Researchers at EPFL have now developed a new microscopy technique that combines two existing ones, allowing scientists to build high-definition 3D images of cells inside and out.

There are plenty of different microscope imaging techniques available to scientists, but they all have their pros and cons. Electron microscopy can reveal intricate details about the surface of a specimen, but it can't be used on living cells because the intensity of the electron beam destroys the sample. Other methods, like fluorescence microscopy, don't harm the sample but come at a cost to resolution.

So for the new study, the researchers at EPFL started by developing their own imaging technique. It's based on an existing one called scanning probe microscopy, which jabs a sample with a probe tip to map out its surface. However, that's invasive to the cells, so the EPFL team replaced this probe with a glass nanopore that measures the flow of ions without needing to touch the sample. They called this method scanning ion conductance microscopy (SICM).

The team combined this new SICM technique with an existing one called stochastic optical fluctuation imaging (SOFI), which can peer inside cells to watch the various molecules and processes going on in there. The two techniques together let scientists take high definition 3D images of the interior and exterior of cells simultaneously.

"A cell's membrane is the place where it interacts with its surroundings," says Samuel Mendes Leitão, an author of the study. "It's where many biological processes and morphological changes occur, like during cell infection. Our system lets researchers analyze molecular arrangements inside the cell, and map out how they correlate with membrane dynamics."

Perhaps most importantly, they can monitor processes over time, on scales from under a second to several days. In tests, the team was able to watch mammalian cells moving around, communicating, differentiating, engulfing molecules through their membranes, and being infected by bacteria.