Many of the most devastating diseases are like black boxes for science. Most cancer deaths, for example, are caused by the stress of the disease spreading throughout the body, driven by some tumor cells being able to travel to different parts of the body and form new ones. But biologists know relatively little about how these aggressive cells function, which hinders knowledge of cancer progression and resistance.
Oncology is not the only field in search of valuable information about single rare cells – all fields, including developmental biology, immunology, stem cell biology, neuroscience and infectious disease, need to study individual cells. By looking at cells one by one rather than at large numbers of cells, researchers can uncover their genetic structure and unique behavior, observing subtle but impactful traits that would otherwise be hidden.
Experts say the key to breakthroughs in all these areas is clear: better single-cell sequencing technology.
To study rare cells, researchers need to isolate individual cells from large groups of human tissue, but doing so threatens the viability of the cells they hope to analyze. Current technologies for isolating cells often do so by cutting small pieces out of a larger tissue piece with a scalpel or razor, which potentially damages the cells so that they can no longer be studied properly. Other methods use enzymes to separate cells, but those processes take time and may jeopardize useful cell characteristics. “And for rare cell types, every little loss matters,” says Katalin Susztakwho studies chronic kidney disease at the University of Pennsylvania.
Hypersonic levitation in cell separation
A new method of separating and suspending cells is called Hypersonic lift and spin (HLS), relies on acoustic resonators and micro-electromechanical systems (MEMS) technology to achieve breakthroughs in biology. The group at China’s Tianjin University responsible for its development found that the device is able to isolate more cells in significantly less time than traditional techniques.
HLS uses a metal probe to transmit billions of vibrations per second into the water mixture surrounding human cancer tissue in a research laboratory. The resulting “liquid jets” peel off one cancer cell from thousands of others in the piece of tissue, a completely contact-free process. The cell is held in place by a liquid jet – suspended in the fluid but free to rotate to any degree – allowing full visual analysis from every angle with advanced microscopy.
xuexin duanJoe, who leads the Tianjin University group, and his colleagues set out to invent a device that would not only reduce the danger to cells during the isolation process, but also speed up the entire process. He began by considering the fact that living cells are generally surrounded by water. “We asked: Could we use a finely tuned physical field within a fluid to act as a gentle, invisible hand?” Duane says.
They came up with a small, high-frequency ultrasound probe that uses three MEMS-based resonators to vibrate tissue in water and enzyme solution. When the device is turned on, the signal generated at 2.49 GHz alerts a printed circuit board to send a high-frequency voltage. Once the voltage reaches the MEMS resonator, inverse piezoelectric effect This is triggered, causing billions of vibrations per second that generate acoustic waves in the surrounding fluid.
A reflector beneath each resonator bounces the waves in a specific pattern, causing the water-enzyme mixture to rapidly flow and rotate—causing liquid jets so powerful that they can remove a single cell from a clump of tissue, but gentle enough that it does no damage in doing so. Once a cell is detached, the same acoustic mechanism allows it to swim and move freely in the fluid.
While much of the design is unique, the HLS is more sophisticated than an entirely new device. “This leverage method has been used before for other types of tasks,” says Jade Hue FanA biomedical MEMS and microfluidics researcher at the University of Florida. He says HLS is “an improvement, not a dramatic change.” Still, Fan thinks the tool shows serious potential.
Researchers at Tianjin University tested their device on human kidney cancer tissue samples. Using HLS, the group was able to separate 90 percent of the cells in 15 minutes, but could only do so for 70 percent of the cells in an hour using traditional methods. HLS performed so well because it helps the enzymes penetrate the tissue and break down cells “without the need for harsh mechanical grinding or prolonged enzymatic exposure,” says Duan.
Concerns over HLS in single-cell research
Suztak of the University of Pennsylvania’s biggest concern is that HLS could pose a threat to cells sensitive to high-frequency radiation. “Even small disturbances in the function of a single cell can matter,” she says. “Will acoustic fields disrupt the cell’s biochemistry?”
Duan is confident that his team’s design is safe for delicate cells because they experience a controlled force, not a raw acoustic wave, he claims. “This intense force field is confined to the fluid, not directly to the cell.”
External experts have more concerns about implementation. Suztek says that “biological laboratories are inexhaustible” so research equipment must be reliable and robust, and MEMS devices in liquids face drift and calibration problems. Cost and ease of access worry Fan, although he believes both issues can be solved by commercial efforts. “How mainstream it becomes really depends on commercialization,” he says.
For these reasons and others, Duan says his team has spun off HLS into a startup company—Convergence Biotech—which aims to develop an HLS Workstation as user-friendly as it is for any laboratory. And he is optimistic about the venture. “We believe that MEMS-based acoustic devices will become a core component of the biological toolkit,” he says.
Single-cell researchers show similar optimism, but with caution. Suztak considers HLS “a clever tool with real promise,” she says, “but it has to prove itself in the messy world of real biology.”
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