A modular brain-on-a-chip for modelling epileptic seizures with functionally connected human neuronal networks

Area of Science:

• Neuroscience
• Biomedical Engineering
• Stem Cell Biology

Background:

• Epilepsies are neurological disorders characterized by recurrent seizures, which can be focal or widespread.
• Current human pluripotent stem cell (hPSC)-derived neuron models lack the ability to replicate connected neuronal networks or focal seizure activity.
• Modeling complex brain circuitry and localized neuronal activity in vitro remains a significant challenge.

Purpose of the Study:

• To develop and validate a novel in vitro platform for modeling focal epilepsies using human stem cell-derived neuronal networks.
• To create a microfluidic device capable of establishing controlled axonal connections between multiple neuronal networks.
• To assess the platform's ability to mimic both local and network-level brain circuitry and seizure dynamics.

Main Methods:

• Development of the Modular Platform for Epilepsy Modelling In Vitro (MEMO), a lab-on-chip device with microfluidic cell culture and microtunnels for axonal connections.
• Culture of three hPSC-derived neuronal networks within the MEMO device for up to 98 days.
• Monitoring of spontaneous neuronal network activity using an integrated custom-made microelectrode array (MEA).
• Application of a convulsant (kainic acid) and an anticonvulsant (phenytoin) to assess localized network responses.

Main Results:

• The MEMO platform successfully cultured connected hPSC-derived neuronal networks for extended periods (up to 98 days).
• Developed neuronal networks exhibited spontaneous burst activity, synchronous both within individual networks and between connected networks.
• The platform demonstrated the ability to model focal seizure activity, with kainic acid increasing bursts only in treated networks.
• Phenytoin's anticonvulsant effect was localized to the treated networks, confirming the chip's capacity for focal drug response modeling.

Conclusions:

• The MEMO platform provides a functional in vitro model for studying human neuronal network activity and epilepsy.
• This device enables the successful modeling of focal seizures and localized drug responses in connected neuronal networks.
• The developed chip represents a significant advancement for in vitro epilepsy research, offering insights into network-level pathophysiology.