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Imaging tool could find early signs of arterial plaque

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Daryl Lovell

Nozomi Nishimura

A brain imaging tool developed at Cornell for neuroscience could have unexpected benefits in research on another vital area of the body: the heart.

A research team led by Nozomi Nishimura, assistant professor in the Meinig School of Biomedical Engineering, has applied multiphoton microscopy to the study of atherosclerosis – the buildup of plaque in the walls of the arteries. This buildup is a major cause of heart disease and stroke.

A descendant of the revolutionary two-photon microscopy born nearly 30 years ago in the Clark Hall laboratory of Cornell biophysicist Watt Webb, the Nishimura group’s work produced high-resolution images of the earliest evidence of plaque buildup – individual fat cells along the arterial wall – in mouse and human tissue samples.

“When you look at tissue under a microscope, there are a lot of indistinct features,” Nishimura said. “But to have something that is this bright, that shows something very specifically related to the disease, is pretty exciting. We believe it has a fair amount of clinical potential because of that specificity.”

The group’s paper, “Label-free Imaging of Atherosclerotic Plaques Using Third-Harmonic Generation Microscopy,” published online Dec. 17 in Biomedical Optics Express, a publication of The Optical Society. Postdoctoral researcher David Small and doctoral student Jason Jones, both of the Nishimura Lab, are co-lead authors.

Nishimura had previously worked with the lab of Chris Xu that produced high-resolution in vivo images of neurons firing deep inside the brain of a mouse. These startlingly clear images, using three-photon microscopy (3PM) developed in Xu’s lab, got Nishimura thinking about other uses for the pioneering imaging technique.

One of the additional signals produced when using 3PM for imaging is third harmonic generation (THG), which detects the interface between materials that respond differently to light. Where most optical techniques require inserting a fluorescent dye molecule or protein – which absorbs laser light and then radiates it back out, usually changing the color – THG doesn’t require any dyes. It relies on the inherent properties of the structures being observed – for Nishimura’s work, fat deposits.

“Whenever you move to different optical mechanisms, there’s a chance that it might reveal some new biology,” she said. “And this is what we took advantage of. It was sort of a ‘good guess’ that things like fats will show up very strongly with third harmonic generation.”

THG revealed detailed morphological information of cellular and extracellular lipid deposits from mouse and human tissue samples that reflect the early stages of the development of atherosclerosis. And without the need to inject dyes or protein markers, the technique is well-suited to studying living tissue.

“This might actually open up a whole new way to look at these plaques, and enable us to study their fine structure and early development,” Nishimura said. “And that could really lead to new predictive tools.”

Nishimura sees clinical application of this technique as possible in the future, combined with existing endoscopic techniques such as ultrasound and optical coherence tomography. For now, she said, 3PM and THG can be powerful tools for research.

“Scientists are trying to understand the progression of diseases like heart failure and small strokes in the brain and the heart,” she said. “Atherosclerosis is a major component of that. And now we have a tool where we can watch and see these deposits form and interact with all the other cells.”

Irwin Tendler ’16, M.Eng. ’17, also contributed to this work, which was supported by grants from the American Heart Association, the Congressionally Directed Medical Research Program and the New York State Department of Health. Confocal images were acquired at the Cornell BRC-Imaging Facility, which is supported by New York State Stem Cell Science and the National Institutes of Health.

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