Table 1.

The main characters of some microfluidic blood-brain barrier (BBB) models.

Source	Main Character of Chip Design	Source of Endothelial Cells	Co-Cultured Cells	Character of Membranes	Protein Used for Channel Coating	Electrode in Chip	Markers Used in Tight Junction Determination	TEER Value of the Models	Molecule Used in Permeability Test	Application
Ref. [36]	16 independent function units, each unit consists of four uniform BBB regions, replicate the complex multicellular architecture, mechanical properties, 3D extracellular matrix	Primary rat BMECs	Primary rat astrocytes	No membrane	Rat tail type-I collagen	No electrode in chip, normal resistance meter	VE-Cadherin, ZO-1, Claunin-5, etc. (immunofluorescence staining)	1298 Ω∙cm2	Sodium fluorescein (376 Da)	Examination of brain metastasis and the therapeutic response of brain tumors
Ref. [40]	Three PDMS layers plus the PC membrane that divides the two chambers.	Primary human BMECs	Primary pericytes, Primary astrocytes and pluripotent stem cell -derived neurons	PC membrane (0.2 μm pores)	Laminin	23 ga stainless steel, not in chip	ZO-1 (immunofluorescence staining)	Reported in Ω/cm2, need to be converted	FITC-dextran (10 and 70 kDa)	Ascorbate transport across the BBB as an indication of active transport
Ref. [58]	Multi-layered channel structure made from patterned PDMS substrate with embedded electrode layers.	bEnd.3 cell line	Astrocytes C6 cell line	PC membrane (10 μm thick, 0.4 μm pores)	Poly-lysine and fibronectin	Two sets AgCl electrodes.	ZO-1 (immunofluorescence staining)	223–280 Ω∙cm2	Not used	Permeability of seven neuroactive drugs and TEER were quantified in models.
Ref. [59]	3 μm pores to allow diffusion of media and tracer between the central and outer compartments	HUVECs	Astrocytes CTX-TNA2 cell line	3 μm pores	Martrigel and fibronectin	No electrode	Not detected	Not measured	Texas red dextran (370 kDa) and rhodamine 123	Comparing permeability of three passive permeability markers and one marker subject to efflux
Ref. [60]	Two separate microchannels supply their respective co-culture tissues independently of one another, and can serve as the microenvironment of the outside and the inside of the BBB respectively.	HUVECs and human lung fibroblasts	Primary rat astrocyte and neurons	No membrane, using fibrin hydrogel	Fibrin hydrogel	No electrode	ZO-1. (immunofluorescence staining)	Not measured	FITC-dextran (20 kDa, 70 kDa)	A platform exhibits direct contact between neural and vascular tissues and a corresponding low permeability characteristic of in vivo BBB
Ref. [61]	Two-chamber system divided by PC membrane	Primary human BMECs	Human induced pluripotent stem cell-derived neurons and astrocytes	PC membrane (0.2 μm pores)	Laminin	Custom-built multifrequency impedance analyzer	ZO-1, claudin -5 (immunofluorescence staining)	Reported in Ω, need to be converted	FITC-dextran (10 kDa)	Understand responses to inflammatory stimulation
Ref. [62]	Small model, two-layer microchannel and membrane with platinum electrodes.	hCMEC/D3 cell line	No co-cultured cells	PC membrane (10 μm thick, 0.4 μm pores)	Collagen I	Platinum electrodes (diameter 200 μm)	ZO-1 (immunofluorescence staining)	36.9–120 Ω∙cm2	Not used	Observe shear stress and TNF-α on BBB function
Ref. [63]	Vascular conduit overlaid on top of a neural chamber separated by a PC membrane	RBE4 cell line	Mixture of neurons (4%), astrocytes (95%), and microglia (1%).	PC membrane (8 μm pores)	Poly-lysine and fibronectin	No electrode	ZO-1 (western blot)	Not measured	Alexafluor-dextran (3 kDa)	TNF-α simulation triggered neuroinflammation
Ref. [64]	The apical and basolateral side separated by 3 μm gaps formed by microfabricated pillars.	RBE4 cell line	No co-cultured cells	No membrane, micro-gaps (50 μm long, 3 μm wide, 3 μm deep) in PDMS wall	Fibronectin	No electrode	ZO-1, claudin (western blot) and P-glycoprotein protein efflux	Not measured	FITC- dextran (3–5 kDa)	Astrocyte-conditioned medium on BBB function
Ref. [65]	Two-compartment microfluidic devices were a membrane between two channels.	bEnd.3 cell line	C8D1A astrocytes cell line	PTFE or PE membrane (0.4 μm pores)	Fibronectin or collagen I	No electrode	Claudin-5 (immunofluorescence staining)	Not measured	FITC-dextran (70 kDa)	Study the optically transparent membrane used in models
Ref. [66]	Composed of an upper and a lower part that are combined with an adhesive film, three microchannel systems are integrated	hCMEC/D3 cell line	Mouse embryonic stem cells derived cortical spheroids	Polyethylene terephthalate membrane and PC membrane	Collagen A	No electrode	VE cadherin, ᵦ-catenin, ZO-1 (immunofluorescence staining)	Not measured	FITC-dextran (3 kDa)	Detect effects of neuroinflammation upon disruption of the endothelial layer in response to inflammatory signals.
Ref. [67]	The porous membrane is situated between the upper and the lower channels made of PDMS. This core is sandwiched by two glass slides with gold electrodes.	hCMEC/D3 cell line, primary rat brain endothelial cells	primary astrocytes and brain pericytes.	PET membrane, (23 μm thick, 0.45 μm pores, pore density 2 × 106/cm2)	Rat tail collagen	A pair of 25-nm thick, transparent, gold electrodes was formed on each glass slide	ᵦ-catenin, ZO-1 (immunofluorescence staining)	monolayer: 28.5 ± 7.2 Ω∙cm2 Co-culture: 114.2 ± 35.7 Ω∙cm2	Sodium fluorescein (376 Da), FITC- dextran (4.4 kDa), Evans blue-labeled albumin (67 kDa)	Design a new device, which can co-culture of 3 types of cells, observe the cells by microscopy, monitor the TEER, and measure the monolayer permeability
Ref. [68]	Creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel	Primary human BMECs	Primary human brain pericytes, primary human brain astrocytes	No membrane	Rat tail collagen I	No electrode	VEcadherin, ZO-1 (immunofluorescence staining)	Not measured	Alexa488- dextran (3 kDa)	Study the secretion profiles of G-CSF, IL-6 and IL-8 when the BBB stimulated with TNF-α
Ref. [69,70]	Two PDMS components are separated by PC membrane and form two-chamber system	hCMEC/D3 cell line	No co-cultured cells	PC membrane (0.4 μm pores)	Fibronectin	Four platinum wire electrodes inserted into two channels	ZO-1 (immunofluorescence staining)	22 ± 1.3 Ω∙cm2	Not used	Developed a stable and easily method to determine TEER in organ-on-chip applications.
Ref. [71]	Transparent polyester porous membrane sandwiched between a top and a bottom overlying channel made of PMMA.	bEnd.3 cell line	No co-cultured cells	Polyester membrane (3 μm pores)	Not used	Platinum electrodes	Claudin-5 (immunofluorescence staining)	About 1000 Ω∙cm2	FITC- bovine serum albumin	Test the ability of a peptide to transport nanoparticles across BBB under flow conditions.
Ref. [72]	Two central hydrogel regions for co-culturing astrocytes and neurons, two side channels for hosting endothelial cells and media.	HUVECs and hCMEC/D3 cell line	Primary rat neurons and astrocytes	No membrane, separated by 9 trapezoidal structures	Poly-lysine and collagen I	No electrode	ZO-1 (immunofluorescence staining)	Not measured	Oregon green 488- dextran (10 kDa), Texas red dextran (70 kDa)	Compounds and factors on neural growth and maturation
Ref. [73]	Four rectangular channels with different heights to allow simultaneous measurements at different shear stresses.	Human BMECs from the BC1 human induced pluripotent stem cell line	No co-cultured cells	No membrane	Fibronectin and collagen IV	No electrode	claudin-5, occludin, and ZO-1 (immunofluorescence staining)	Not measured	Not used	Study the role of shear stress in modulating the character of human brain microvascular endothelial cells derived from induced pluripotent stem cells.
Ref. [74]	Consists of a cell insert and three 3D printed plastic layers with two electrodes	BMECs from human induced pluripotent stem cells	Primary rat astrocytes	PC membrane (0.4 μm pores)	Collagen IV and fibronectin	Two 0.8 mm diameter Ag/AgCl pellet electrode	ZO-1, Claunin-5. (immunofluorescence staining)	Peaked above 4000 Ω·cm2, sustained above 2000 Ω·cm2	FITC-dextran (70, 20 and 4 kDa), Caffeine, cimetidine, and doxorubicin	Model research
Ref. [75]	A double layer microfluidic device with an embedded membrane, the top layer contains a single channel, the bottom channel contains an array of 6 channels	hCMEC	No co-cultured cells	Polyester membrane (0.4 μm pores)	Fibronectin	No electrode	Not detected	Not measured	fluorescent sodium salt (376 Da), FITC- dextran (70 kDa)	Pulsed electric fields may enhance drug delivery to the brain by disrupting the integrity of the BBB and allowing otherwise impermeable drugs to reach target areas.
Ref. [76]	Two isolated compartments with the hydrogel reservoir	hCMEC/D3 cell line	p5–p7 normal human astrocytes	No membrane	Collagen I, matrigel, hyaluronan	No electrode in chip, normal impedance spectroscopy	ZO-1. (immunofluorescence staining)	Static condition: about 200 Ω·cm2 flow condition: about 1000 Ω·cm2	FITC-dextran (4 kDa)	Indicated that the mechanical stress exerted by blood flow is an important regulator of transport both across and along the walls of cerebral microvasculature.
Ref. [77]	A 4 × 4 intersecting microchannel array forms 16 BBB sites on a chip, with a multielectrode array integrated to measure the TEER from all 16 different sites.	Primary mouse BMECs	Primary mouse astrocytes	PC membrane (10 μm thick, 0.4 μm pores)	Fibronectin or matrigel	Multielectrode arrays, a thin titanium adhesion layer and a gold layer	ZO-1. (immunofluorescence staining)	Reported in Ω, need to be converted	Texas Red dextran (3 kDa), Alexa 546 dextran (10 kDa), FITC dextran (70 kDa)	Developed multisite BBB chip is expected to be used for screening drug by more accurately predicting their permeability through BBB as well as their toxicity.
Ref. [78]	Microchannel with temporary chitosan-based membrane	hCMEC/D3 cell line	P6-P10 human astrocytes from the cerebral cortex	temporary chitosan-based membrane	Hydrogel matrigel	No electrode	Not detected	Not measured	Not used	To obtain a co-culture without a nonphysiological membrane making use of a temporary chitosan membrane in a microfluidic channel.
Ref. [79]	Bio-printing, 10 μm average diameter tubes encasing a liquid flow having around 1 mm·s−1 average speed. On the surface of each tube regular pores allowing for mass transport.	bEnd.3 cell line	U87 glioblastoma cells	No membrane, porous tubular structures on tube surface (pore diameter: 1 μm)	Not used	No electrode in chip, commercially Voltohmmeter with two electrodes	ZO-1. (immunofluorescence staining)	75 ± 2 Ω∙cm2	Dextran	Presented a dynamic 3D biohybrid model of the BBB able to reproduce at 1:1 scale the capillaries of the neurovascular system.
Ref. [80]	High-throught, the model harbors 96 or 40 chips in a 384-well plate. In each chip, a perfused vessel of BMECs was grown against an extracellular matrix gel, astrocytes and pericytes were added on the other side of the gel to complete the BBB model.	Human TY10 cell line (isolated from normal brain tissue from a patient with meningioma)	Human hBPCT cell line pericytes from brain tissue of a patient t. Human hAst cell line astrocytes from human primary astrocytes distributed by Lonza.	No artificial membranes, using extracellular matrix gel	Collagen-I	No electrode	claudin-5, VE-cadherin, PECAM-1 (immunofluorescence staining)	Not measured	FITC-dextran (20 kDa)	Developed a high-throughput plate-based model, and used to assess passage of large biopharmaceuticals across the BBB.