A modular brain-on-a-chip for modelling epileptic seizures with functionally connected human neuronal networks

Pelkonen, Anssi; Mzezewa, Ropafadzo; Sukki, Lassi; Ryynänen, Tomi; Kreutzer, Joose; Hyvärinen, Tanja; Vinogradov, Andrey; Aarnos, Laura; Lekkala, Jukka; Kallio, Pasi; Narkilahti, Susanna

doi:10.1016/j.bios.2020.112553

Cited by 54 publications

(59 citation statements)

References 48 publications

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“…Moreover, every step taken to add complexity may increase the variability and cause problems with reproducibility, particularly with self-organizing organoids. Nevertheless, successful efforts have been made to model focal seizures in vitro in a microfluidic device integrated with MEA [ 124 ]. In this device, three separate networks with synchronized bursting can be grown that make network-to-network contact via axonal connections through microtunnels.…”

Section: Future Directions and Challenges In In Vitro Seizure Liability Assessmentmentioning

confidence: 99%

“…In this device, three separate networks with synchronized bursting can be grown that make network-to-network contact via axonal connections through microtunnels. When one network is exposed to the convulsant kainate, the resulting seizure is local and does not spread to the other networks, thus allowing modeling of focal seizures [ 124 ].…”

Section: Future Directions and Challenges In In Vitro Seizure Liability Assessmentmentioning

confidence: 99%

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Novel test strategies for in vitro seizure liability assessment

Tukker¹,

Westerink

2021

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The increasing incidence of mental illnesses and neurodegenerative diseases results in a high demand for drugs targeting the central nervous system (CNS). These drugs easily reach the CNS, have a high affinity for CNS targets, and are prone to cause seizures as an adverse drug reaction. Current seizure liability assessment heavily depends on in vivo or ex vivo animal models and is therefore ethically debated, labor intensive, expensive, and not always predictive for human risk. Areas covered The demand for CNS drugs urges the development of alternative safety assessment strategies. Yet, the complexity of the CNS hampers reliable detection of compound-induced seizures. This review provides an overview of the requirements of in vitro seizure liability assays and highlights recent advances, including micro-electrode array (MEA) recordings using rodent and human cell models. Expert opinion Successful and cost-effective replacement of in vivo and ex vivo models for seizure liability screening can reduce animal use for drug development, while increasing the predictive value of the assays, particularly if human cell models are used. However, these novel test strategies require further validation and standardization as well as additional refinements to better mimic the human in vivo situation and increase their predictive value.

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Section: Future Directions and Challenges In In Vitro Seizure Liability Assessmentmentioning

confidence: 99%

Section: Future Directions and Challenges In In Vitro Seizure Liability Assessmentmentioning

confidence: 99%

Novel test strategies for in vitro seizure liability assessment

Tukker¹,

Westerink

2021

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

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“…[13][14][15] These were followed by microfluidic polydimethylsiloxane (PDMS)based devices, which currently represent the most common device type owing to their ease of fabrication and possibility of producing complex and highly controllable devices. [10,11,[16][17][18][19] Axonal isolation in PDMS microfluidic devices is based on microtunnels whose dimensions allow the passage of axons Axonal dysfunction and degeneration are important pathological features of central nervous system (CNS) diseases and traumas, such as Alzheimer's disease, traumatic brain injury, ischemic stroke and spinal cord injury. Engineered microfluidic chips combined with human pluripotent stem cell (hPSC)-derived neurons provide valuable tools for targeted in vitro research on axons to improve understanding of disease mechanisms and enhance drug development.…”

mentioning

confidence: 99%

Directional Growth of Human Neuronal Axons in a Microfluidic Device with Nanotopography on Azobenzene‐Based Material

Ristola

Fedele

Hagman

et al. 2021

Adv Materials Inter

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The polarized morphology of neurons allows the transmission of neuronal signals along long, slender axons over extended distances. The dysfunction and degeneration of axons are important hallmarks of many neurological disorders and traumas ranging from spinal cord injury to neurodegenerative diseases such as Alzheimer's disease. Thus, targeted research on axons is of great importance for improving the understanding of central nervous system (CNS) diseases and developing treatments for these devastating conditions, many of which lack disease-alleviating or disease-preventing therapies. [1,2] Human pluripotent stem cell (hPSC)-derived neural cells hold great promise for in vitro disease modeling and drug discovery for CNS diseases. [3,4] hPSCs provide an unlimited cell source for producing several types of neurons, and induced pluripotent stem cell (iPSC) technology enables the generation of patient-derived neurons that can recapitulate disease characteristics in vitro. [5,6] hPSC-based models have been used to study CNS diseases associated with axonal dysfunction and degeneration. [7][8][9] However, the full potential of in vitro modeling requires combining hPSC biology with state-of-the-art engineering technologies.Axonal research has been remarkably accelerated by the development of engineered in vitro devices that guide the organization of neurons, allowing the isolation of the axonal microenvironment. These compartmentalized devices enable precise spatial control, for example, targeted monitoring, measurement, and manipulation of axons, which are unfeasible or difficult to perform with conventional in vitro culture systems or in vivo. [10][11][12] The first devices used for neuron compartmentalization were Campenot chambers, which use a Teflon ring for the separation of neuronal somas and axons. [13][14][15] These were followed by microfluidic polydimethylsiloxane (PDMS)based devices, which currently represent the most common device type owing to their ease of fabrication and possibility of producing complex and highly controllable devices. [10,11,[16][17][18][19] Axonal isolation in PDMS microfluidic devices is based on microtunnels whose dimensions allow the passage of axons Axonal dysfunction and degeneration are important pathological features of central nervous system (CNS) diseases and traumas, such as Alzheimer's disease, traumatic brain injury, ischemic stroke and spinal cord injury. Engineered microfluidic chips combined with human pluripotent stem cell (hPSC)-derived neurons provide valuable tools for targeted in vitro research on axons to improve understanding of disease mechanisms and enhance drug development. Here, a polydimethylsiloxane (PDMS) microfluidic chip integrated with a light patterned substrate is utilized to achieve both isolated and unidirectional axonal growth of hPSC-derived neurons. The isolation of axons from somas and dendrites and robust axonal outgrowth to adjacent, axonal compartment, is achieved by optimized cross-sectional area and length of PDMS microtunnels in the microflu...

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“…The comparison of burst counts is further complicated by the variety of different burst detection algorithms in the field [ 141 ]. In addition, there are few reports on neural oscillations or LFP analysis in human 2D cultures on MEAs [ 61 ], even though many publications report oscillatory firing behavior [ 119 , 128 , 132 , 142 , 143 ].…”

Section: Hpsc-derived 2d Brain Models Of Measmentioning

confidence: 99%

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays

Pelkonen

Pistono

Klecki

et al. 2021

Cells

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Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.

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A modular brain-on-a-chip for modelling epileptic seizures with functionally connected human neuronal networks

Cited by 54 publications

References 48 publications

Novel test strategies for in vitro seizure liability assessment

Novel test strategies for in vitro seizure liability assessment

Directional Growth of Human Neuronal Axons in a Microfluidic Device with Nanotopography on Azobenzene‐Based Material

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays

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