Abstract

‍

This invited review explores the latest advancements in 3D neuronal microphysiological systems (MPS) and their potential to replicate key structural and functional aspects of the human nervous system. From brain organoids and peripheral nerve models to engineered microenvironments and electrophysiological assessments, the paper outlines essential design considerations and translational applications that support a vision of a functional nervous system-on-a-chip. By integrating bioengineering, stem cell biology, and microfabrication, these systems promise more predictive, human-relevant tools for drug discovery, disease modeling, and ultimately reducing reliance on animal testing.

‍

Key Learnings

‍

• 3D neural cultures outperform 2D systems in recapitulating the structure, function, and connectivity of in vivo nervous tissue.

• Brain organoids and peripheral nerve MPS enable study of myelination, synaptic activity, neuroinflammation, and disease mechanisms.

• Electrophysiological readouts such as microelectrode arrays (MEA) are essential for real-time monitoring of neural function and drug effects.

• MPS models can now integrate glial diversity, enabling more complete modeling of neurodegenerative and neurodevelopmental conditions.

• Translational potential includes applications in drug screening, modeling the neuromuscular junction, and assessing neurotoxicity and viral infections.

‍

Methods

‍

This review synthesizes data and design principles from a wide range of studies related to:

• 3D brain organoid and spheroid formation using iPSC-derived neural cells

• Peripheral nerve MPS incorporating Schwann cells, sensory/motor neurons, and engineered myelination

• Use of MEAs, optogenetics, and calcium imaging for functional validation

• Inclusion of glial cells (astrocytes, oligodendrocytes, microglia) for advanced modeling

• Application of growth-restrictive hydrogels, bioengineered scaffolds, and microfluidic designs to mimic native histoarchitecture

‍

Conclusions

‍

3D neuronal microphysiological systems offer a transformative leap in how we model the central and peripheral nervous systems. These models go beyond symptom management by enabling high-fidelity representations of human neurobiology, including myelination, cell-cell signaling, and disease progression. Their increasing physiological relevance makes them critical tools for predictive toxicology, regenerative medicine, and drug discovery. The future of neuroscience research and therapeutic development will be shaped by these dynamic, functional nervous system-on-a-chip platforms.

‍

Reference

‍

Anderson WA, Bosak A, Hogberg HT, Hartung T, Moore MJ. Advances in 3D neuronal microphysiological systems: towards a functional nervous system on a chip. In Vitro Cell Dev Biol Anim. 2021;57(3):191–206. doi:10.1007/s11626-020-00532-8