Flexible Organic Electronic Devices for Pulsed Electric Field Therapy of Glioblastoma

Glioblastoma is difficult to eradicate with standard oncology therapies due to its high degree of invasiveness. Bioelectric treatments based on pulsed ...

Mines Saint-Etienne

Infrared neural stimulation is a promising tool for stimulating the brain because it can be used to excite with high spatial precision without the need of delivering or inserting any exogenous agent into the tissue. Very few studies have explored its use in the brain, as most investigations have focused on sensory or motor nerve stimulation. Using intravital calcium imaging with the genetically encoded calcium indicator GCaMP6f, here we show that the application of infrared neural stimulation induces intracellular calcium signals in Layer 2/3 neurons in mouse cortex in vivo. The number of neurons exhibiting infrared-induced calcium response as well as the amplitude of those signals are shown to be both increasing with the energy density applied. By studying as well the spatial extent of the stimulation, we show that reproducibility of the stimulation is achieved mainly in the central part of the infrared beam path. Stimulating in vivo at such a degree of precision and without any exogenous chromophores enables multiple applications, from mapping the brain's connectome to applications in systems neuroscience and the development of new therapeutic tools for investigating the pathological brain.

Two-photon GCaMP6f imaging of infrared neural stimulation evoked calcium signals in mouse cortical neurons in vivo.

Effective closed-loop neuromodulation relies on the acquisition of appropriate physiological control variables and the delivery of an appropriate stimulation signal. In particular, electroneurogram (ENG) data acquired from a set of electrodes applied at the surface of the nerve may be used as a potential control variable in this field. Improved electrode technologies and data processing methods are clearly needed in this context. In this work, we evaluated a new electrode technology based on multichannel organic electrodes (OE) and applied a signal processing chain in order to detect respiratory-related bursts from the phrenic nerve. Phrenic ENG (pENG) were acquired from nine Long Evans rats in situ preparations. For each preparation, a 16-channel OE was applied around the phrenic nerve's surface and a suction electrode was applied to the cut end of the same nerve. The former electrode provided input multivariate pENG signals while the latter electrode provided the gold standard for data analysis. Correlations between OE signals and that from the gold standard were estimated. Signal to noise ratio (SNR) and ROC curves were built to quantify phrenic bursts detection performance. Correlation score showed the ability of the OE to record high-quality pENG. Our methods allowed good phrenic bursts detection. However, we failed to demonstrate a spatial selectivity from the multiple pENG recorded with our OE matrix. Altogether, our results suggest that highly flexible and biocompatible multi-channel electrode may represent an interesting alternative to metallic cuff electrodes to perform nerve bursts detection and/or closed-loop neuromodulation.

Assessment of the Use of Multi-Channel Organic Electrodes to Record ENG on Small Nerves: Application to Phrenic Nerve Burst Detection.

Glioblastoma Multiforme is a highly lethal form of brain cancer, resistant to traditional therapeutic approaches and oftentimes hardly resectable. The application of pulsed electric fields (PEF) is gaining prominence as a highly effective approach for combating malignant tumors. However, PEF application at high voltages can generate reactive oxygen species through electrochemical events at electrodes, which can greatly affect intracellular processes and damage healthy cells. Here, we present an in depth study on the cellular impact of coating metal electrodes with an organic polymer PEDOT:PSS. We compared the effect of PEF application through coated and uncoated gold electrodes on the U87 human glioblastoma cell line. The results show that PEF application using PEDOT:PSS-coated electrodes does not induce intracellular ROS generation, even at high voltages, contrary to that observed with uncoated electrodes. PEF delivery with PEDOT:PSS coated electrodes results in minimal cell electroporation and a lower intracellular calcium response than uncoated metal electrodes. The application of the antioxidant MnTBAP allowed us to establish that superoxide generation is partially responsible for the higher intracellular calcium response observed in uncoated metal electrodes. The results demonstrate that PEDOT-coated electrodes allow for PEF application without intracellular ROS generation, with the trade-off being a diminished electroporation efficiency. These electrodes could therefore be useful for PEF application in ROS-sensitive tissues, as well as for disentangling the effect of PEFs on cells from the metabolic impact of electrolytic events arising from the electrode material.

David Moreau

Centre CMP,
Bioelectronics Department,
Centre CMP, Bioelectronics Department

Mines Saint-Etienne

Flexible Organic Electronic Devices for Pulsed Electric Field Therapy of Glioblastoma

David Moreau

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Mines Saint-Etienne

Flexible Organic Electronic Devices for Pulsed Electric Field Therapy of Glioblastoma

Centre CMP,
Bioelectronics Department,
Centre CMP, Bioelectronics Department