LABEL-FREE LIVE CELL IMAGING: SRS microscopy maps distribution of lipids, drugs

Just a month after the journal Science published a demonstration of label-free imaging in living cells and tissues using stimulated Raman scattering (SRS)1, several groups reported work using the technique during BiOS/Photonics West. “I’m really glad to see we’re not alone,” says Harvard University chemistry professor Xiaoliang Sunney Xie, who led the discovery of approach. “That means people need it. It’s useful.”

In developing SRS, Xie’s group seems to have stolen a page from Intel’s “let’s obsolete our work before the competition does” playbook. Known for a decade of progress in CARS (coherent anti-Stokes Raman) microscopy, the team has now surpassed its earlier achievements. “SRS microscopy not only is more sensitive than CARS and orders of magnitude more sensitive than confocal Raman microscopy, but also provides SRS spectra that are identical to spontaneous Raman spectra,” says Xie. “We were able to map distributions of saturated and unsaturated lipids in a live cell, making possible real-time studies of omega-3 polyunsaturated fatty acid metabolism and its health benefits,” he explains. Xie’s group also measured distributions of a drug in skin tissue, opening new possibilities for label-free studies of pharmacokinetics.

In the Science paper, graduate student Christian W. Freudiger, postdoctoral fellow Wei Min, and a group of coworkers explain that their SRS-based three-dimensional multiphoton vibrational imaging technique achieves its superior sensitivity by implementing high-frequency (megahertz) phase-sensitive detection. SRS microscopy has a major advantage over CARS in that it offers background-free and readily interpretable chemical contrast, they note.

Xie’s group used SRS microcopy to selectively image eicosapentaenoic acid (EPA), an omega-3 lipid, by tuning into the characteristic Raman band at 3015cm-1 (purple). This is distinctly different from the band at 2930cm-1 for both saturated and unsaturated lipids (orange). It is clear how EPA is actively taken up from the culturing media and enriched in lipid droplets (top right) whereas saturated lipids are distributed in many other organelles (top left). (Image courtesy of Wei Min and Chris Freudiger, Harvard University)
Click here to enlarge image

As a first application, Xie’s team collaborated with Professor Jing X. Kang’s group at Harvard Medical School, using the SRS system to monitor a cell’s uptake of omega-3 polyunsaturated fatty acids. Omega-3 is a lipid that mainly exists in fish oil and is commonly used as a dietary supplement. The team was able to distinguish omega-3 fatty acids from the normal saturated lipids in a live cell, opening the possibility of studying lipid metabolism in real time and its many related diseases such as obesity.

In another partnership, with Dr. Jason Tsai of Pfizer, the researchers demonstrated the ability to measure distributions in skin of the common drug retinoic acid. This demonstrates the use of SRS microscopy for label-free studies of distributions and dynamic changes of drugs in living cell or tissues–which is expected to have widespread application in the drug industry. “This is a very novel way of generating contrast,” Tsai told BioOptics World, adding that the technique has “three characteristics that are enticing: it requires no labeling, it’s noninvasive, and it yields data in 3-D.” Tsai notes that the SRS’s impact has yet to be fully elucidated, but speaking for himself (and not on behalf of Pfizer) he says it is easy to see how it could improve early phase drug development among other applications.

Xie says biological specimens tolerate SRS well because it uses comparatively little laser power. –BG

  1. C.W. Freudiger et al, Science, Dec. 19, 2008.

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