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UW Researchers Exploring Light-Sheet Microscopy for Clinical Pathology

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NEW YORK (360Dx) – University of Washington researchers have developed a light-sheet microscopy platform that is potentially useful for pathology of large clinical samples.

The approach, which was described in a paper published today in Nature Biomedical Engineering, could enable faster, non-destructive two- and three-dimensional analyses for purposes including guiding surgical margins and making diagnostic and prognostic decisions from patient biopsies, said Jonathan Liu, director of the University of Washington's Molecular Biophotonics Laboratory and senior author on the paper. 

Light-sheet microscopy uses a laser to illuminate a cross-section of tissue, generating signal that is then collected in a beam moving perpendicular to the laser's path. The separate illumination and collection paths mean, the author's noted, that each can be "individually optimized," while the technique's ability to analyze samples in cross-sections allows it to scan rapidly through large samples while maintaining three-dimensional information.

Compared to commonly used camera-based tissue microscopy methods, light-sheet microscopy offers comparable speed while boosting imaging quality and depth to levels more akin to that achieved via slower three-dimensional laser scanning microscopy, the authors said.

Additionally, because the technique images fresh, intact tissue, it requires significantly less sample prep than conventional pathology, which involves upfront fixing and mounting and sectioning steps.

"Simplicity and speed are the two main advantages of the [light-sheet microscopy] technique," Liu said. He noted that the method is currently used in life sciences research applications like developmental biology and neuroscience studies, but that he and his colleagues believe it could eventually "be a game-changer for clinical pathology."

The impetus for the project came from study co-author Nicholas Reder, a University of Washington pathology resident.

"When I first started at the University of Washington in 2014, he emailed me out of the blue and said, 'I want to talk to you about these [pathology] problems I was thinking about,'" Liu said.

"At the time, our ideas were very sort of rudimentary," he said, "and then one thing led to another. But [the effort] was always really driven by the clinical problems. From the ground up, this microscope was built specifically for the clinical needs."

In the Nature Biomedical Engineering study, the researchers demonstrated the platform's ability to perform volumetric imaging of core-needle biopsies as well as post-operative analysis of resected tumor tissue to examine surgical margins and in-surgery analysis of the same.

Liu said the platform's high speed makes in-surgery margin analysis a particularly promising application of the technology.

"This is such a fast microscope that we can image an entire margin, the entire circumference of the surgical incision, within say, 15 or 20 minutes, and we can tell the surgeon that the margin is clean, meaning you are done, or that there is still residual tumor at the margin, which means you have to keep cutting," he said.

This is an area of great interest in cancer clinical research, generally, with a variety of parties exploring different methods for rapidly assessing margins during surgery.

Liu suggested that one advantage of the light-sheet microscopy approach is that it provides images that look essentially like those pathologists currently work with.

"What clinicians trust and what they've been using for decades is microscopic pathology," he said. "There's a certain look to those tissues, a certain staining pattern, a certain coloring. We have replicated that with our microscope, so hopefully that makes it very easy to adopt for them. They already trust that technique. We're doing it better, faster, over larger areas. So, we feel like that can really give us a boost in terms of getting into the clinic."

The other area where Liu said he and his colleagues believe the method could be particularly useful is three-dimensional imaging of large specimens where, he said, the hope is that the additional information the technique provides could help improve the ability to diagnose and grade tumors.

In the Nature Biomedical Engineering study, the authors used the case of prostate cancer to give an example of how the technique might fit into clinical practice. Currently, they noted, large samples are subdivided into several smaller samples that are then fixed, sectioned, mounted, and stained so that pathologists can examine them. This means, though, that in many cases, only a subset of sections from the original specimen are examined.

The light-sheet microscopy system, the authors wrote, could "be used for rapid non-destructive triage inspection of fresh specimens to streamline the pathology workflow," allowing clinicians to identify tissue sections containing cancer that could then, if desired, be investigated further using conventional workflows.

The non-destructive nature of the technique also helps it fit in with downstream molecular technqiues, Liu suggested.

"In this modern era of molecular medicine, [clinicians] don't want to just do pathology, they also want to DNA sequencing and other types of tests with that same small amount of tissue," he said. "We don't have to cut the tissue. We don't have to destroy any of it and mount it on glass. We're doing studies right now to show that we can preserve the tissue so that it's still usable downstream for DNA sequencing, RNA sequencing, those types of tests."

Liu said the technology was still in the early days at least so far as clinical adoption was concerned.

"There are huge investments in the current technologies in every hospital," he said. "So, you really have to provide a lot of advantages before they abandon that and adopt something new. It's not going to be a one- or two-year transition. We're thinking it will take two decades for this to really roll out. But we hope that in 10 or 20 years this type of technology will be sort of the standard of care, and gone will be the days of producing glass slides and cutting tissues with a knife."

Liu said there are currently a number of smaller microscopy companies that produce commercial light-sheet microscopes, though these are optimized for research, as opposed to clinical use. He added that larger companies like Phillips, Zeiss, and Leica have also shown interest in the method, but, he said, more data on the approach will likely be needed to drive commercial development.

"We're going to have to do a lot of clinical studies to prove that what we have is better" than standard pathology techniques, he said, adding that he and his colleagues are currently writing grant proposals to line up funding for such efforts.

"We really hope in the years to come that we can do controlled studies where we show that we can predict patient outcomes better than traditional pathology, or that we can predict which treatments are better for the patients compared to current pathology methods," he said.

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