Advances in 3D neuronal microphysiological systems: towards a functional nervous system on a chip

Abstract

Microphysiological systems (MPS) designed to study the complexities of the peripheral and central nervous systems have made marked improvements over the years and have allowed researchers to assess in two and three dimensions the functional interconnectivity of neuronal tissues. The recent generation of brain organoids has further propelled the field into the nascent recapitulation of structural, functional, and effective connectivities which are found within the native human nervous system. Herein, we will review advances in culture methodologies, focused especially on those of human tissues, which seek to bridge the gap from 2D cultures to hierarchical and defined 3D MPS with the end goal of developing a robust nervous system-on-a-chip platform. These advances have far-reaching implications within basic science, pharmaceutical development, and translational medicine disciplines.

Morphine-sensitive synaptic transmission emerges in embryonic rat microphysiological model of lower afferent nociceptive signaling

“…The application of MPS has exciting potential for basic research into the neurobiology of pain and efficient screening of novel analgesics. The use of hPSC-derived tissue in MPS has recently garnered considerable interest, as it stands to eliminate interspecies differences that often confound translational research and enable patient-specific disease modeling and therapeutic intervention ( 20 , 71 ). However, nearly everything we know about the neurobiology of pain has been described using preclinical animal models.…”

A Novel Three-Dimensional Culture Device Favors a Myelinating Morphology of Neural Stem Cell-Derived Oligodendrocytes

“…In conclusion, a 3D microenvironment is essential for the proper differentiation and maturation of neural cells, shifting research toward the development of systems with different levels of complexity (Baldassarro et al, 2016) to avoid the production of immense amounts of discrepant data with low translational power, typical of the 2D-based gold standards for pre-clinical neurobiological research (Baldassarro et al, 2021). The main goal is to develop "microphysiological systems" to bridge the gap between these standardized 2D screening platforms and 3D systems which incorporate aspects of the tissue microenvironment (Anderson et al, 2021). In this preliminary study we described the first step of a simple and innovative 3D system for producing microenvironment-based strategies for OL studies, taking us another step closer to an ideal, yet still elusive in vitro model, one which strikes an optimal balance between a simplification of the model itself and the complexity of the myelination process.…”

A multimodal 3D neuro-microphysiological system with neurite-trapping microelectrodes

“…Such systems can simulate aspects of human physiology better than standard 2D approaches and reveal neuronal networks and processes at a resolution that is impossible in a whole organism. However, exploring the functional phenotype of 3D neuronal structures requires the capability to measure the electrical activity of individual neurons with millisecond resolution 37 . Commercial MEAs for 2D cultures perform poorly for 3D cultures, while recent solutions for 3D in vitro electrophysiological recordings 18,38 are incompatible with the throughput and simple cross-platform integration required by drug discovery efforts.…”