Advances in microfluidic in vitro systems for neurological disease modeling

Abstract

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Neuronal cultures show bidirectional axonal conduction with antidromic action potentials depolarizing the soma

“…Taken together, our results reshapes our understanding on how information flows in neuronal cultures by showing that EAPs/antidromic conduction occur in in vitro models of hippocampal and DRG neurons. Several studies have been trying to impose unidirectional outgrowth of axons via complex physical/chemical patterning (reviewed in (Aebersold et al, 2016; Holloway et al, 2021)). Our study suggests that unidirectional axonal outgrowth may not necessarily lead to unidirectional information flow, a finding with important implications for the “brain-on-chip” field.…”

“…The axon is often seen as a mere transmission cable for action potential (AP) propagation but this a very limiting view, partially arising from the technical challenges in recording from the thin axonal branches of vertebrate neurons (Alcami & El Hady, 2019; Debanne, Campanac, Bialowas, Carlier, & Alcaraz, 2011). Recent breakthroughs, made possible by in vitro technological developments such as super-resolution microscopy (Chéreau, Saraceno, Angibaud, Cattaert, & Nägerl, 2017), voltage imaging (Peterka, Takahashi, & Yuste, 2011), fluorescence-guided subcellular patch-clamp (Sasaki, Matsuki, & Ikegaya, 2011), microfluidic tools (Holloway et al, 2021; Estrela Neto et al, 2016), or microelectrode arrays (MEAs) (Emmenegger, Obien, Franke, & Hierlemann, 2019) have opened new insights into axonal signal conduction and generated a renewed interest in axon physiology. Accordingly, accumulating evidence shows that the computational repertoire of the axon is much more complex than traditionally thought (for reviews see (Alcami & El Hady, 2019; Bucher & Goaillard, 2011; Debanne et al, 2011; Sasaki, 2013; Traub, Whittington, Maier, Schmitz, & Nagy, 2020)).…”

Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system

“…In addition to selecting an appropriate cell source, it is crucial to verify the cells' functionality in the platform , as the platform itself might harm or otherwise alter cells' functionality. For example, brain parenchymal cells—unlike many other tissues, which are exposed to high shear flow (e.g., endothelium and epithelium)—are typically exposed to very low shear stress (approximately 0.01 dyne/cm 2 ); 12 therefore, culturing neurons in a microfluidic channel, under flow, might be harmful for the neurons, if the shear is not well monitored. A recent work by Lu et al further illustrates the importance of validating cell functionality in the platform, in showing that many of the currently used protocols for creating brain pluripotent stem cell (hPSC)-derived brain microvascular endothelial cells (iBMECS) actually create epithelium rather than endothelium.…”

“… 16 Accordingly, OoCs hold obvious appeal for CNS research, and several microfluidics-based CNS modeling systems (i.e., “Brains-on-a-Chip”) have already been developed—as discussed in numerous perspectives 17–21 and reviews. 12,22–35 …”

Deposition chamber technology as building blocks for a standardized brain-on-chip framework

“…Notably, recent advances on in vitro modeling applied to neuroscience exploit the potential of organ-on-a-chip (OoC) microfluidic technology [6][7][8] to regulate the connectivity between several compartmentalized neuronal populations, and hence recreate simplistic, yet relevant, neuronal networks [9][10][11][12][13][14] . Neuro-engineered OoC microfluidics, also known as neurofluidic devices, demonstrate the capacity to isolate, control, and manipulate cellular environments 15,16 , allowing to coculture different neural cell types while these are fluidly isolated [17][18][19] .…”