Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development

doi:10.1002/adhm.202303180

Review

. 2024 Aug;13(21):e2303180.

doi: 10.1002/adhm.202303180. Epub 2024 Mar 12.

Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development

Atharva R Mulay¹, Jihyun Hwang^{1

2}, Deok-Ho Kim^{2

3

4

5

6

7}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
² Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁴ Center for Microphysiological Systems, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁵ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁶ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, 21218, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21205, USA.

PMID: 38430211
PMCID: PMC11338747 (available on 2025-08-01)
DOI: 10.1002/adhm.202303180

Review

Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development

Atharva R Mulay et al. Adv Healthc Mater. 2024 Aug.

. 2024 Aug;13(21):e2303180.

doi: 10.1002/adhm.202303180. Epub 2024 Mar 12.

Authors

Atharva R Mulay¹, Jihyun Hwang^{1

2}, Deok-Ho Kim^{2

3

4

5

6

7}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
² Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
³ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁴ Center for Microphysiological Systems, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁵ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁶ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, 21218, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21205, USA.

PMID: 38430211
PMCID: PMC11338747 (available on 2025-08-01)
DOI: 10.1002/adhm.202303180

Abstract

The blood-brain barrier (BBB) is a highly controlled microenvironment that regulates the interactions between cerebral blood and brain tissue. Due to its selectivity, many therapeutics targeting various neurological disorders are not able to penetrate into brain tissue. Pre-clinical studies using animals and other in vitro platforms have not shown the ability to fully replicate the human BBB leading to the failure of a majority of therapeutics in clinical trials. However, recent innovations in vitro and ex vivo modeling called organs-on-chips have shown the potential to create more accurate disease models for improved drug development. These microfluidic platforms induce physiological stressors on cultured cells and are able to generate more physiologically accurate BBBs compared to previous in vitro models. In this review, different approaches to create BBBs-on-chips are explored alongside their application in modeling various neurological disorders and potential therapeutic efficacy. Additionally, organs-on-chips use in BBB drug delivery studies is discussed, and advances in linking brain organs-on-chips onto multiorgan platforms to mimic organ crosstalk are reviewed.

Keywords: blood‐brain barrier; drug development; multiorgan‐on‐a‐chip; neurological disorders; organ‐on‐a‐chip; pre‐clinical studies.

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Conflict of interest statement

Conflict of Interest

The authors declare the following competing financial interest(s): D.-H.K. is a scientific founder and equity holder of Curi Bio, Inc.

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[1] Daneman R & Prat A The Blood–Brain Barrier. Cold Spring Harb. Perspect. Biol 7, a020412 (2015). - PMC - PubMed

[2] Daneman R & Prat A The Blood–Brain Barrier. Cold Spring Harb. Perspect. Biol 7, a020412 (2015). - PMC - PubMed

[3] Blanchette M & Daneman R Formation and maintenance of the BBB. Mech. Dev 138, 8–16 (2015). - PubMed

[4] Blanchette M & Daneman R Formation and maintenance of the BBB. Mech. Dev 138, 8–16 (2015). - PubMed

[5] Rubin LL & Staddon JM The Cell Biology of the Blood-Brain Barrier. Annu. Rev. Neurosci 22, 11–28 (1999). - PubMed

[6] Rubin LL & Staddon JM The Cell Biology of the Blood-Brain Barrier. Annu. Rev. Neurosci 22, 11–28 (1999). - PubMed

[7] Armulik A et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010). - PubMed

[8] Armulik A et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010). - PubMed

[9] Hirschi KK & D’Amore PA Pericytes in the microvasculature. Cardiovasc. Res 32, 687–698 (1996). - PubMed

[10] Hirschi KK & D’Amore PA Pericytes in the microvasculature. Cardiovasc. Res 32, 687–698 (1996). - PubMed

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Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development

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Microphysiological Blood-Brain Barrier Systems for Disease Modeling and Drug Development

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