BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

L.M. Griep, F. Wolbers, B. de Wagenaar, Paulus Martinus ter Braak, B.B. Weksler, A. Romero, P.O. Couraud, I. Vermes, Andries Dirk van der Meer, Albert van den Berg

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understood and therefore a realistic model of the BBB is essential. We present here the smallest model of the BBB yet, using a microfluidic chip, and the immortalized human brain endothelial cell line hCMEC/D3. Barrier function is modulated both mechanically, by exposure to fluid shear stress, and biochemically, by stimulation with tumor necrosis factor alpha (TNF-alpha), in one single device. The device has integrated electrodes to analyze barrier tightness by measuring the transendothelial electrical resistance (TEER). We demonstrate that hCMEC/D3 cells could be cultured in the microfluidic device up to 7 days, and that these cultures showed comparable TEER values with the well-established Transwell assay, with an average (+/- SEM) of 36.9 Omega.cm(2) (+/- 0.9 Omega.cm(2)) and 28.2 Omega.cm(2) (+/- 1.3 Omega.cm(2)) respectively. Moreover, hCMEC/D3 cells on chip expressed the tight junction protein Zonula Occludens-1 (ZO-1) at day 4. Furthermore, shear stress positively influenced barrier tightness and increased TEER values with a factor 3, up to 120 Omega.cm(2). Subsequent addition of TNF-alpha decreased the TEER with a factor of 10, down to 12 Omega.cm(2). This realistic microfluidic platform of the BBB is very well suited to study barrier function in detail and evaluate drug passage to finally gain more insight into the treatment of neurodegenerative diseases.
    Original languageUndefined
    Pages (from-to)145-150
    Number of pages6
    JournalBiomedical microdevices
    Volume15
    Issue number1
    DOIs
    Publication statusPublished - Feb 2013

    Keywords

    • TNF-α
    • hCMEC/D3
    • EWI-23777
    • Blood-brain barrier
    • IR-87419
    • Transwell
    • Shear stress
    • METIS-300047
    • Micro-fluidics

    Cite this

    Griep, L.M. ; Wolbers, F. ; de Wagenaar, B. ; ter Braak, Paulus Martinus ; Weksler, B.B. ; Romero, A. ; Couraud, P.O. ; Vermes, I. ; van der Meer, Andries Dirk ; van den Berg, Albert. / BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. In: Biomedical microdevices. 2013 ; Vol. 15, No. 1. pp. 145-150.
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    abstract = "The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understood and therefore a realistic model of the BBB is essential. We present here the smallest model of the BBB yet, using a microfluidic chip, and the immortalized human brain endothelial cell line hCMEC/D3. Barrier function is modulated both mechanically, by exposure to fluid shear stress, and biochemically, by stimulation with tumor necrosis factor alpha (TNF-alpha), in one single device. The device has integrated electrodes to analyze barrier tightness by measuring the transendothelial electrical resistance (TEER). We demonstrate that hCMEC/D3 cells could be cultured in the microfluidic device up to 7 days, and that these cultures showed comparable TEER values with the well-established Transwell assay, with an average (+/- SEM) of 36.9 Omega.cm(2) (+/- 0.9 Omega.cm(2)) and 28.2 Omega.cm(2) (+/- 1.3 Omega.cm(2)) respectively. Moreover, hCMEC/D3 cells on chip expressed the tight junction protein Zonula Occludens-1 (ZO-1) at day 4. Furthermore, shear stress positively influenced barrier tightness and increased TEER values with a factor 3, up to 120 Omega.cm(2). Subsequent addition of TNF-alpha decreased the TEER with a factor of 10, down to 12 Omega.cm(2). This realistic microfluidic platform of the BBB is very well suited to study barrier function in detail and evaluate drug passage to finally gain more insight into the treatment of neurodegenerative diseases.",
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    author = "L.M. Griep and F. Wolbers and {de Wagenaar}, B. and {ter Braak}, {Paulus Martinus} and B.B. Weksler and A. Romero and P.O. Couraud and I. Vermes and {van der Meer}, {Andries Dirk} and {van den Berg}, Albert",
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    BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. / Griep, L.M.; Wolbers, F.; de Wagenaar, B.; ter Braak, Paulus Martinus; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; van der Meer, Andries Dirk; van den Berg, Albert.

    In: Biomedical microdevices, Vol. 15, No. 1, 02.2013, p. 145-150.

    Research output: Contribution to journalArticleAcademicpeer-review

    TY - JOUR

    T1 - BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    AU - Griep, L.M.

    AU - Wolbers, F.

    AU - de Wagenaar, B.

    AU - ter Braak, Paulus Martinus

    AU - Weksler, B.B.

    AU - Romero, A.

    AU - Couraud, P.O.

    AU - Vermes, I.

    AU - van der Meer, Andries Dirk

    AU - van den Berg, Albert

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    AB - The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understood and therefore a realistic model of the BBB is essential. We present here the smallest model of the BBB yet, using a microfluidic chip, and the immortalized human brain endothelial cell line hCMEC/D3. Barrier function is modulated both mechanically, by exposure to fluid shear stress, and biochemically, by stimulation with tumor necrosis factor alpha (TNF-alpha), in one single device. The device has integrated electrodes to analyze barrier tightness by measuring the transendothelial electrical resistance (TEER). We demonstrate that hCMEC/D3 cells could be cultured in the microfluidic device up to 7 days, and that these cultures showed comparable TEER values with the well-established Transwell assay, with an average (+/- SEM) of 36.9 Omega.cm(2) (+/- 0.9 Omega.cm(2)) and 28.2 Omega.cm(2) (+/- 1.3 Omega.cm(2)) respectively. Moreover, hCMEC/D3 cells on chip expressed the tight junction protein Zonula Occludens-1 (ZO-1) at day 4. Furthermore, shear stress positively influenced barrier tightness and increased TEER values with a factor 3, up to 120 Omega.cm(2). Subsequent addition of TNF-alpha decreased the TEER with a factor of 10, down to 12 Omega.cm(2). This realistic microfluidic platform of the BBB is very well suited to study barrier function in detail and evaluate drug passage to finally gain more insight into the treatment of neurodegenerative diseases.

    KW - TNF-α

    KW - hCMEC/D3

    KW - EWI-23777

    KW - Blood-brain barrier

    KW - IR-87419

    KW - Transwell

    KW - Shear stress

    KW - METIS-300047

    KW - Micro-fluidics

    U2 - 10.1007/s10544-012-9699-7

    DO - 10.1007/s10544-012-9699-7

    M3 - Article

    VL - 15

    SP - 145

    EP - 150

    JO - Biomedical microdevices

    JF - Biomedical microdevices

    SN - 1387-2176

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    ER -