Making a 3-D Microscope: Technique brings entire sample into focus

A new imaging technique creates microscopic three-dimensional views of tissues within a patient’s body and can update those images several times a second. The technology could be a boon for guided surgery, in which doctors use computer-generated images of hard-to-see areas in the body to perform delicate operations, such as cutting out brain tumors.

IN FOCUS. In a normal microscopic image of a mock tissue made of small particles suspended in silicone (left), only a thin plane is in focus. A new technique can create an in-focus image of the entire structure (right). Nature Physics

Optical microscopes normally have a shallow depth of field, so only a thin slice of tissue is in focus at any time. But now Tyler Ralston of the University of Illinois at Urbana-Champaign and his colleagues have extracted information from light passing through out-of-focus areas and used it to construct sharp images on a computer. The result is a 3-D view that shows the entire tissue in focus, Ralston’s group reports in the February Nature Physics.

“There’s this misconception out there, both in the public and in the scientific community, that if something is blurry, it’s not useful,” says coauthor Stephen Boppart, also at Urbana-Champaign. The new technique represents a “paradigm shift in the way that we think about this [out-of-focus] information,” he adds.

The process, called interferometric synthetic aperture microscopy, doesn’t simply try to sharpen the out-of-focus parts of a typical picture. Instead, it collects information on how light is bent and scattered by the out-of-focus tissue and uses that information to infer the structure of the tissue that caused the scattering. The resulting 3-D image is not a photograph but an image calculated using optical physics.

“This approach is completely new to optics,” comments Brett Bouma of Harvard Medical School in Boston. A similar technique, called synthetic aperture radar, has long been used to construct 3-D landscapes from radio waves emitted by an airplane or satellite and reflected by the ground back to the craft. Ralston’s team is the first to apply the method to visible light, Bouma says.

“If this can be implemented in the clinic, it will have a huge impact,” Bouma predicts.

In tests on excised samples of a human-breast tumor, Ralston’s group found that synthetic 3-D images closely matched sets of images taken with routine microscopy. The new technique can resolve details as small as 2 micrometers (µm) across and so can easily examine individual cells, which are 10 to 30 µm wide.

“This would let [surgeons] take out tissue with microscopic precision,” Boppart says.

Ralston and his colleagues have already adapted their technique to produce several images per second, which could give surgeons a 3-D, microscopic view as they operate. The technique is compatible with fiber-optic catheters that are threaded through blood vessels and other openings to enable doctors to perform microscopy inside patients’ bodies.

The technique might also be valuable for biological research, Ralston notes. For example, embryologists could use it to watch cells during the development of the internal organs of an embryo.

“All of a sudden, we have access to a lot of information that we didn’t have before,” Boppart says. “We just can’t envision where this is going to lead.”

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