Perfused drop microfluidic device for brain slice culture-based drug discovery

Liu, Jing; Pan, Liping; Cheng, Xuanhong; Berdichevsky, Yevgeny

doi:10.1007/s10544-016-0073-z

Cited by 14 publications

(15 citation statements)

References 41 publications

(51 reference statements)

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“…4(d); n = 36 cultures, from 10 animals]. The time course of epileptogenesis was consistent with previous observations in organotypic hippocampal cultures maintained on rocking plates [2], [3], [5], [6] and in perfused drops [19].…”

Section: B Validation Of In Vitro Model Of Epileptogenesis On μFlow-measupporting

confidence: 89%

“…[ Fig. 4(c)], as described previously [3,6,19]. The chronic data revealed epileptogenesis in organotypic cultures on μflow-MEA: a latent period after dissection, then spontaneous appearance of interictal and ictal events which continued in the later period.…”

Section: B Validation Of In Vitro Model Of Epileptogenesis On μFlow-measupporting

confidence: 75%

“…This limits applicability of typical MEAs to screens using organotypic hippocampal culture model of epilepsy. Our previously developed perfused drop technique can highly increase the throughput of organotypic culture experiments [19]. In this technique, hippocampal slice was maintained on a glass substrate in a medium drop confined by a polydimethylsiloxane (PDMS) culture well.…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery

Liu

Sternberg

Ghiasvand

et al. 2019

IEEE Trans. Biomed. Eng.

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Objective: Hippocampal slice cultures spontaneously develop chronic epilepsy several days after slicing and are used as an in vitro model of post-traumatic epilepsy. Here, we describe a hybrid microfluidic-microelectrode array (μflow-MEA) technology that incorporates microfluidic perfusion network and electrodes into a miniaturized device for hippocampal slice culture based antiepileptic drug discovery. Methods: Field potential simulation was conducted to help optimize the electrode design to detect seizure-like population activity. Epilepsy-on-a-chip model was validated by chronic electrical recording, neuronal survival quantification, and anticonvulsant test. To demonstrate the application of μflow-MEA in drug discovery, we utilized a two-stage screening platform to identify potential targets for antiepileptic drugs. In Stage I, lactate and lactate dehydrogenase biomarker assays were performed to identify potential drug candidates. In Stage II, candidate compounds were retested with μflow-MEA based chronic electrical assay to provide electrophysiological confirmation of biomarker results. Results and Conclusion: We screened 12 receptor tyrosine kinases inhibitors, and EGFR/ ErbB-2 inhibitor and cFMS inhibitor were identified as novel antiepileptic compounds. Significance: This epilepsy-on-a-chip system provides the means for rapid dissection of complex signaling pathways in epileptogenesis, paving the way for high-throughput antiepileptic drug discovery.

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Section: B Validation Of In Vitro Model Of Epileptogenesis On μFlow-measupporting

confidence: 89%

Section: B Validation Of In Vitro Model Of Epileptogenesis On μFlow-measupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery

Liu

Sternberg

Ghiasvand

et al. 2019

IEEE Trans. Biomed. Eng.

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“…Multielectrode arrays (MEAs) have been utilized to confirm the electrical activity of neural cells in neural networks [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Considering MEAs’ capability for not only the in situ detection of cellular electrical signals, but also electrical stimulation, they are ideal tools to apply to nervous system-on-a-chip systems.…”

Section: Future Directionsmentioning

confidence: 99%

Microdevice Platform for In Vitro Nervous System and Its Disease Model

2017

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The development of precise microdevices can be applied to the reconstruction of in vitro human microenvironmental systems with biomimetic physiological conditions that have highly tunable spatial and temporal features. Organ-on-a-chip can emulate human physiological functions, particularly at the organ level, as well as its specific roles in the body. Due to the complexity of the structure of the central nervous system and its intercellular interaction, there remains an urgent need for the development of human brain or nervous system models. Thus, various microdevice models have been proposed to mimic actual human brain physiology, which can be categorized as nervous system-on-a-chip. Nervous system-on-a-chip platforms can prove to be promising technologies, through the application of their biomimetic features to the etiology of neurodegenerative diseases. This article reviews the microdevices for nervous system-on-a-chip platform incorporated with neurobiology and microtechnology, including microfluidic designs that are biomimetic to the entire nervous system. The emulation of both neurodegenerative disorders and neural stem cell behavior patterns in micro-platforms is also provided, which can be used as a basis to construct nervous system-on-a-chip.

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“…These culture techniques complicate efforts to use organotypic cultures on chips, although special perforated or rocking MEAs have been developed for this purpose [ 68 , 69 , 70 , 71 ]. More recently, a method for maintaining organotypic cultures on planar, unperforated substrates has been reported [ 72 ]. This method was used to develop a multi-slice platform for drug discovery [ 73 ] and to re-create commissural and perforant pathways of the hippocampal formation [ 74 ].…”

Section: Structured Organotypic and 3d Dissociated Neural Culturesmentioning

confidence: 99%

Neural Circuits on a Chip

Hasan

Berdichevsky

2016

Micromachines

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Neural circuits are responsible for the brain’s ability to process and store information. Reductionist approaches to understanding the brain include isolation of individual neurons for detailed characterization. When maintained in vitro for several days or weeks, dissociated neurons self-assemble into randomly connected networks that produce synchronized activity and are capable of learning. This review focuses on efforts to control neuronal connectivity in vitro and construct living neural circuits of increasing complexity and precision. Microfabrication-based methods have been developed to guide network self-assembly, accomplishing control over in vitro circuit size and connectivity. The ability to control neural connectivity and synchronized activity led to the implementation of logic functions using living neurons. Techniques to construct and control three-dimensional circuits have also been established. Advances in multiple electrode arrays as well as genetically encoded, optical activity sensors and transducers enabled highly specific interfaces to circuits composed of thousands of neurons. Further advances in on-chip neural circuits may lead to better understanding of the brain.

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Perfused drop microfluidic device for brain slice culture-based drug discovery

Cited by 14 publications

References 41 publications

Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery

Epilepsy-on-a-Chip System for Antiepileptic Drug Discovery

Microdevice Platform for In Vitro Nervous System and Its Disease Model

Neural Circuits on a Chip

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