New Views of Inside the Body: Optical Imaging for Biomedical Applications

Seeing Inside: Optical Frequency Domain Imaging and Ultra-Miniature Endoscopy
Gary Tearney, MD, Associate Professor of Pathology, Harvard Medical School; Assistant Physicist, Wellman Center for Photomedicine; Program Leader, Optical Diagnostics, CIMIT, gtearney@partners.org
Moderator: Sergio Fantini, Phd, Associate Dean for Graduate Education, School of Engineering, Tufts University, sergio.fantini@tufts.edu

Coronary artery disease is the leading cause of death in developed nations. In the United States, over half of all deaths due to coronary artery disease occur before the victim reaches the hospital, so it seems that new diagnostic tools are needed to identify at-risk patients. The majority of acute myocardial infarctions occur when a vulnerable plaque ruptures in a coronary artery. These vulnerable plaques are usually thin-capped, rich in lipids, and filled with macrophages. The method most commonly used to detect these plaques is ultrasonic imaging, which provides 100-um resolution; but researchers are currently seeking to adapt optical coherence tomography (OCT), with its 10-um resolution, to the imaging of coronary arteries. The technique involves splitting a beam of white light, bouncing one arm of the split beam off a sample, recombining the beams, and extracting an image from the interference pattern. Using OCT, doctors can measure the thickness of a plaque’s cap, determine whether the plaque is filled with lipids, and visualize macrophage accumulation. The practicality of OCT, however, is limited by the fact that the technique only works if blood is occluded from the coronary artery being imaged. To get around this limitation, researchers have turned to optical frequency domain imaging (OFDI), a variant of OCT that uses a fixed reference beam and Fourier transforms of spectral data. This new approach preserves the resolution of OCT but is much faster, enabling doctors to quickly image coronary arteries without blocking all blood flow. The next step for the researchers developing OFDI is to promote its widespread acceptance in the medical community.

Another imaging technique being developed to enable doctors to better see inside the body is ultra-miniature endoscopy. Today, endoscopic probes are usually over 1 mm in diameter. Smaller probes (less than 300 um in diameter) would be preferable because they would cause little pain and little tissue damage. As of now, smaller probes are not widely used because their resolution is poor. If they have only a few optical fibers, they produce pixilated images, and if they have a lot of optical fibers, they are inflexible. Spectral encoding for endoscopy (SEE), a technique being developed by a research team led by Dr. Tearney of Harvard Medical School, may provide a way to make endoscopic probes smaller than ever before. The new technique uses a single optical fiber with a diffraction grating on its end, and it produces images with about ten times as many pixels as obtained in images produced by probes with fiber bundles. Using SEE, 2-D images, 3-D images, and video can be obtained. Dr. Tearney and his collaborators hope that the probes they are designing will eventually help doctors perform life-saving surgeries. When performing surgeries on developing fetuses, for example, doctors need very small probes because using large probes could cause placental damage and spontaneous abortions.

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Endo-Microscopy and Biomechanical Engineering: Novel Technologies and Applications
Seok-Hyun (Andy) Yun, PhD, Assistant Professor, Harvard Medical School; Assistant Physicist, MGH, syun@partners.org
Moderator: Tayyaba Hasan, PhD, Professor of Dermatology, HMS; Director, Office for Research Career Development, Wellman Center for Photomedicine, MGH, thasan@partners.org

In the seventeenth century, Robert Hooke made groundbreaking advances in the disciplines of physics and biology, coming up with a force law for springs and becoming the first to observe cells. The work being done today in the lab of Seok Hyun Yun of Harvard Medical School builds upon both of Hooke’s scientific interests.

One goal of Yun’s lab is to develop fluorescent microscopic techniques capable of imaging single cells in living mice. Many transgenic mice with fluorescently tagged proteins are available, but usually, these mice must be sacrificed if they are to be studied under the microscope. Yun and his collaborators have come up with a way to image fluorescent cells in living mice, and they have begun to use the technique to study chronic organ rejection, a condition that plagues many people with transplanted organs. In mice with transplanted hearts, the new technique can be used to watch fluorescently tagged macrophages migrating into the new heart, and it can be used to watch antigen-presenting cells migrating out of the heart and into the lymph nodes and other parts of the body.

Yun’s lab also studies the elasticity of different tissues in the body. Cell elasticity is involved in many significant biological processes such as wound healing, force sensing, and even tumor development. At the moment, it is difficult to measure elasticity in vivo. A non-invasive yet quantitative technique is needed, and Yun’s team is in the process of developing such a method. Their confocal Brillouin microscopy technique measures Brillouin scattering, or light waves produced by collective vibrations in a sample. They have used the technique to demonstrate that in mice, the lens becomes stiffer with age. In the future, their microscopic technique may become a valuable tool used to study a variety of eye-related conditions, from presbyopia (the loss of focusing ability with age) to cataracts.

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