RT Journal Article
SR Electronic
T1 Continuous monitoring reveals protective effects of <em>N</em>-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.26.433307
DO 10.1101/2021.03.26.433307
A1 Isabelle Matthiesen
A1 Dimitrios Voulgaris
A1 Polyxeni Nikolakopoulou
A1 Thomas E. Winkler
A1 Anna Herland
YR 2021
UL http://biorxiv.org/content/early/2021/03/28/2021.03.26.433307.abstract
AB 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 &lt;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 StatementThe authors have declared no competing interest.