Background: structure and functions of the BBB
Main text
BBB dysfunction in neurological disorders
Contradictory findings across animal models of neurological diseases and their impact on human studies
Alzheimer’s disease (AD)
Huntington’s disease
Parkinson’s disease
Stroke
Importance of permeability studies in advanced BBB-on-chip models
Date published | Microvessel/endothelial compartment size | Material and membrane | Biological coating | Endothelial cell type | Additional cells in co-culture (type) | Barrier permeability tracer | Permeability measurement (cm/s) | TEER (Ω cm2) | Shear stress (dyne/cm2) | Ref# |
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2019 | Microfluidic device (200 μM width, 100 μM height) | PDMS | Human fibronectin (300 μg/ml) | Immortalized human cerebrovascular endothelial cells (hcmec\D3) | Astrocytes cultured in basolateral compartment | 10 kDa and 70 kDa FITC dextran | 10 kDa FITC dextran: 15 × 10−6 cm/s 70 kDa FITC dextran: 3.7 × 10−6 cm/s | NA | 2.73 | [143] |
2019 | 150 μM | PDMS | Collagen type IV and Fibronectin | BMECs derived from human iPSCs | N/A | Lucifer yellow, Alexa 647 conjugated 10 kDa dextran | Lucifer yellow: 5–6 × 10−7 Alexa 647 conjugated 10 kDa dextran: below detection limit | 2000–4000 | 1 | [144] |
2019 | (Two channels) 2 cm long and 1 mm wide; top and bottom channels were 1 and 0.2 mm high | PDMS), 2-channel, separated from a parallel vascular microchannel by a porous (2 μm diameter), polyethylene terephthalate (PET) membrane | Collagen type IV and fibronectin | iPS-BMVECs | Primary human pericytes and astrocytes | Fluorescent labeled of dextran tracers (3, 10, or 70 kDa) | 8.9, 1.1, and 0.24 × 10−8 cm/s for 3,10, and 70 kDa | 24,000a | 6 | |
2019 | 150 μm | Collagen type 1 rat (hydrogel) | Collagen type IV and fibronectin | iPS-BMVECs | NA | Lucifer yellow, Rhodamine 123 (R123), and 10 kDa dextran | LY = 2.84 ± 0.41 × 10−7 cm/s R123 = 1.32 ± 0.16 × 10−7 cm/s The permeability of 10 kDa dextran in dhBMEC microvessels was below the detection limit | NA | 4 | [71] |
2019 | Cylindrical template rod (150 μm) | Collagen type 1 rat hydrogel | Collagen type IV and fibronectin | Human iPSC-ECs | Human iPSC-pericyte | Lucifer yellow, and 10 kDa dextran | LY = 4 × 10−7 cm/s The permeability of 10 kDa dextran was below the detection limit | NA | 4 | [145] |
2018 | Self orgnized less than 100 μm | Fibrin gel | Fibronectin | Human iPSC-ECs | Primary human pericytes and astrocytes | 40 and 10 kDa FTIC-dextrans | Of 8.9 × 10−8 cm/s and 2.2 × 10−7 cm/s for 40 kDa and 10 kDa FTICdextran, | NA | NA | [146] |
2017 | Microfluidic chip with fluidic channels (190 μM height and 920 μM width) | PDMS, hydrogel channel is 580 μM wide while the fluidic channel is 920 μM wide. Endothelial cells seeded in the fluid channels. Astrocyte and Neurons mixed in collagen-1 and perfused in the hydrogel channels | Poly-d-Lysine | HUVEC or hcmec\D3 | Primary cortical neuron from rat, primary astrocytes from rat | 10 kDa Oregon green 488 dextran, 70 kDa Texas red dextran | 10 kDa Oregon green 488 dextran in HUVEC: 7 × 10−5 cm/s 70 kDa Texas Red Dextran in HUVEC: 5 × 10−5 cm/s 10 kDa Oregon green 488 dextran in hcmec\D3: 1 × 10−5 cm/s 70 kDa Texas Red Dextran in hcmec\D3: 0.25 × 10−5 cm/s | NA | NA | [73] |
2017 | Microfluidic device (width 2 mm and height of 0.2, 0.6 and 1 mm) | PDMS with polyester membrane (0.4 μM) | Fibronectin solution | Immortalized mouse endothelial cells (Bend3) | Immortalized mouse pericytes adhering to polyester membrane on 2nd channel and mouse astrocyte type I clone on the bottom of 2nd channel | 10 kDa Oregon green 488 dextran 70 kDa Texas red dextran | Monoculture: HUVEC: 7 × 10−5 cm/s (10 kDa), 5 × 10−5 cm/s (70 kDa) hcmec\D3 | Single culture: ~ 134 Bi culture: ~ 260 Triculture: ~ 310 | NA | [147] |
2017 | (300 μm * 160μm) | Polycarbonate insert with 04 μm pore size | Collagen type IV and fibronectin | Human iPSC-ECs | Rat primary astrocytes | 4, 20 and 70 KDa FITC-dextrans | 4 kDa = 10−7 and 20 and 70 was close to10−8 cm/s | 2000–4000 | 0.25 | [72] |
2017 | 180 μm cylindrical rod | Collagen type I hydrogel in PDMS | Collagen | (hCMEC/D3) | Human astrocytes | 4 kDa FITC-dextran | 0.8 × 10−6 cm/s | 200-1000 | 0.5 | [148] |
2016 | PDMS with collagen hydrogel inside (1 mm * 1 mm) | Collagen type 1 rat | NA | Primary human endothelial cells | Primary human pericytes and astrocytes | 3 kDa fluorescent dextran | 2–4 × 10−6 cm/s | NA | 1 | [149] |
2016 | Two rectangular PDMS channels with 3.7 cm × 0.2 cm × 0.2 cm size | Polycarbonate membrane with a thickness of 23 μm and a pore size 0.45 μm | Rat tail collagen | hCMEC/D3 | NA | Sodium fluorescein (376 Da), 4 kDa FITC-dextran, f Evans blue-labeled albumin (67 kDa) | Sodium fluorescein = 1.57 × 10−6cm/s 4 kDa Dextran = 1.32 × 10−6 Evans blue = 0.15 × 10−6cm/s | 28 | 0.15 | [150] |
2016 | Two rectangular PDMS channels with 3.7 cm × 0.2 cm × 0.2 cm size | Polycarbonate membrane with a thickness of 23 μm and a pore size 0.45 μm | Rat tail collagen | Primary rat brain endothelial cells | Rat primary pericytes and astroglia | Sodium fluorescein (376 Da), 4 kDa FITC-dextran, f Evans blue-labeled albumin (67 kDa) | Sodium fluorescein = 1.15 × 10−6cm/s 4 kDa Dextran = 0.20 × 10−6 Evans blue = 0.04 × 10−6cm/s | 114.2 | 0.15 | [150] |
2015 | Microfluidic chip with vascular channel having 100 μM height | PDMS, 0.2 μM Polycarbonate membrane | Laminin | Primary hBMVEC | Primary astrocytes, and pericytes plus neurons differentiated from hiPSCs | 10 kDa and 70 kDa FITC Dextran | Not measured. Only absolute fluorescence measured | Custom built impedance measurement (~ 12,000a) | NA | [96] |
2015 | 3D printed vessels having 235 and 260 μM diameters | 3D co-printing Vero White Plus-FullCure 835 resin as main framework and poly-vinyl alcohol (PVA) as a dissolvable support material | Fibronectin | Bend3 cells | N/A | 40 kDa FITC dextran | 2.27 × 10−7 cm/s | NA | NA | [151] |
2015 | Rectangular PDMS channel (6.3 mm × 100 μm) | PDMS | Fibronectin | Neonatal rat brain capillary endothelial cells | Primary cultures of neonatal rat astrocytes | 10 and 70 kDa fluorescent dextran | 2.9 ± 1.0 × 10−6 | 150-180 | 3.8 × 10−3 | [152] |
2015 | Rectangular PDMS channel (1 mm × 150 μm) | PDMS | Collagen IV–fibronectin | bEnd3 | Immortalized mouse astrocyte C8D1A | 70 KDa dextran | 5.9 × 10−7 cm/s | NA | 5 | [153] |
2013 | Rectangular PDMS channel (200 μm × 100 μm) | PDMS | Fibronectin | Rat brain EC (RBE4 cells) | N/A | 3 and 5 KD FITC-dextran | Relative comparison only | NA | NA | [154] |
2013 | PDMS channel (100 μM × 500 μM) | PDMS | Fibronectin | Rat brain EC (RBE4 cells) | E18 rat cortical cells | 3 kDa Alexa fluor-dextran | Relative comparison only | NA | NA | [155] |
2012 | Rectangular PDMS channel with a length of 1 cm, a width of 500 μm and a depth of 100 μm | Polycarbonate membrane with a thickness of 10 μm and a pore size of 0.4 μm | Rat collagen type I | (hCMEC/D3) | N/A | N/A | N/A | 120 | 5.8 | [156] |
2011 | 11 hollow polypropylene fibers (600 ± 90 μM) inside a sealed chamber (the extraluminal space) accessible by ports | Polypropylene with transcapillary pores (2 to 4 μM) | Fibronectin | Normal adult human brain microvascular endothelial cells | Human adult astrocytes | Sucrose, phenytoin and diazepam | Sucrose: 3.16 × 10−6, phenytoin: 6.75 × 10−5, diazepam: 6.88 × 10−3 cm/s | ~ 500 on the 21st day | 4 | [157] |
2002 | 11 hollow polypropylene fibers (600 ± 90 μM) inside a sealed chamber (the extraluminal space) accessible by ports | Polypropylene hollow fiber apparatus with 12 μM pores | Fibronectin | Bovine aortic endothelial cells (BAEC) | Rat glial cell tumor line | N/A | N/A | 500 | NA | [90] |