By Kate Wheeling
BU News Service

Brain tumor surgery is a balancing act. Cut out too much and your patient leaves with neurologic damage; too little and the tumor grows back. Surgeons use MRIs to locate tumors, but in the operating room they’re left with visual and tactile cues – discoloration here, a firm spot there – to guide them around tumors. These methods are surprisingly imprecise for a field in which precision is critical.

Now researchers at Harvard University and the University of Michigan are applying Stimulated Raman Scattering Microscopy, a technique recently developed in Dr. Sunney Xie’s Harvard laboratory, to differentiate between tumors and healthy tissue on a microscopic scale.

A study to evaluate the technique, published in September in Science Translational Medicine, focused on a tumor type called glioblastomas that grow winding tendrils throughout the brain. Glioblastomas are a particularly aggressive form of brain tumor – patients rarely survive more than a year after diagnosis. Tumor cores are easy to spot because they are crowded with dying cells, but the edges can be tricky. Tumor edges are a mixture of tumor cells and healthy tissue, making it impossible to tell where the tumor ends and normal tissue begins.

That is why these tumors recur “almost universally,” says Dr. Daniel Orringer, a neurosurgeon at the University of Michigan and co-author on the study. According to Orringer, surgeons routinely leave behind tumor cells that could have been safely removed. They just can’t see them under standard operating conditions.

To test whether Stimulated Raman Scattering Microscopy could help surgeons visualize tumor margins, researchers implanted human glioblastoma cancer cells into mice and waited for them to grow into tumors. Then they placed a laser scanning microscope over a hole in the skull of live mice and focused laser beams over a single focal spot of tissue at a time. The lasers caused different tissue types (e.g. healthy, lipid-rich brain tissue or protein-rich tumor tissue) to vibrate at different intensities. A computer program turned the vibrational signals from each point into a color-coded picture of the brain in real time, where tumor cells appeared blue and normal brain as green.

Using these computer generated images, researchers could distinguish tumors in tissue that appeared normal with standard techniques. Then when the group used the microscopy technique on human brain tissue samples, they found that the same cues used to distinguish tumor and normal tissue in mice held up in human tissue.

The group hopes to use Stimulated Raman Scattering Microscopy to maximize tumor removal and optimize surgical outcomes in humans, but right now the apparatus is too cumbersome for human applications. “What I would like to be able to do and what my colleagues tell me is possible to do is to develop a toothbrush-sized probe that we can place into someone’s head during surgery,” Orringer explained.

A prototype of this probe already exists, but several obstacles keep it from operating rooms. The concept needs to be validated using more human tissue samples and animal studies of the probe itself will need to be carried out. Aside from probe development, the group needs to build new lasers to achieve the same image quality in surgery that they had in the lab. They’re teaming up with two start-ups, Invenio Imaging and AdvancedMEMS, to address these engineering problems.

The cost may end up impeding biomedical applications even more than the technological obstacles, but experts say it’s worth it. Jerome Mertz, Professor of Biomedical Engineering at Boston University explains, “It’s a very expensive technique, but it’s really the only way to do what they’re doing.”