Reconstruction of directed neuronal networks in a microfluidic device with asymmetric microchannels

Courte, Josquin; Renault, Renaud; Jan, Audric; Viovy, Jean‐Louis; Peyrin, Jean‐Michel; Villard, Catherine

doi:10.1016/bs.mcb.2018.07.002

Cited by 25 publications

(25 citation statements)

References 22 publications

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“…Currently used OoC technologies applied to neuroscience have mostly focused on creating aligned and linear cell-cell interfaces, ranging from 2 18,32 , 3 33 . or 5 34 compartments connected, rather than on fabricating an in vitro model which specifically mimics the complex 3D connectivity across various brain regions.…”

Section: Resultsmentioning

confidence: 99%

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

Libralesso

Miny³

et al. 2021

Preprint

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In vitro modeling of human brain connectomes is key to explore the structure-function relationship of the central nervous system. The comprehension of this intricate relationship will serve to better study the pathological mechanisms of neurodegeneration, and hence to perform improved drug screenings for complex neurological disorders, such as Alzheimers and Parkinsons diseases. However, currently used in vitro modeling technologies lack potential to mimic physiologically relevant neural structures, because they are unable to represent the concurrent interconnectivity between myriad subtypes of neurons across multiple brain regions. Here, we present an innovative microfluidic design that allows the controlled and uniform deposition of various specialized neuronal populations within unique plating chambers of variable size and shape. By applying our design, we offer novel neuro-engineered microfluidic platforms, so called neurofluidic devices, which can be strategically used as organ-on-a-chip platforms for neuroscience research. Through the fine tuning of the hydrodynamic resistance and the cell deposition rate, the number of neurons seeded in each plating chamber can be tailored from a thousand up to a million, creating multi-nodal circuits that represent connectomes existing within the intact brain. These advances provide essential enhancements to in vitro platforms in the quest accurately model the brain for the investigation of human neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

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

Libralesso

Miny³

et al. 2021

Preprint

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“…Furthermore, most in vitro studies of neurologic diseases lack cell–cell contact and interstitial fluid flow, which can affect communication between nonsynaptic neurons [ 47 ]. Recent innovations in chip-based technologies have made it possible to control neuronal connectivity in vitro for deciphering pathological and physiological processes in neuronal networks [ 48 ]. Whilst these models will not replace animal models, for example, for behavioral or cognitive studies, they can be useful for examining underlying mechanisms of disease.…”

Section: Modeling Viral Diseases In Organ Chipsmentioning

confidence: 99%

Human Organs-on-Chips for Virology

Tang

Abouleila

et al. 2020

Trends in Microbiology

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While conventional in vitro culture systems and animal models have been used to study the pathogenesis of viral infections and to facilitate development of vaccines and therapeutics for viral diseases, models that can accurately recapitulate human responses to infection are still lacking. Human organ-on-a-chip (Organ Chip) microfluidic culture devices that recapitulate tissue–tissue interfaces, fluid flows, mechanical cues, and organ-level physiology have been developed to narrow the gap between in vitro experimental models and human pathophysiology. Here, we describe how recent developments in Organ Chips have enabled re-creation of complex pathophysiological features of human viral infections in vitro .

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“…A detailed version of the protocol used for the fabrication of SU-8 master mold, resin mold and culture chips can be found in [8]. Briefly, microchannels and culture compartments were drawn using QCAD.…”

Section: Microfluidic Culture Chipsmentioning

confidence: 99%

“…While these questions are barely testable in vivo, microfluidic approaches, which allow in vitro reconstruction of neural networks, may prove helpful to address these issues [8,11,14]. Here, we describe a new microfluidic design which allows full control of axonal outgrowth direction and therefore reconstruction of fully oriented binary neuronal networks.…”

Section: Introductionmentioning

confidence: 99%

Quantitative study of alpha-synuclein prion-like spreading in fully oriented reconstructed neural networks reveals non-synaptic dissemination of seeding aggregates

Courte

Bousset

et al. 2021

Preprint

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The trans-neuronal spread of protein aggregates in a prion-like manner underlies the progression of neuronal lesions in the brain of patients with synucleinopathies such as Parkinson's disease. Despite being studied actively, the mechanisms of alpha-synuclein (aSyn) aggregates propagation remain poorly understood. This hinders the development of therapeutic approaches aiming at preventing the spatial progression of intracellular inclusions in neural networks. To assess the role of synaptic structures and neuron characteristics in the transfer efficiency of aggregates with seeding propensity, we developed a novel microfluidic culture system which allows for the first time to reconstruct in vitro fully oriented and synaptically connected neural networks. This is achieved by filtering axonal growth with unidirectional "axon valves" microchannels. We exposed the presynaptic compartment of reconstructed networks to well characterized human aSyn aggregates differing in size: Fibrils and Oligomers. Both aggregates were transferred to postsynaptic neurons through active axonal transport, albeit with poor efficiency. By manipulating network maturity, we compared the transfer rate of aggregates in networks with distinct levels of synaptic connectivity. Surprisingly, we found that transfer efficiency was lower in mature networks with higher synaptic connectivity. We then investigated the seeding efficiency of endogenous aSyn in the postsynaptic population. We found that exposure to Fibrils, and not Oligomers, resulted in low efficiency trans-neuronal seeding which was restricted to postsynaptic axons. Finally, we assessed the impact of neuron characteristics and aSyn expression on the propagation of aSyn aggregates. By reconstructing chimeric networks, we found that neuron characteristics, such as the brain region from which they originate or aSyn expression levels, did not significantly impact aggregates transfer, and observed no trans-neuronal seeding where the presynaptic population did not express aSyn. Overall, we demonstrate that this novel platform uniquely allows the quantitative interrogation of original aspects of the trans-neuronal propagation of seeding pathogenic entities.

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Reconstruction of directed neuronal networks in a microfluidic device with asymmetric microchannels

Cited by 25 publications

References 22 publications

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

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

Human Organs-on-Chips for Virology

Quantitative study of alpha-synuclein prion-like spreading in fully oriented reconstructed neural networks reveals non-synaptic dissemination of seeding aggregates

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