The blood-brain barrier (BBB) is the tightest endothelial barrier in humans. Characterized by the presence of tight endothelial junctions and adherens junctions, the primary function of the BBB is to maintain brain homeostasis through the control of solute transit across the barrier. The specific features of this barrier make for unique modes of transport of solutes, nanoparticles, and cells across the BBB. Understanding the different routes of traffic adopted by each of these is therefore critical in the development of targeted therapies. In an attempt to move towards controlled experimental assays, multiple groups are now opting for the use of microfluidic systems. A comprehensive understanding of bio-transport processes across the BBB in microfluidic devices is therefore necessary to develop targeted and efficient therapies for a host of diseases ranging from neurological disorders to the spread of metastases in the brain.
References
1.
N. J.
Abbott
, A. A. K.
Patabendige
, D. E. M.
Dolman
, S. R.
Yusof
, and D. J.
Begley
, “Structure and function of the blood–brain barrier
,” Neurobiol. Dis.
37
, 13
–25
(2010
).2.
J.
Barar
, M. A.
Rafi
, M. M.
Pourseif
, and Y.
Omidi
, “Blood-brain barrier transport machineries and targeted therapy of brain diseases
,” Bioimpacts
6
, 225
–248
(2016
).3.
R.
Cecchelli
et al., “Modelling of the blood-brain barrier in drug discovery and development
,” Nat. Rev. Drug Discovery
6
, 650
–61
(2007
).4.
N. J.
Abbott
, L.
Rönnbäck
, and E.
Hansson
, “Astrocyte-endothelial interactions at the blood-brain barrier
,” Nat. Rev. Neurosci.
7
, 41
–53
(2006
).5.
Disorders, Brain Foundation.
6.
J.
Gaugler
, B.
James
, T.
Johnson
, K.
Scholz
, and J.
Weuve
, “2016 Alzheimer's disease facts and figures
,” Alzheimers Dementia
12
, 459
–509
(2016
).7.
A.
Rossi
et al., “Projection of the prevalence of Parkinson's disease in the coming decades: Revisited
,” Mov. Disord.
33
, 156
–159
(2017
).8.
G.
D'Andrea
, L.
Palombi
, G.
Minniti
, A.
Pesce
, and P.
Marchetti
, “Brain metastases: Surgical treatment and overall survival
,” World Neurosurg.
97
, 169
–177
(2017
).9.
W.
Löscher
and H.
Potschka
, “Blood-brain barrier active efflux transporters: ATP-binding cassette gene family
,” NeuroRX
2
, 86
–98
(2005
).10.
M. W.
van der Helm
, A. D.
van der Meer
, J. C. T.
Eijkel
, A.
van den Berg
, and L. I.
Segerink
, “Microfluidic organ-on-chip technology for blood-brain barrier research
,” Tissue Barriers
4
, e1142493
(2016
).11.
F.
Sohet
and R.
Daneman
, “Genetic mouse models to study blood-brain barrier development and function
,” Fluids Barriers CNS
10
, 1
(2013
).12.
I. W. Y.
Mak
, N.
Evaniew
, and M.
Ghert
, “Lost in translation: Animal models and clinical trials in cancer treatment
,” Am. J. Transl. Res.
6
, 114
–118
(2014
).13.
M.-F.
Chesselet
and S. T.
Carmichael
, “Animal models of neurological disorders
,” Neurotherapeutics
9
, 241
–244
(2012
).14.
D.
Pamies
, T.
Hartung
, and H. T.
Hogberg
, “Biological and medical applications of a brain-on-a-chip
,” Exp. Biol. Med.
239
, 1096
–1107
(2014
).15.
W. M.
Pardridge
, “Blood-brain barrier delivery
,” Drug Discovery Today
12
, 54
–61
(2007
).16.
Y.
Chen
and L.
Liu
, “Modern methods for delivery of drugs across the blood–brain barrier
,” Adv. Drug Delivery Rev.
64
, 640
–665
(2012
).17.
D. H.
Jo
, J. H.
Kim
, J.-I.
Heo
, J. H.
, Kim
, and C.-H.
Cho
, “Interaction between pericytes and endothelial cells leads to formation of tight junction in hyaloid vessels
,” Mol. Cells
36
, 465
–471
(2013
).18.
J. I.
Alvarez
et al., “The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence
,” Science
334
, 1727
–1731
(2011
).19.
C. F.
Lien
et al., “Absence of glial α-dystrobrevin causes abnormalities of the blood-brain barrier and progressive brain edema
,” J. Biol. Chem.
287
, 41374
–41385
(2012
).20.
J. I.
Alvarez
, T.
Katayama
, and A.
Prat
, “Glial influence on the blood brain barrier
,” Glia
61
, 1939
–1958
(2013
).21.
A.-C.
Luissint
, C.
Artus
, F.
Glacial
, K.
Ganeshamoorthy
, and P.-O.
Couraud
, “Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation
,” Fluids Barriers CNS
9
, 23
(2012
).22.
I. R.
Murray
et al., “Skeletal and cardiac muscle pericytes: Functions and therapeutic potential
,” Pharmacol. Ther.
171
, 65
–74
(2017
).23.
V.
Chintalgattu
et al., “Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity
,” Sci. Transl. Med.
5
, 187ra69
(2013
).24.
D. Y.
Park
et al., “Plastic roles of pericytes in the blood–retinal barrier
,” Nat. Commun.
8
, 15296
(2017
).25.
A.
Alimperti
et al., “Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N-cadherin balance in mural cell–endothelial cell-regulated barrier function
,” Proc. Natl. Acad. Sci.
114
, 8758
–8763
(2017
).26.
F. L.
Cardoso
, D.
Brites
, and M. A.
Brito
, “Looking at the blood–brain barrier: Molecular anatomy and possible investigation approaches
,” Brain Res. Rev.
64
, 328
–363
(2010
).27.
D. F.
Balkovetz
, “Tight junction claudins and the kidney in sickness and in health
,” Biochim. Biophys. Acta
1788
, 858
–863
(2009
).28.
N.
Kirschner
and J. M.
Brandner
, “Barriers and more: Functions of tight junction proteins in the skin
,” Ann. N. Y. Acad. Sci.
1257
, 158
–166
(2012
).29.
A.-M.
Tokes
, Z.
Schaff
, A. M.
Szasz
, and J.
Kulka
, “The distribution of tight junctions and junctional proteins in the human body
,” in Tight Junctions in Cancer Metastasis
(Springer
, Dordrecht
, 2013
), pp. 29
–64
.30.
Current Frontiers and Perspectives in Cell Biology
, edited by A.
Najman
(InTech
, 2012
).31.
H.-C.
Bauer
, I. A.
Krizbai
, H.
Bauer
, and A.
Traweger
, “‘You Shall Not Pass’—Tight junctions of the blood brain barrier
,” Front. Neurosci.
8
, 392
(2014
).32.
C.
Bardet
et al., “Claudin loss-of-function disrupts tight junctions and impairs amelogenesis
,” Front. Physiol.
8
, 326
(2017
).33.
K.
Ebnet
, “Junctional adhesion molecules (JAMs): Cell adhesion receptors with pleiotropic functions in cell physiology and development
,” Physiol. Rev.
97
, 1529
–1554
(2017
).34.
H. K.
Campbell
, J. L.
Maiers
, and K. A.
DeMali
, “Interplay between tight junctions and adherens junctions
,” Exp. Cell Res.
358
, 39
–44
(2017
).35.
G. A.
Rosenberg
, “Cerebrospinal fluid: Formation, absorption, markers, and relationship to blood–brain barrier
,” in Primer on Cerebrovascular Diseases
, 2nd ed., edited by L. R.
Caplan
et al. (Academic Press
, 2017
), Chap. 4, pp. 25
–31
.36.
A.
Tietz
and B.
Engelhardt
, “Brain barriers: {{crosstalk}} between complex tight junctions and adherens junctions
,” J. Cell Biol.
209
, 493
–506
(2015
).37.
E.
Dejana
, E.
Tournier-Lasserve
, and B. M.
Weinstein
, “The control of vascular integrity by endothelial cell junctions: Molecular basis and pathological implications
,” Dev. Cell
16
, 209
–221
(2009
).38.
Y.
Luo
and G. L.
Radice
, “N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis
,” J. Cell Biol.
169
, 29
–34
(2005
).39.
E. L. F.
Holzbaur
, L. A.
Ligon
, M.
Tokito
, and S.
Karki
, “Dynein binds to β-catenin and may tether microtubules at adherens junctions
,” Nat. Cell Biol.
3
, 913
(2001
).40.
L.
Fernández-Martín
et al., “Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function
,” Arterioscler. Thromb. Vasc. Biol.
32
, e90
–e102
(2012
).41.
C.
Derada Troletti
, P.
de Goede
, A.
Kamermans
, and H. E.
de Vries
, “Molecular alterations of the blood–brain barrier under inflammatory conditions: The role of endothelial to mesenchymal transition
,” Biochim. Biophys. Acta
1862
, 452
–460
(2016
).42.
A.
Rahman
, K.
Tihanyi
, I.
Choudhary
, and M.
Vastag
, Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates
(Bentham Science Publishers
, 2011
).43.
H.
Karanth
and M.
Rayasa
, “Nanotechnology in Brain Targeting
,” Int. J. Pharmaceutical Sci. Nanotech.
1
(1
), 9
–24
(2018
).44.
W. A.
Banks
, “Characteristics of compounds that cross the blood-brain barrier
,” BMC Neurol.
9
, S3
(2009
).45.
P.
Arranz-Gibert
et al., “Lipid bilayer crossing—The gate of symmetry. water-soluble phenylproline-based blood-brain barrier shuttles
,” J. Am. Chem. Soc.
137
, 7357
–7364
(2015
).46.
N. J.
Abbott
, “Blood–brain barrier structure and function and the challenges for CNS drug delivery
,” J. Inherited Metab. Dis.
36
, 437
–449
(2013
).47.
H.
Fischer
, R.
Gottschlich
, and A.
Seelig
, “Blood-brain barrier permeation: Molecular parameters governing passive diffusion
,” J. Membr. Biol.
165
, 201
–211
(1998
).48.
C. A.
Lipinski
, F.
Lombardo
, B. W.
Dominy
, and P. J.
Feeney
, “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
,” Adv. Drug Delivery Rev.
64
, 4
–17
(2012
).49.
A.
Dahlin
et al., “Gene expression profiling of transporters in the solute carrier and ATP-binding cassette superfamilies in human eye substructures
,” Mol. Pharm.
10
, 650
–663
(2013
).50.
W.
Wu
, A. V.
Dnyanmote
, and S. K.
Nigam
, “Remote communication through solute carriers and ATP binding cassette drug transporter pathways: An update on the remote sensing and signaling hypothesis
,” Mol. Pharmacol.
79
, 795
–805
(2011
).51.
K. A.
Nałęcz
, “Solute carriers in the blood–brain barier: Safety in abundance
,” Neurochem. Res.
42
, 795
–809
(2017
).52.
A.
Seelig
, “The role of size and charge for blood–brain barrier permeation of drugs and fatty acids
,” J. Mol. Neurosci.
33
, 32
–41
(2007
).53.
A. H.
Schinkel
, “P-Glycoprotein, a gatekeeper in the blood-brain barrier
,” Adv. Drug Delivery Rev.
36
, 179
–194
(1999
).54.
Z.
Ni
, Z.
Bikadi
, M. F.
Rosenberg
, and Q.
Mao
, “Structure and function of the human breast cancer resistance protein (BCRP/ABCG2)
,” Curr. Drug Metab.
11
, 603
–617
(2010
).55.
M. W.
Smith
and M.
Gumbleton
, “Endocytosis at the blood–brain barrier: From basic understanding to drug delivery strategies
,” J. Drug Target.
14
, 191
–214
(2006
).56.
A. R.
Jones
and E. V.
Shusta
, “Blood-brain barrier transport of therapeutics via receptor-mediation
,” Pharm. Res.
24
, 1759
–1771
(2007
).57.
F.
Hervé
, N.
Ghinea
, and J.-M.
Scherrmann
, “CNS delivery via adsorptive transcytosis
,” AAPS J.
10
, 455
–472
(2008
).58.
C.
Saraiva
et al., “Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases
,” J. Controlled Release
235
, 34
–47
(2016
).59.
J. V.
Georgieva
, D.
Hoekstra
, and I. S.
Zuhorn
, “Smuggling drugs into the brain: An overview of ligands targeting transcytosis for drug delivery across the blood-brain barrier
,” Pharmaceutics
6
, 557
–583
(2014
).60.
H.
Wolburg
, K.
Wolburg-Buchholz
, and B.
Engelhardt
, “Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact
,” Acta Neuropathol.
109
, 181
–190
(2005
).61.
C.
Pieper
, P.
Pieloch
, and H. J.
Galla
, “Pericytes support neutrophil transmigration via interleukin-8 across a porcine co-culture model of the blood-brain barrier
,” Brain Res.
1524
, 1
–11
(2013
).62.
J. P.
Konsman
, B.
Drukarch
, and A.-M.
Van Dam
, “(Peri)vascular production and action of pro-inflammatory cytokines in brain pathology
,” Clin. Sci.
112
, 1
–25
(2007
).63.
Y.
Takeshita
and R. M.
Ransohoff
, “Inflammatory cell trafficking across the blood-brain barrier (BBB): Chemokine regulation and in vitro models
,” Immunol. Rev.
248
, 228
–239
(2012
).64.
Y.
Kienast
et al., “Real-time imaging reveals the single steps of brain metastasis formation
,” Nat. Med.
16
, 116
–122
(2010
).65.
U. H.
Weidle
, F.
Birzele
, G.
Kollmorgen
, and R.
Rüger
, “Dissection of the process of brain metastasis reveals targets and mechanisms for molecular-based intervention
,” Cancer Genomics Proteomics
13
, 245
–258
(2016
).66.
C.
Fazakas
et al., “Transmigration of melanoma cells through the blood-brain barrier: Role of endothelial tight junctions and melanoma-released serine proteases
,” PLoS One
6
, e20758
(2011
).67.
Y.
Rolland
, M.
Demeule
, L.
Fenart
, and R.
Béliveau
, “Inhibition of melanoma brain metastasis by targeting melanotransferrin at the cell surface
,” Pigm. Cell Melanoma Res.
22
, 86
–98
(2009
).68.
A.
Boussommier-Calleja
, R.
Li
, M. B.
Chen
, S. C.
Wong
, and R. D.
Kamm
, “Microfluidics: A new tool for modeling cancer–immune interactions
,” Trends Cancer
2
, 6
–19
(2016
).69.
H.
Xu
et al., “A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors
,” Sci. Rep.
6
, 36670
(2016
).70.
S.
Lundquist
et al., “Prediction of drug transport through the blood-brain barrier in vivo: A comparison between two in vitro cell models
,” Pharm. Res.
19
, 976
–981
(2002
).71.
A.
Wolff
, M.
Antfolk
, B.
Brodin
, and M.
Tenje
, “In vitro blood–brain barrier models—An overview of established models and new microfluidic approaches
,” J. Pharm. Sci.
104
, 2727
–2746
(2015
).72.
C. J.
Czupalla
, S.
Liebner
, and K.
Devraj
, “In vitro models of the blood–brain barrier
,” in Cerebral Angiogenesis
(Humana Press
, New York, NY
, 2014
), pp. 415
–437
.73.
H. C.
Helms
et al., “In vitro models of the blood-brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use
,” J. Cereb. Blood Flow Metab.
36
, 862
(2016
).74.
Y.
Wang
et al., “In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells
,” Neural Regen. Res.
10
, 2011
–2017
(2015
).75.
V.
Siddharthan
, Y. V.
Kim
, S.
Liu
, and K. S.
Kim
, “Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells
,” Brain Res.
1147
, 39
–50
(2007
).76.
K.
Hatherell
, P. O.
Couraud
, I. A.
Romero
, B.
Weksler
, and G. J.
Pilkington
, “Development of a three-dimensional, all-human in vitro model of the blood-brain barrier using mono-, co-, and tri-cultivation Transwell models
,” J. Neurosci. Methods
199
, 223
–229
(2011
).77.
H. M.
Gibbons
and M.
Dragunow
, “Adult human brain cell culture for neuroscience research
,” Int. J. Biochem. Cell Biol.
42
, 844
–856
(2010
).78.
D. E.
Eigenmann
et al., “Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies
,” Fluids Barriers CNS
10
, 33
(2013
).79.
Y. K.
Kurokawa
et al., “Human induced pluripotent stem cell-derived endothelial cells for three-dimensional microphysiological systems
,” Tissue Eng. Part C
23
, 474
–484
(2017
).80.
G. A.
Calderon
et al., “Tubulogenesis of co-cultured human iPS-derived endothelial cells and human mesenchymal stem cells in fibrin and gelatin methacrylate gels
,” Biomater. Sci.
5
, 1652
–1660
(2017
).81.
E. S.
Lippmann
et al., “Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells
,” Nat. Biotechnol.
30
, 783
–791
(2012
).82.
E. S.
Lippmann
, A.
Al-Ahmad
, S. M.
Azarin
, S. P.
Palecek
, and E. V.
Shusta
, “A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources
,” Sci. Rep.
4
, 4160
(2014
).83.
Y.
He
, Y.
Yao
, S. E.
Tsirka
, and Y.
Cao
, “Cell-culture models of the blood–brain barrier
,” Stroke J. Cereb. Circ.
45
, 2514
–2526
(2014
).84.
Y. I.
Wang
, H. E.
Abaci
, and M. L.
Shuler
, “Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening
,” Biotechnol. Bioeng.
114
, 184
–194
(2017
).85.
J. A.
Brown
et al., “Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor
,” Biomicrofluidics
9
, 054124
(2015
).86.
G.
Adriani
, D.
Ma
, A.
Pavesi
, R. F.
Kamm
, and E. L. K.
Goh
, “A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier
,” Lab Chip
17
, 448
–459
(2017
).87.
A.
Herland
et al., “Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood-brain barrier on a chip
,” PLoS One
11
, e0150360
(2016
).88.
S.
Bang
et al., “A low permeability microfluidic blood-brain barrier platform with direct contact between perfusable vascular network and astrocytes
,” Sci. Rep.
7
, 8083
(2017
).89.
L.
Cucullo
, M.
Hossain
, V.
Puvenna
, N.
Marchi
, and D.
Janigro
, “The role of shear stress in blood-brain barrier endothelial physiology
,” BMC Neurosci.
12
, 40
(2011
).90.
D. T.
Phan
et al., “Blood-brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood-central nervous system interface
,” Exp. Biol. Med.
242
, 1669
–1678
(2017
).91.
M.
Kaya
and B.
Ahishali
, “Assessment of permeability in barrier type of endothelium in brain using tracers: Evans blue, sodium fluorescein, and horseradish peroxidase
,” in Permeability Barrier
(Humana Press
, 2011
), pp. 369
–382
.92.
N. R.
Saunders
, K. M.
Dziegielewska
, K.
Møllgård
, and M. D.
Habgood
, “Markers for blood-brain barrier integrity: How appropriate is evans blue in the twenty-first century and what are the alternatives?
,” Front. Neurosci.
9
, 385
(2015
).93.
A.
Hoffmann
et al., “High and low molecular weight fluorescein isothiocyanate (FITC)–dextrans to assess blood-brain barrier disruption: Technical considerations
,” Transl. Stroke Res.
2
, 106
–111
(2011
).94.
B.
Srinivasan
et al., “TEER measurement techniques for in vitro barrier model systems
,” J. Lab. Autom.
20
, 107
–126
(2015
).95.
M. W.
Helm
et al., “Simple and stable transendothelial electrical resistance measurement in organs-on-chips
,” in The 19th International Conference on Miniaturized Systems for Chemistry and Life Sciences
(Chemical and Biological Micro Systems Society
, 2015
), pp. 771
–773
.96.
L. M.
Griep
et al., “BBB on chip: Microfluidic platform to mechanically and biochemically modulate blood-brain barrier function
,” Biomed. Microdevices
15
, 145
–150
(2013
).97.
R.
Shawahna
, X.
Decleves
, and J.-M.
Scherrmann
, “Hurdles with using in vitro models to predict human blood-brain barrier drug permeability: A special focus on transporters and metabolizing enzymes
,” Curr. Drug Metab.
14
, 120
–136
(2013
).98.
S. N.
Bhatia
and D. E.
Ingber
, “Microfluidic organs-on-chips
,” Nat. Biotechnol.
32
, 760
–772
(2014
).99.
Y.
Shin
et al., “Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels
,” Nat. Protoc.
7
, 1247
–59
(2012
).100.
W.
Pan
, K. P.
Stone
, H.
Hsuchou
, V. K.
Manda
, Y.
Zhang
, and A. J.
Kastin
, “Cytokine signaling modulates blood-brain barrier function
,” Curr. Pharm. Des.
17
, 3729
–3740
(2011
).101.
J. A.
Macdonald
, N.
Murugesan
, and J. S.
Pachter
, “Endothelial cell heterogeneity of blood-brain barrier gene expression along the cerebral microvasculature
,” J. Neurosci. Res.
88
, 1457
–1474
(2009
).102.
K.
Kisler
, A. R.
Nelson
, A.
Montagne
, and B. V.
Zlokovic
, “Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease
,” Nat. Rev. Neurosci.
18
, 419
–434
(2017
).103.
W. M.
Pardridge
, “Drug transport across the blood-brain barrier
,” J. Cereb. Blood Flow Metab.
32
, 1959
–1972
(2012
).104.
D. S.
Miller
, B.
Bauer
, and A. M. S.
Hart
, “Modulation of P-glycoprotein at the blood-brain barrier: Opportunities to improve CNS pharmacotherapy
,” Pharmacol. Rev.
60
, 196
–209
(2009
).105.
L.
Probert
, “TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects
,” Neuroscience
302
, 2
–22
(2015
).106.
W.
Pan
, H.
Hsuchou
, H.
Tu
, and A. J.
Kastin
, “Developmental changes of leptin receptors in cerebral microvessels: Unexpected relation to leptin transport
,” Endocrinology
149
, 877
–885
(2008
).107.
T.
Wyss-Coray
, “Inflammation in Alzheimer disease: Driving force, bystander or beneficial response?
,” Nat. Med.
12
, 1191
–1197
(2006
).108.
A.
Chaudhuri
, F.
Duan
, B.
Morsey
, Y.
Persidsky
, and G. D.
Kanmogne
, “HIV-1 activates proinflammatory and interferon-inducible genes in human brain microvascular endothelial cells: Putative mechanisms of blood-brain barrier dysfunction
,” J. Cereb. Blood Flow Metab.
28
, 697
–711
(2008
).109.
L.
Cucullo
, N.
Marchi
, M.
Hossain
, and D.
Janigro
, “A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system
,” J. Cereb. Blood Flow Metab.
31
, 767
–777
(2011
).110.
E. V.
Shusta
, “Blood-brain barrier genomics, proteomics, and new transporter discovery
,” NeuroRx
2
, 151
–161
(2005
).111.
B.
Poller
et al., “The human brain endothelial cell line hCMEC/D3 as a human blood-brain barrier model for drug transport studies
,” J. Neurochem.
107
, 1358
–1368
(2008
).112.
E.
Urich
, S. E.
Lazic
, J.
Molnos
, I.
Wells
, and P. O.
Freskgård
, “Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models
,” PLoS One
7
, e38149
(2012
).113.
A.
Appelt-Menzel
et al., “Establishment of a human blood-brain barrier co-culture model mimicking the neurovascular unit using induced pluri- and multipotent stem cells
,” Stem Cell Rep.
8
, 894
–906
(2017
).114.
B.
Prabhakarpandian
et al., “SyM-BBB: A microfluidic blood brain barrier model
,” Lab Chip
13
, 1093
–1101
(2013
).115.
T.
Osaki
, Y.
Shin
, V.
Sivathanu
, M.
Campisi
, and R. D.
Kamm
, “In vitro microfluidic models for neurodegenerative disorders
,” Adv. Healthcare Mater.
7
, 1700489
(2017
).116.
S.
Ohtsuki
et al., “Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model
,” Mol. Pharm.
10
(1
), 289
–296
(2012
).117.
Y.
Sano
et al., “Establishment of a new conditionally immortalized human brain microvascular endothelial cell line retaining an in vivo blood-brain barrier function
,” J. Cell. Physiol.
225
, 519
–528
(2010
).118.
H.
Franke
, H. J.
Galla
, and C. T.
Beuckmann
, “An improved low-permeability in vitro-model of the blood-brain barrier: Transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol
,” Brain Res.
818
, 65
–71
(1999
).119.
Y.
Zhang
et al., “Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability
,” Drug Metab. Dispos.
34
, 1935
–1943
(2006
).120.
S. G.
Canfield
et al., “An isogenic blood–brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells
,” J. Neurochem.
140
, 874
–888
(2017
).121.
R. J.
Rist
et al., “F-actin cytoskeleton and sucrose permeability of immortalised rat brain microvascular endothelial cell monolayers: Effects of cyclic AMP and astrocytic factors
,” Brain Res.
768
, 10
–18
(1997
).122.
S. R.
Yusof
, A.
Avdeef
, and N. J.
Abbott
, “In vitro porcine blood-brain barrier model for permeability studies: PCEL-X software pKaFLUXmethod for aqueous boundary layer correction and detailed data analysis
,” Eur. J. Pharm. Sci.
65
, 98
–111
(2014
).123.
J. A.
Kim
et al., “Collagen-based brain microvasculature model in vitro using three-dimensional printed template
,” Biomicrofluidics
9
, 024115
(2015
).124.
E. W.
Esch
, A.
Bahinski
, and D.
Huh
, “Organs-on-chips at the frontiers of drug discovery
,” Nat. Rev. Drug Discovery
14
, 248
–260
(2015
).125.
R.
Booth
and H.
Kim
, “Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB)
,” Lab Chip
12
, 1784
(2012
).126.
G.
Quadrato
, J.
Brown
, and P.
Arlotta
, “The promises and challenges of human brain organoids as models of neuropsychiatric disease
,” Nat. Med.
22
, 1220
–1228
(2016
).127.
C. F.
Cho
et al., “Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents
,” Nat. Commun.
8
, 15623
(2017
).128.
M.
Grskovic
, A.
Javaherian
, B.
Strulovici
, and G. Q.
Daley
, “Induced pluripotent stem cells—Opportunities for disease modelling and drug discovery
,” Nat. Rev. Drug Discovery
10
, 915
–929
(2011
).129.
R.
Prantil-Baun
et al., “Physiologically-based pharmacokinetic and pharmacodynamic analysis enabled by microfluidically linked organs-on-chips
,” Annu. Rev. Pharmacol. Toxicol.
58
, 37
–64
(2016
).130.
K.
Domanskya
, D. C.
Lesliea
, J.
McKinneya
, J. P.
Frasera
, J. D.
Sliza
, T.
Hamkins-Indika
, G. A.
Hamiltona
, A.
Bahinskia
, and D. E.
Ingber
, “Clear castable polyurethane elastomer for fabrication of microfluidic devices
,” Lab Chip
13
, 3956
–3964
(2013
).131.
W. M.
Pardridge
, “Drug and gene delivery to the brain: The vascular route
,” Neuron
36
, 555
–558
(2002
).132.
L. S.
Honig
, B.
Vellas
, M.
Woodward
, M.
Boada
, R.
Bullock
, M.
Borrie
, K.
Hager
, N.
Andreasen
, E.
Scarpini
, H.
Liu-Seifert
, M.
Case
, R. A.
Dean
, A.
Hake
, K.
Sundell
, V.
Poole Hoffmann
, C.
Carlson
, R.
Khanna
, M.
Mintun
, R.
DeMattos
, K. J.
Selzler
, and E.
Siemers
, “Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease
,” N Engl J Med
378
, 321
–330
(2018
).133.
A.
Abbott
and E.
Dolgin
, “News in focus
,” Nature
540
, 15
–16
(2016
).134.
W. J.
Huang
, W. W.
Chen
, and X.
Zhang
, “Proteasome inhibitors in glioblastoma
,” Oncol. Lett.
13
, 1058
–1062
(2017
).135.
S.
Veszelka
, A.
Bocsik
, F. R.
Walter
, D.
Hantosi
, and M. A.
Deli
, “Blood-brain barrier co-culture models to study nanoparticle penetration: Focus on co-culture systems
,” Acta Biol. (Szeged)
59
, 157
–168
(2015
).136.
G.
Tosi
et al., “The ‘fate’ of polymeric and lipid nanoparticles for brain delivery and targeting: Strategies and mechanism of blood–brain barrier crossing and trafficking into the central nervous system
,” J. Drug Delivery Sci. Technol.
32
, 66
–76
(2016
).137.
D.
Belletti
et al., “Exploiting the versatility of cholesterol in nanoparticles formulation
,” Int. J. Pharm.
511
, 331
–340
(2016
).138.
S. P.
Manninger
et al., “An exploratory study of ferumoxtran-10 nanoparticles as a blood-brain barrier imaging agent targeting phagocytic cells in CNS inflammatory lesions
,” Am. J. Neuroradiol.
26
, 2290
–2300
(2005
).139.
B.
Chertok
et al., “Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors
,” Biomaterials
29
, 487
–496
(2008
).140.
X.
Meng
et al., “Specific targeting of gliomas with multifunctional superparamagnetic iron oxide nanoparticle optical and magnetic resonance imaging contrast agents
,” Acta Pharmacol. Sin.
28
, 2019
–2026
(2007
).141.
Z.
Bakhtiary
et al., “Targeted superparamagnetic iron oxide nanoparticles for early detection of cancer: Possibilities and challenges
,” Nanomed. Nanotechnol. Biol. Med.
12
, 287
–307
(2016
).142.
K.
Hu
et al., “Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: Preparation, characterization and efficacy in Parkinsons disease
,” Int. J. Pharm.
415
, 273
–283
(2011
).143.
J. A.
Loureiro
et al., “Cellular uptake of PLGA nanoparticles targeted with anti-amyloid and anti-transferrin receptor antibodies for Alzheimer's disease treatment
,” Colloids Surf. B
145
, 8
–13
(2016
).144.
T.
Moos
and E. H.
Morgan
, “Restricted transport of anti-transferrin receptor antibody (OX26) through the blood-brain barrier in the rat
,” J. Neurochem.
79
, 119
–129
(2001
).145.
S.
Paris-robidas
, V.
Emond
, C.
Tremblay
, and D.
Soulet
, “In vivo labeling of brain capillary endothelial cells after intravenous injection of monoclonal antibodies targeting the transferrin receptor
,” Mol. Pharmacol.
80
, 32
–39
(2011
).146.
R.
Dal Magro
et al., “ApoE-modified solid lipid nanoparticles: A feasible strategy to cross the blood-brain barrier
,” J. Controlled Release
249
, 103
–110
(2017
).147.
O.
Gartziandia
et al., “Chitosan coated nanostructured lipid carriers for brain delivery of proteins by intranasal administration
,” Colloids Surf. B
134
, 304
–313
(2015
).148.
B. D.
Chithrani
, A. A.
Ghazani
, and W. C. W.
Chan
, “Determing the size and shape dependence of gold nanoparticles uptake into mammalian cells
,” Nano Lett.
6
, 662
–668
(2006
).149.
F.
Lu
, S. H.
Wu
, Y.
Hung
, and C. Y.
Mou
, “Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles
,” Small
5
, 1408
–1413
(2009
).150.
W.
Jiang
, B. Y. S.
Kim
, J. T.
Rutka
, and W. C. W.
Chan
, “Nanoparticle-mediated cellular response is size-dependent
,” Nat. Nanotechnol.
3
, 145
–150
(2008
).151.
C.
Åberg
, “Quantitative analysis of nanoparticle transport through in vitro blood-brain barrier models
,” Tissue Barriers
4
, e1143545
(2016
).152.
H.
Ding
et al., “Enhanced blood-brain barrier transm
,” Nanotechnology
25
(5
), 055101
(2014
).153.
Y. C.
Kuo
and C. Y.
Shih-Huang
, “Solid lipid nanoparticles carrying chemotherapeutic drug across the blood-brain barrier through insulin receptor-mediated pathway
,” J. Drug Target.
21
, 730
–738
(2013
).154.
S.
Pilakka-Kanthikeel
, V. S. R.
Atluri
, V.
Sagar
, and M.
Nair
, “Targeted brain derived neurotropic factors (BDNF) delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: An in-vitro study
,” PLoS One
8
, e62241
(2013
).155.
R.
Prades
et al., “Delivery of gold nanoparticles to the brain by conjugation with a peptide that recognizes the transferrin receptor
,” Biomaterials
33
, 7194
–7205
(2012
).156.
D.
Ye
et al., “Nanoparticle accumulation and transcytosis in brain endothelial cell layers
,” Nanoscale
5
, 11153
(2013
).157.
J.
Chang
et al., “Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood-brain barrier
,” Int. J. Pharm.
379
, 285
–292
(2009
).158.
Y. C.
Kuo
and C. Y.
Chung
, “Transcytosis of CRM197-grafted polybutylcyanoacrylate nanoparticles for delivering zidovudine across human brain-microvascular endothelial cells
,” Colloids Surf. B
91
, 242
–249
(2012
).159.
Y. C.
Kuo
and C. L.
Lee
, “Methylmethacrylate-sulfopropylmethacrylate nanoparticles with surface RMP-7 for targeting delivery of antiretroviral drugs across the blood-brain barrier
,” Colloids Surf. B
90
, 75
–82
(2012
).160.
K. K.
Cheng
et al., “Highly stabilized curcumin nanoparticles tested in an in vitro blood–brain barrier model and in alzheimer's disease Tg2576 mice
,” AAPS J.
15
, 324
–336
(2013
).161.
N.
Nikandish
, L.
Hosseinzadeh
, A. H.
Azandaryani
, and K.
Derakhshandeh
, “The role of nanoparticle in brain permeability: An in-vitro BBB model
,” Iran. J. Pharm. Res.
15
, 403
–413
(2016
).162.
E.
Brun
, M.
Carrière
, and A.
Mabondzo
, “In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO2 nanoparticles
,” Biomaterials
33
, 886
–896
(2012
).163.
S.
Hanada
et al., “Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles' brain permeability in association with particle size and surface modification
,” Int. J. Mol. Sci.
15
, 1812
–1825
(2014
).164.
J. V.
Georgieva
et al., “Surface characteristics of nanoparticles determine their intracellular fate in and processing by human blood-brain barrier endothelial cells in vitro
,” Mol. Ther.
19
, 318
–325
(2011
).165.
H.
Baghirov
et al., “Feasibility study of the permeability and uptake of mesoporous silica nanoparticles across the blood-brain barrier
,” PLoS One
11
, 1
–22
(2016
).166.
A.
Bonoiu
et al., “MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier
,” Brain Res.
1282
, 142
–155
(2009
).167.
G.
Xu
et al., “Bioconjugated quantum rods as targeted probes for efficient transmigration across an in vitro blood-brain barrier
,” Bioconjugate Chem.
19
, 1179
–1185
(2008
).168.
L.
Shen
and H. F.
Ji
, “Contribution of degradation products to the anticancer activity of curcumin
,” Clin. Cancer Res.
15
, 7108
(2009
).169.
Q.
Wang
et al., “Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier
,” Int. J. Pharm.
288
, 349
–359
(2005
).170.
D. J.
Mc Carthy
, M.
Malhotra
, A. M.
O'Mahony
, J. F.
Cryan
, and C. m.
O'Driscoll
, “Nanoparticles and the blood-brain barrier: Advancing from in-vitro models towards therapeutic significance
,” Pharm. Res.
32
, 1161
–1185
(2015
).171.
M. N.
Pangalos
, L. E.
Schechter
, and O.
Hurko
, “Drug development for CNS disorders: strategies for balancing risk and reducing attrition
,” Nat. Rev. Drug Discovery
6
, 521
–32
(2007
).© 2018 Author(s).
2018
Author(s)
You do not currently have access to this content.
