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Raman probe could aid brain surgeons Meningiomas are silent growths. They develop when arachnoid cells in the meninges, the membranes that surround the brain, grow rampantly. Meningiomas are usually slow-growing tumors, and they increase pressure within the skull; this can cause headaches, sickness, and visual problems. To treat these growths, surgeons routinely cut away all of the tumor matter, a procedure known as resection. The challenge for the surgeon is to remove all of the tumor-infiltrated matter, including parts of the dura, the outermost layer of the meninges. Even a tiny bit of tumor can cause the meningioma to reappear, as it does in nearly one-third of all patients over a 15-yr time span. Meningiomas make up onefifth of all brain tumors. Although removing these cells may be routine, finding them is not. Currently, surgeons have no way to determine whether they have taken out all of the tumor matter. The situation is just as bad during the diagnostic phase. “Unfortunately, in many cases biopsies are taken blindly from a tissue region,” says Gerwin J. Puppels of Erasmus University Rotterdam (The Netherlands). Surgeons can’t know whether these samples are really representative of a patient’s condition, he adds. Now, in the December 15 issue of Analytical Chemistry (pp 7958–7965), Puppels and his colleagues describe a method based on Raman spectroscopy that promises to be the first step in detecting residual meningioma cells in vivo. The group’s Raman probe would have the additional benefit of providing surgeons with realtime guidance while operating. The first step for the Dutch scientists was to develop a protocol that reliably distinguishes between dura and tumor matter in plated samples. Their method takes advantage of the fact that every compound has a signature Raman spectrum. Dura and meningioma consist of different materials: Dura has a high collagen content, whereas the tumor itself has
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(a) A 1932 828 µm section of brain tissue with (b) dura matter shown in green and meningioma shown in red. In (c), the same tissue is labeled with d and m instead.
a high lipid content. These molecular differences give rise to large differences in the spectra. The researchers examined two common tumor types and one rare type. In total, they looked at 38 tissue samples taken from 20 patients and compared them with known spectra. The team then collected spectral data and plotted Raman maps. To quantify their findings, the researchers developed a correlation model that was based on linear discriminant analysis. The Raman maps correlated to the microscopic images. Overall, Puppels and colleagues could distinguish dura matter from tumor with an accuracy of 100%.
Although pure dura and meningioma samples can be identified very well, a surgeon would not have the benefit of gathering pure dura or meningioma spectra. Puppels et al. searched for a method to detect tumor matter in a spectrum containing both dura and tumor material. “The challenge lies in the fact that you want to be able to detect tumor tissue, even when it makes up only a small fraction of the tissue volume from which a spectrum is recorded,” Puppels says. At the moment, the researchers need ≥20% tumor matter in a probe to achieve reliable identification. That is too high, Puppels says. “That limit of detection is not yet very impressive but can be improved upon . . . by better instrumentation,” Puppels explains. Raman spectroscopy has long been used to study human tissue in vitro, but only a handful of articles have addressed brain tissue. It is a particularly attractive method because it does not need contrasting agents and is nondestructive. Several groups have reported the use of miniature fiber-optic probes that have delivered high-quality Raman spectra from patients. The next step will be to combine these laboratory findings with a flexible fiber-optic Raman probe. One challenge is eliminating the intense background signal generated in the optical fiber by the laser used in the experiments. A possible way around this problem is to use light in the highwavenumber region for in vivo applications; such light does not generate a background signal. “Because this renders the technology so simple, we believe that for many potential clinical applications, this is the quickest way forward, despite the fact that the spectral information that can be obtained in the high-wavenumber region is not as rich as that of the fingerprint region,” Puppels says. Although the group is working on brain tumors, Puppels believes the application will be useful in detecting many other illnesses. a —Eva von Schaper
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