<i>In vitro</i> models of molecular and nano-particle transport across the blood-brain barrier

Hajal, Cynthia; Campisi, Marco; Mattu, Clara; Chiono, Valeria; Kamm, Roger D.

doi:10.1063/1.5027118

Cited by 67 publications

(50 citation statements)

References 168 publications

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“…[ 29 ] However, crucial cellular, genetic, immunologic, and molecular differences exist between humans and mice, limiting the capability of animal models to screen for therapeutics that effectively target the human brain. [ 30,31 ] Animal models also raise ethical issues, are costly and time‐consuming. [ 32 ] As such, more human‐relevant and efficient platforms are needed.…”

Section: Introductionmentioning

confidence: 99%

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

Lee

Campisi

Osaki

et al. 2020

Adv Healthcare Materials

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Polymer nanoparticles (NPs), due to their small size and surface functionalization potential have demonstrated effective drug transport across the blood–brain–barrier (BBB). Currently, the lack of in vitro BBB models that closely recapitulate complex human brain microenvironments contributes to high failure rates of neuropharmaceutical clinical trials. In this work, a previously established microfluidic 3D in vitro human BBB model, formed by the self‐assembly of human‐induced pluripotent stem cell‐derived endothelial cells, primary brain pericytes, and astrocytes in triculture within a 3D fibrin hydrogel is exploited to quantify polymer NP permeability, as a function of size and surface chemistry. Microvasculature are perfused with commercially available 100–400 nm fluorescent polystyrene (PS) NPs, and newly synthesized 100 nm rhodamine‐labeled polyurethane (PU) NPs. Confocal images are taken at different timepoints and computationally analyzed to quantify fluorescence intensity inside/outside the microvasculature, to determine NP spatial distribution and permeability in 3D. Results show similar permeability of PS and PU NPs, which increases after surface‐functionalization with brain‐associated ligand holo‐transferrin. Compared to conventional transwell models, the method enables rapid analysis of NP permeability in a physiologically relevant human BBB set‐up. Therefore, this work demonstrates a new methodology to preclinically assess NP ability to cross the human BBB.

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Section: Introductionmentioning

confidence: 99%

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

Lee

Campisi

Osaki

et al. 2020

Adv Healthcare Materials

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“…Recent advances in organ-on-a-chip technology have provided the ability to recapitulate the microenvironment of the BBB 18,19 . Existing in vitro human BBB-on-chip models have made efforts to reconstitute the tight endothelial barrier function using several platforms that include monoculture of brain endothelial cells 20 and co-culture of endothelial cells with astrocytes in twodimensional (2D) 21 and 3D 22,23 microenvironments.…”

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confidence: 99%

Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

et al. 2020

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Challenges in drug development of neurological diseases remain mainly ascribed to the blood-brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions. We demonstrate on-chip mimicry of the BBB structure and function by cellular interactions, key gene expressions, low permeability, and 3D astrocytic network with reduced reactive gliosis and polarized aquaporin-4 (AQP4) distribution. Moreover, our model precisely captures 3D nanoparticle distributions at cellular levels and demonstrates the distinct cellular uptakes and BBB penetrations through receptor-mediated transcytosis. Our BBB platform may present a complementary in vitro model to animal models for prescreening drug candidates for the treatment of neurological diseases.

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“…This result was different from our initial hypothesis that the efflux rate would be higher in BBB model due to increased expression of p-gp. However, transport system in BBB is not only limited to p-gp, but it is orchestrated by various modes such as carrier-mediated, receptor-mediated or paracellular transport [42–44]. This complex system could not be fully reconstituted in our in vitro model, therefore, this should be targeted to improve functional physiology in following future studies.…”

Section: Discussionmentioning

confidence: 99%

3D brain angiogenesis model to reconstitute maturation of functional human blood-brain barrier in vitro

Lee

Chung

Jeon

2018

Preprint

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The human central nervous system (CNS) vasculature expresses a distinctive barrier phenotype, the blood–brain barrier (BBB). As the BBB contributes to low efficiency in CNS pharmacotherapy by restricting drug transport, the development of an in vitro human BBB model has been in demand. Here, we present a microfluidic model of CNS angiogenesis having three‐dimensional (3D) lumenized vasculature in concert with perivascular cells. We confirmed the necessity of the angiogenic tri‐culture system (brain endothelium in direct interaction with pericytes and astrocytes) to attain essential phenotypes of BBB vasculature, such as minimized vessel diameter and maximized junction expression. In addition, lower vascular permeability is achieved in the tri‐culture condition compared to the monoculture condition. Notably, we focussed on reconstituting the functional efflux transporter system, including p‐glycoprotein (p‐gp), which is highly responsible for restrictive drug transport. By conducting the calcein‐AM efflux assay on our 3D perfusable vasculature after treatment of efflux transporter inhibitors, we confirmed the higher efflux property and prominent effect of inhibitors in the tri‐culture model. Taken together, we designed a 3D human BBB model with functional barrier properties based on a developmentally inspired CNS angiogenesis protocol. We expect the model to contribute to a deeper understanding of pathological CNS angiogenesis and the development of effective CNS medications.

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In vitro models of molecular and nano-particle transport across the blood-brain barrier

Cited by 67 publications

References 168 publications

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

3D brain angiogenesis model to reconstitute maturation of functional human blood-brain barrier in vitro

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