, Samad Ahadian and Ali Khademhosseini, Terasaki Institute for Biomedical Innovation; Jinfeng Li and Peter J. Burke, UC Irvine; Leo Huan-Hsuan Hsu, Xiaochuan Dai and Xiaocheng Jiang, Tufts University; Zheyuan Liu, Massachusetts Institute of Technology; and Xingcai Zhang, Harvard University.
This work was supported by the National Institutes of Health (1 R35 GM138250 01).