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Building a better mouse … imager

Oct 2006
Hank Hogan

Instead of building a better mousetrap, researchers often try to build a better mouse — at least when modeling disease is the goal. They use mouse models to track and understand the progress of a disease, as well as to evaluate the effect and efficacy of various treatments.

The mouse imaging program at Harvard University’s Center for Molecular Imaging Research in Charleston, Mass., is heavily involved in mouse modeling. To meet the needs of 10 or so principal investigators, Umar Mahmood, the mouse imaging program director and an associate professor of radiology at Harvard Medical School, places certain conditions on the center’s general use imaging systems. For example, systems cannot be prototypes or able to handle only limited volumes, such as a single mouse a day. “Our goal is to run tens of mice a day through our systems,” he said.

Furthermore, results must be reproducible, and the systems must be operable by a technician. The two, Mahmood noted, are related because having a technician operate the system avoids the problem of a researcher unfamiliar with the equipment having to wrestle with it, to the detriment of measuring results.

That is one reason why the program uses commercial products such as the fluorescence molecular tomography system made by Woburn, Mass.-based VisEn Medical Inc. At the mouse imaging program there are different imaging modalities, including those based on CT, MRI, radioisotopes and various optical approaches. Mahmood noted that the program attempts to integrate these methods to come up with the best solution for a particular problem — for example, imaging slight changes in the vascularity of tumors.

The surface image shows a sarcoma in the thigh of a mouse (left); a quantitative tomographic map of the tumor vascular volume fraction (right) was obtained using the VisEn tomographic system and Angiosense 680, a fluorescent blood pool agent. Courtesy of Umar Mahmood and Lars Stangenberg.

For certain applications, an optical approach works best, he added. This is particularly true for those cases when the whole animal is visualized first with a fluorescent probe and then a smaller section, such as part of a tumor, is imaged on a single-cell scale.

However, one problem with optical methods is the scattering of photons by tissue. This phenomenon makes it difficult to determine the concentration, depth and size of a buried fluorescence source. As a result, the fluorescence concentration can appear to decrease with depth, even though it actually has not.

The fluorescence molecular tomography system solves this problem using an approach that the company created by commercializing a technique developed by Harvard researchers. In the method, 50,000 to 100,000 source-detector pair measurements of buried fluorescence are made, typically in a two- to four-minute scan. This captured data is normalized to account for optical nonuniformities, and the corrected data is used in a model that accounts for photon scattering in tissue. The reconstruction usually takes from one to three minutes. The result is a three-dimensional spatial distribution of fluorescence concentration throughout the scan area.

To penetrate tissue, the system is optimized to work with near-IR probes, specifically those at 680 and 750 nm. It uses two near-IR laser diodes — one at 670 and the other at 745 nm — for excitation and a cooled CCD camera for detection over an area as large as 5 cm on a side. Software that comes with the system handles data acquisition, topographic reconstruction and image analysis as well as file archiving and retrieval.

Studies have indicated that the fluorescence concentration measured in this way does not vary with depth, leading to a quantifiable result of fluorescent probes from deep within the tissue of an animal model. Combined with the correct probes for illuminating the biology in question, the result is a map of what is going on functionally in the animal.

In one study under way at the mouse imaging program, the focus is on tumor vascularization. Because the imaging is noninvasive and covers different wavelengths, it is possible to use the same animals and even tumors before and after therapy in the study. “You could use each tumor or each animal as its own control, helping remove some of the biological variation,” Mahmood said.

Because it eliminates the need to average across animals and then subtract or ratio those averages, this ability allows researchers to confidently see smaller changes. The data distribution is, in effect, tighter, Mahmood noted.

For all of these benefits, however, the system cannot provide everything. It does not provide, for example, a map that shows the anatomical collocalization between the probes and the structures inside the animal. It achieves better than 1-mm resolution, but that reveals information about the processes taking place and not about the anatomy. VisEn’s president and CEO Kirtland Poss noted that the information the system provides is important in both academic research and drug development. Tracking biology translates to being able to follow biomarkers of disease progression and therapeutic efficacy, he explained.

He noted that imaging methods that do provide accurate morphologic information do not really reveal biological aspects. “You’re looking at two fundamental metrics, with the morphology and biology,” he said.

Simultaneously extracting both sets of information would be useful, although that is not something that the system alone is specifically designed to do. “We can get some coregistration using two different systems, but combining our platform in real time with another morphologic imaging modality, such as MRI and CT, makes a lot of sense,” he said.

The company is working on a product for researchers that will have such multimodality imaging. Poss would not state when this new offering might be ready, but he did say that it would not be in the short term.

Contact: Umar Mahmood, Harvard Medical School, Center for Molecular Imaging Research, Massachusetts General Hospital, Boston; e-mail:; Kirtland Poss, VisEn Medical Inc., Woburn, MA; e-mail:

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