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Inside the Lab Microscopy and imaging, Histology, Technology and innovation

Capsule Capture

At a Glance

  • Current diagnostic microscopy methods require patient sedation, followed by tissue excision, processing, staining and microscopic observation
  • In vivo microscopy offers the opportunity to perform diagnostic examinations in living patients without the need for tissue sampling
  • The Tearney lab has developed a tethered capsule endomicroscope the size of a pill for noninvasively imaging the upper GI tract
  • The technology may allow mass population screening for upper GI tract disease and bring diagnosis and treatment to underserved areas

Microscopic tissue examination isn’t easy, either for the patient or for the doctor performing the tests. At the moment, to make a microscopic diagnosis, the doctor must identify the diseased tissue, biopsy the tissue of interest, process it, stain it on a slide and look at it under a brightfield microscope. But this method has great limitations – you can’t always remove the necessary tissue, or doing so might be unsafe. Even if it is possible, excision is time-consuming, expensive and, if the disease cannot be seen by eye, requires random sampling from the region of interest, which gives rise to additional sampling error, especially when performed over a large area. These disadvantages have given rise to the field of in vivo microscopy; the goal being to perform microscopy in living patients without the need for tissue sampling.

In my laboratory, we’ve developed a variety of in vivo microscopic imaging techniques for the diagnosis of Barrett’s esophagus and related conditions. Our aim was to capture the entirety of the esophagus at once, obtaining microscopic images of each location so that we can mitigate the possibility of sampling error. When we started out, we developed a balloon that can be put into the esophagus; it can image the entire esophagus in under a minute, and it produces 3D microscopic images at very high resolution. But that didn’t address all the inherent disadvantages of standard tissue microscopy – it was still necessary to sedate the patient for endoscopy. Our conclusion was that we’d like to build a screening tool that allowed patients to come in for a quick, inexpensive Barrett’s esophagus screening test that required no sedation.


A close up photograph of the tethered capsule endomicroscopy device adjacent to a penny for scale. The optics that spin to create a circumferential microscopic image of the esophagus are held in the brass element that can be seen within the capsule.

How it works

To achieve that goal, we decided to try using a capsule about the size of a vitamin pill, into which we inserted the microscopy optics. The capsule is connected to the imaging system by a flexible tether less than a millimeter in diameter, which contains the optical fiber that transmits light and a driveshaft that spins in the tether to rotate the optics in the capsule. The patient swallows the capsule, allowing it to travel down the esophagus to the stomach while we obtain cross-sectional images of the entire esophagus during its passage. Once the capsule arrives in the stomach, we pull it back up again at a constant velocity, again taking images until it emerges. The entire procedure involves four passes (two descents and two ascents), takes about five minutes, and can be conducted in the doctor’s office. Because patients do not need to be sedated, they like the procedure much better and they don’t even have to take time off work to recover. The entire process takes only about 5 minutes, a nurse or PA can administer the device, the pill can be swallowed in any setting, and the capsules are configured to be very inexpensive, too. So it’s ideal as a screening technology for Barrett’s esophagus – most people who have the disease are unaware of it.

We’ve tested our system in about 50 patients so far. Approximately 90 percent were able to tolerate swallowing the capsule without any trouble, and in almost all cases, we obtained excellent images – not just of a selected area, but of the entire organ. There’s no other tool at the moment that can do that, which makes the capsule a powerful device for comprehensive screening. In my opinion, it’s a big step forward for medicine; these are new concepts and they have the promise to really change how we screen for disease.

We’re now exploring the technology for a wide variety of upper gastrointestinal (GI) tract problems, making further modifications as necessary. For instance, we have a different capsule that does confocal microscopy and we’re seeing if we can use it to identify eosinophils. We’re interested in looking at cancers of the esophagus and stomach – which we’ve found we can image with incredible clarity – and, eventually, also other disorders of the intestine. It’s exciting because I think we have the capability to create a new platform for all kinds of upper GI tract diagnoses.

Overcoming the obstacles

There are a few clear challenges along the way to large-scale implementation of capsule technology. One of those is cost; though the capsule itself is designed to be inexpensive, the imaging technology at the other end of the tether is not. Before we can begin to use this type of system for mass population screening, the imaging technology’s cost and footprint need to be significantly reduced. There’s also the issue of data – microscopic images of entire GI tract organs is a huge volume of information, and the data management aspect is a problem we have yet to solve. I mean that not just in the computational sense, but also the diagnostic, because while trained pathologists are very capable of, for example, making the diagnosis of Barrett’s versus non-Barrett’s, doing that for hundreds of thousands of cases a year with mass screening will present a challenge of its own. None of these issues is insurmountable, but we need to address them before we can fully realize the promise of population screening by capsule endomicroscopy.

One of the major targets of our development is to bring this technology to remote or underserved areas. Sites where the screenings were performed wouldn’t necessarily have to have high-volume data storage physically present; it might be possible to send the information to the cloud, where it could be read remotely by pathologists or, at some point in the future, perhaps even diagnosed automatically by the computer. Because the capsules themselves are low-cost, can be disinfected for reuse, and save the cost and effects of sedating the patient, this form of imaging is ideal not only for primary screening, but for use in lower-income regions. Though it has many uses, I believe capsule endomicroscopy will prove an especially powerful tool in areas where there is a tremendous need for screening and no access to endoscopy.


A three-dimensional representation of a tethered capsule endomicroscopy dataset acquired from a patient showing a portion of the

gastroesophageal junction.

Pathologist participation

I think pathologists are the most qualified people to be diagnosing in vivo microscopy images. After all, we’re trained to recognize tissue microstructures and morphologies, and to look at the patterns in those structures to render a diagnosis. But we’ve shown (1) that postdocs, technicians, nurses and gastroenterologists and pathologists can all be trained to render a diagnosis of Barrett’s versus non-Barrett’s based on these types of images. So if the only question is whether or not a patient has Barrett’s esophagus, in my mind that’s a pretty straightforward diagnosis and people can be trained relatively easily to make it in a reproducible manner – which will be useful if we begin screening programs that massively increase the influx of images awaiting diagnosis.

But there are tasks that only a pathologist can do. For instance, trying to diagnose dysplasia in Barrett’s esophagus is a much harder task than simply diagnosing whether or not a patient has Barrett’s at all. There are different levels of complexity, and pathologists would certainly have to be involved as complexity increased or we encountered data with patterns not previously seen. I personally think pathologists have a major role to play in the adoption of in vivo microscopy in general, as well as in the diagnosis of capsule endomicroscopy data.

I hope that someday, pathologists will come into their offices, open up the digital pathology applications on their computers, and the digital in vivo microscopy images they have to read that day will come up on their screens – in addition to whole slide images and other forms of digital data that they will need to embrace. My vision is that one day not too far in the future, pathologists will see capsule technology and all types of in vivo microscopy as just another way of bringing images to them for diagnosis.

Guillermo J. Tearney is professor of pathology at Harvard Medical School, Mike and Sue Hazard Family MGH Research Scholar and heads his lab at the Wellman Center for Photomedicine at the Massachusetts General Hospital, Boston, USA.

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  1. J Sauk et al., “Interobserver agreement for the detection of Barrett’s esophagus with optical frequency domain imaging,” Dig Dis Sci, 58, 2261–2265 (2013).
About the Author
Guillermo Tearney

Professor of pathology at Harvard Medical School and an affiliated faculty member of the Harvard-Massachusetts Institute of Technology (MIT) division of health sciences technology, Guillermo received his MD from Harvard and his PhD in electrical engineering and computer science from MIT. His research is focused on developing and clinically validating noninvasive, high-resolution optical imaging methods for disease diagnosis. “I think pathologists are the most qualified people to be diagnosing in vivo microscopy, and have a major role to play in its adoption.”

Guillermo (Gary) Tearney is a Mike and Sue Hazard Family MGH Research Scholar, Professor of Pathology at Harvard Medical School, an Affiliated Faculty member of the Harvard-MIT Division of Health Sciences and Technology (HST), and maintains his lab at the Wellman Center for Photomedicine at the Massachusetts General Hospital. Guillermo received his MD magna cum laude from Harvard Medical School and his PhD in Electrical Engineering and Computer Science from MIT.

His research interests focus on the development and clinical validation of non-invasive, high-resolution optical imaging methods for disease diagnosis. Guillermo’s lab was the first to perform human imaging in the coronary arteries and gastrointestinal tract in vivo with Optical Coherence Tomography (OCT), which provides cross-sectional images of tissue architectural microstructure at a resolution of 10 µm. He has also conducted many of the seminal studies validating OCT and is considered an expert on OCT image interpretation. Recently, his lab has invented a next generation OCT technology, termed µOCT, which has a resolution of 1 µm and is capable of imaging cells and subcellular structures in the coronary wall.

Other technologies he has developed include a confocal endomicroscope capable of imaging the entire esophagus, the world’s smallest endoscope, a microscope capable of imaging at the nanoscale, and novel spectroscopy and multimodality imaging techniques. He has an active program in Raman spectroscopy and has conducted the first intracoronary Raman in vivo. He is co-editor of The Handbook of Optical Coherence Tomography and has written over 200 peer-reviewed publications, including papers that have been highlighted on the covers of Science, Nature Medicine, Circulation, Gastroenterology, and Journal of American College of Cardiology.

With over 400 patent applications (~80 granted) and licenses on more than 200 patents/applications resulting in commercial medical devices, Guillermo has also been a principal investigator on over 40 grants. His work extends beyond the lab, with many of his technologies being produced commercially.

He is the chair of the Research Advisory Committee for the Institute for Aging Research, a member of the Scientific Advisory Board for Massachusetts Life Sciences Center and the Clinical Advisory Board for NinePoint Medical, and he has founded the International Working Group on Intravascular OCT Standardization and Validation, a group that is dedicated to establishing standards to ensure the widespread adoption of this imaging technology. “I think pathologists are the most qualified people to be diagnosing in vivo microscopy, and have a major role to play in its adoption.”

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