A Transparent, Microfluidic Lab On A Chip For Multi-Modal Cell Culture Monitoring For Neurotoxicity Research.

Abstract

Studying neurotoxicological responses in a physiologically relevant and translatable manner remains a major challenge in biomedical research. Consequently, there has been a major push toward establishing human tissue-native approaches in research and diagnostic pipelines. Here, we present a transparent microfluidic lab-on-a-chip platform integrating an embedded array of enzymatic electrochemical glutamate sensors for real-time monitoring of extracellular neurotransmitter dynamics in human induced pluripotent stem cell-derived (hiPSC) neuronal cell cultures. The system enables continuous, multimodal-compatible interrogation of cellular responses under controlled microenvironmental conditions. We validated the platform by measuring glutamate dynamics in under baseline conditions and following exposure to the environmental neurotoxins methylmercury (MeHg) and manganese (Mn); both known to alter glutamate dynamics. The sensors exhibited stable operation over more than one week in culture and reliably detected glutamate transients with concentrations up to 120 μM glutamate. MeHg exposure resulted in significant alterations in extracellular glutamate relative to control conditions, indicating disrupted glutamate homeostasis. Similarly, neuronal cultures exposed to 500 μM Mn for 24 h demonstrated significantly altered glutamate uptake dynamics. These results validate the proposed platform as a robust tool for investigating neurotoxin-induced perturbations in glutamatergic signaling and demonstrate the feasibility of integrating electrochemical enzymatic sensing into microfluidic systems for neurotoxicity research and discovery.