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Squeezing Cells to Deliver Large Molecules

Kelly Rae Chi

By simply squeezing cells, you can deliver large molecules across their membranes. So how does that work exactly? Find out...

Whether it’s a carbon nanotube or a protein, researchers who want to inject a large molecule into a cell have somewhat limited options. But now scientists at the Massachusetts Institute of Technology in Boston have come up with a simple and inexpensive microfluidics solution: by squishing cells through a tight constriction, holes in cell membranes can be created that allow large molecules to diffuse into the cells. The findings were published this week in Proceedings of the National Academy of Sciences (1).

By simply squeezing cells, you can deliver large molecules across their membranes. Source: MIT

When used to deliver transcription factors to convert human adult cells into induced pluripotent stem (iPS) cells, the cell-squeezing chips increased the number of iPS colonies formed 10–100-fold compared to traditional methods of electroporation and cell-penetrating peptides.

The chip is about the size of a quarter, and the design is simple by microfluidics standards, said coauthor Armon Sharei, a graduate student working with the study’s senior authors Klavs Jensen and Robert Langer. It costs only $10–15 to make one device, and less than dollar with large-scale production. As a result, the method could be an attractive option for a variety of research and clinical applications.

The concept was discovered by accident. Previously, the scientists were attempting to inject large particles into cells by shooting them with a tiny jet of liquid containing those particles. The researchers found that they could deliver molecules when the cells were closer to the jet. But instead of penetrating the cells, the jet injection seemed to be compressing the cells.

So Sharei and colleagues overhauled the design, creating a device that mixed together cells and large particles in the inlet channel, pushed the mix through 45 parallel channels containing narrow constrictions, and then collected the treated cells through an outlet channel.

Exactly how the constrictions create holes in cells remains unknown. “One thing that really complicated it for us is, because of the way these devices are designed, the cells go through it so fast that we can’t capture them with the high speed cameras,” Sharei said.

The cells move through the constrictions at a blistering pace—20,000 cells/second. As a result, some get damaged, but many cells recover within five minutes.

To balance delivery efficiency and cell viability, the researchers can adjust the size of the constriction. And not surprisingly, one size doesn’t fit all cell types. So the scientists created a family of more than 30 chips that vary in width and length of the constrictions.

Now, Sharei and his colleagues are researching the device’s potential for cancer vaccine development. The idea is to inject patient cells with molecules that prime the immune system against a particular cancer, and then return them to the patient.

In addition, the team is working to improve the device before commercializing it. For one thing, clogging remains an issue, but that can be overcome by using more than one device or by adding more channels. “By making a chip with a hundred or thousand channels, we should definitely have a case where one device would provide plenty of cells for a patient, and then you throw it out when you’re done,” Sharei said.


1. Sharei, A., J. Zoldan, A. Adamo, W. Y. Y. Sim, N. Cho, E. Jackson, S. Mao, S. Schneider, M.-J. J. Han, A. Lytton-Jean, P. A. Basto, S. Jhunjhunwala, J. Lee, D. A. Heller, J. W. W. Kang, G. C. Hartoularos, K.-S. S. Kim, D. G. Anderson, R. Langer, and K. F. Jensen. 2013. A vector-free microfluidic platform for intracellular delivery. Proceedings of the National Academy of Sciences of the United States of America (January).