Long-Term Multiparameter Sensing Integrated On-Chip Ultrasound for Epileptic Neuron Modulation

Ultrasound neuromodulation holds great potential for treating neurological disorders. However, the molecular mechanisms underlying its effects remain unclear. There is a lack of systematic safety evaluation and standardized quantification of therapeutic outcomes. To address these challenges, this study integrates on-chip ultrasound with multiparameter cellular monitoring to quantitatively assess the therapeutic effects of various ultrasound parameters on neurological diseases from both electrophysiological and metabolic perspectives. Long-term monitoring is employed for a comprehensive evaluation of ultrasound safety. Notably, the combination of high-resolution, synchronous signal monitoring and biochemical indicators provides a deeper and more thorough understanding of the molecular mechanisms involved in ultrasound neuromodulation. Furthermore, using an on-chip epileptic neuron model, it is demonstrated that epileptic neurons exhibit high-frequency firing and synchronized oscillations in excitability, temperature, intracellular calcium, and mitochondrial calcium concentrations. The application of on-chip ultrasound effectively suppresses epileptiform discharges in neurons and inhibits both these oscillations and neuronal bursting events. When tuning with acoustic enhancer sodium valproate-loaded nanobubbles, the antiepileptic therapy effect can be significantly enhanced by maintaining mitochondrial calcium homeostasis. By integrating multiparameter long-term monitoring with on-chip ultrasound, this study presents an advanced approach for investigating the mechanisms of ultrasound neuromodulation, facilitating standardized evaluation and long-term safety assessment.