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. 2023 May 30;13(6):591.
doi: 10.3390/bios13060591.

Discriminating Glioblastoma from Peritumoral Tissue by a Nanohole Array-Based Optical and Label-Free Biosensor

Víctor García-Milán  1 , Alfredo Franco  2   3 , Margarita Estreya Zvezdanova  3 , Sara Marcos  4 , Rubén Martin-Laez  1 , Fernando Moreno  2   3 , Carlos Velasquez  1   3   5 , José L Fernandez-Luna  3   6
Affiliations

Discriminating Glioblastoma from Peritumoral Tissue by a Nanohole Array-Based Optical and Label-Free Biosensor

Víctor García-Milán et al. Biosensors (Basel). .

Abstract

In glioblastoma (GBM) patients, maximal safe resection remains a challenge today due to its invasiveness and diffuse parenchymal infiltration. In this context, plasmonic biosensors could potentially help to discriminate tumor tissue from peritumoral parenchyma based on differences in their optical properties. A nanostructured gold biosensor was used ex vivo to identify tumor tissue in a prospective series of 35 GBM patients who underwent surgical treatment. For each patient, two paired samples, tumor and peritumoral tissue, were extracted. Then, the imprint left by each sample on the surface of the biosensor was individually analyzed, obtaining the difference between their refractive indices. The tumor and non-tumor origins of each tissue were assessed by histopathological analysis. The refractive index (RI) values obtained by analyzing the imprint of the tissue were significantly lower (p = 0.0047) in the peritumoral samples (1.341, Interquartile Range (IQR) 1.339-1.349) compared with the tumor samples (1.350, IQR 1.344-1.363). The ROC (receiver operating characteristic) curve showed the capacity of the biosensor to discriminate between both tissues (area under the curve, 0.8779, p < 0.0001). The Youden index provided an optimal RI cut-off point of 0.003. The sensitivity and specificity of the biosensor were 81% and 80%, respectively. Overall, the plasmonic-based nanostructured biosensor is a label-free system with the potential to be used for real-time intraoperative discrimination between tumor and peritumoral tissue in patients with GBM.

Keywords: biosensor; extraordinary optical transmission; glioblastoma; refractive index.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of the workflow. (a) Axial (upper panels) and coronal (lower panels) MRI images showing the tumor area (red) of a patient with a left temporal lobe GBM. The tumor area is defined by the contrast-enhanced portion of the T1-weighted sequence and is preplanned in the Brainlab Elements software. Green lines pinpoint the specific sites where the tissue samples were taken. (b) Heatmap showing the shift of the plasmon resonance wavelength at each position on the biosensor due to the RI of the imprint. A total of 144 measurements covering the entire biosensor were obtained for each tissue sample. A representative histogram showing the RI values of the imprints left by peritumoral (green) and tumor (red) tissues is shown. RIU, refractive index units. (c) Schematic representation of tumor and peritumoral areas of a GBM showing the tumor border and the necrotic tumor core. The right image shows a representative hematoxylin-eosin-stained section revealing the tumor-peritumoral tissue border.
Figure 2
Figure 2
Main parts of the biosensor device. (a) Halogen lamp as source of light. (b) Adapted upright microscope. (c) Sample holder with the biosensor (in yellow with vertical lines) at the bottom of a well that is filled with saline buffer during the measurements. (d) Scanning electron micrograph of the nanostructured gold film. (e) Optical fiber. (f) Spectrophotometer. (g) Representative spectral shift due to optical differences between GBM tumors and peritumoral tissues. As a background reference, the spectrum of phosphate buffered saline (PBS) is also included.
Figure 3
Figure 3
Representation of the experimental system and the proposed setup in the operating room. The upper panel shows the different steps, starting with tissue collection, which is deposited onto the biosensor. Then, tissue is removed, and optical measurements of the imprints left by both GBM and peritumoral tissues are obtained. The lower panel shows a representation of the proposed setup that would be used during a surgical procedure. Light passes through the fiber towards the biosensor, located at the tip of a holder, and is reflected back to a microspectrometer for real-time identification of the tissue. Arrows indicate the direction of the light. Illustration adapted from templates by BioRender.com.
Figure 4
Figure 4
Optical measurements of tissue imprints. Histograms show the RI values of the imprints left on the biosensor by peritumoral (green) and tumor (red) tissue. A magnified image of a representative histogram is shown in Figure 1B.
Figure 5
Figure 5
Receiver operating characteristic plot showing the biosensor’s capacity to discriminate between tumor and peritumoral tissues.
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