Intracranial-Implanted Coupled Electrode Tumor Treating Fields (ICE-TTF) Enable Efficient and Directionally Tunable Electric-Field Delivery for Glioma

BACKGROUND: Tumor treating fields (TTFields) improve survival in glioblastoma (GBM), but their clinical efficacy is limited by inefficient electric-field delivery through the high-impedance scalp and skull. This attenuation reduces intratumoral electric-field intensity and increases superficial power deposition, while external arrays remain associated with skin-interface complications. METHODS: We propose an intracranial-implanted coupled-electrode TTFields strategy (ICE-TTF), in which a single depth electrode implanted in the tumor cavity is coupled with distributed extracranial counter-electrodes. Finite-element modeling was used to optimize electrode geometry and evaluate electric-field and thermal distributions. A segmented intracranial electrode was examined for directional field switching. Short-term anti-tumor activity was assessed in rat glioma models using bioluminescence imaging and histology. Impedance monitoring and electrochemical assays were performed to evaluate interface behavior, short-term electrode stability, and tissue response. RESULTS: In simulations, ICE-TTF generated tumor electric-field intensities within the TTFields-relevant range with substantially lower power and lower temperature rise than external TTFields under matched coverage assumptions. Segmented contacts enabled switching between predominantly radial and tangential field components. In vivo, ICE-TTF attenuated the BLI-derived tumor-burden signal and reduced proliferative activity. Electrode-tissue impedance was associated with BLI-derived tumor-burden progression, supporting its potential as a candidate monitoring signal. Electrochemical modeling, ion-release measurements, and short-term histology supported short-term electrochemical stability and peri-electrode tissue compatibility of Pt-Ir electrodes under the tested high-frequency stimulation conditions. CONCLUSIONS: ICE-TTF represents a candidate reduced-implant-burden intracranial TTFields delivery architecture. The current data support simulation-based field-delivery feasibility, short-term proof-of-concept anti-tumor activity, and future impedance-informed monitoring, while direct comparative efficacy, survival benefit, and closed-loop control remain to be validated.