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Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

View ORCID ProfileIsabelle Matthiesen, View ORCID ProfileDimitrios Voulgaris, View ORCID ProfilePolyxeni Nikolakopoulou, View ORCID ProfileThomas E. Winkler, View ORCID ProfileAnna Herland
doi: https://doi.org/10.1101/2021.03.26.433307
Isabelle Matthiesen
1Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Malvinas Väg 10 pl 5, 100 44 Stockholm, Sweden E-mail:
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  • For correspondence: aherland@kth.se
Dimitrios Voulgaris
1Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Malvinas Väg 10 pl 5, 100 44 Stockholm, Sweden E-mail:
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Polyxeni Nikolakopoulou
2AIMES, Center for Integrated Medical and Engineering Science, Department of Neuroscience, Karolinska Institute, Solnavägen 9 / B8, 171 65 Solna, Sweden
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Thomas E. Winkler
1Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Malvinas Väg 10 pl 5, 100 44 Stockholm, Sweden E-mail:
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  • For correspondence: winklert@kth.se aherland@kth.se
Anna Herland
1Division of Micro- and Nanosystems, KTH Royal Institute of Technology, Malvinas Väg 10 pl 5, 100 44 Stockholm, Sweden E-mail:
2AIMES, Center for Integrated Medical and Engineering Science, Department of Neuroscience, Karolinska Institute, Solnavägen 9 / B8, 171 65 Solna, Sweden
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  • For correspondence: winklert@kth.se aherland@kth.se
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Abstract

Microphysiological systems mimic the in-vivo cellular ensemble and microenvironment with the goal of providing more human-like models for biopharmaceutical research. We report the first such model of the blood-brain barrier (BBB-on-chip) featuring both isogenic human induced pluripotent stem cell (hiPSC)-derived cells and continuous barrier integrity monitoring with <2-minute temporal resolution. We showcase its capabilities in the first microphysiological study of nitrosative stress and antioxidant prophylaxis. Relying on off-stoichiometry thiol-ene epoxy (OSTE+) for fabrication greatly facilitates assembly and sensor integration compared to the prevalent polydimethylsiloxane devices. The integrated cell-substrate endothelial resistance monitoring allows us to capture formation and breakdown of our blood-brain barrier model, consisting of co-cultured hiPSC-derived endothelial-like and astrocyte-like cells. We observe clear cellular disruption when exposing the BBB-on-chip to the nitrosative stressor linsidomine, and report on the barrier permeability and barrier-protective effects of the antioxidant N-acetylcysteine amide. Using metabolomic network analysis, we further find drug-induced changes consistent with prior literature regarding, e.g., cysteine and glutathione involvement. A model like ours opens new possibilities for drug screening studies and personalized medicine, relying solely on isogenic human-derived cells and providing high-resolution temporal readouts that can help in pharmacodynamic studies.

Competing Interest Statement

The authors have declared no competing interest.

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Posted March 28, 2021.
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Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit
Isabelle Matthiesen, Dimitrios Voulgaris, Polyxeni Nikolakopoulou, Thomas E. Winkler, Anna Herland
bioRxiv 2021.03.26.433307; doi: https://doi.org/10.1101/2021.03.26.433307
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Continuous monitoring reveals protective effects of N-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit
Isabelle Matthiesen, Dimitrios Voulgaris, Polyxeni Nikolakopoulou, Thomas E. Winkler, Anna Herland
bioRxiv 2021.03.26.433307; doi: https://doi.org/10.1101/2021.03.26.433307

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