A team of engineers reports that separating circulating cancer cells from blood cells for diagnostic, prognostic, and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, that they developed.

“Looking for circulating tumor cells in a blood sample is like looking for a needle in a haystack,” said Tony Jun Huang, Ph.D., professor of engineering science and mechanics at Penn State. “Typically, the CTCs are about one in every one billion blood cells in the sample.”

Existing methods of separation use tumor-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance. Other methods rely on size, deformability or electrical properties. Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device, according to Dr. Huang.

Acoustic-based separations are potentially important because they are noninvasive and do not alter or damage cells. However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.

“In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,” added Ming Dao, Ph.D., principal research scientist, materials science and engineering at MIT. “With an integrated experimental/modeling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.”

The researchers worked both experimentally and with models to optimize the separation of CTCs from blood. They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation. Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection. The team, which also included researchers from the University of Notre Dame and Carnegie Mellon, published its study (“Acoustic separation of circulating tumor cells”) in PNAS.

Tilted-angle standing surface acoustic waves can separate cells using small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses, noted the researchers. Also, each cell experiences the acoustic wave for only a fraction of a second. In addition, cells do not require labeling or surface modification. All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.

If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.

The researchers used two types of human cancer cells to optimize the acoustic separation (HELA cells and MCF7 cells), both of which are similar in size. They then ran an experiment separating these cells and had a separation rate of more than 83%. They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83%.

“Because these devices are intended for use with human blood, they need to be disposable,” said Dr. Huang. “We are currently figuring out manufacturing and mass production possibilities.”

Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis.

“Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state,” wrote the investigators.








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