Recent advancements on in vitro blood-brain barrier model: A reliable and efficient screening approach for preclinical and clinical investigation

References

• Solár P, Zamani A, Kubíčková L, et al. Choroid plexus and the blood-cerebrospinal fluid barrier in disease. Fluids Barriers CNS. 2020 May 6;17(1):35.
   PubMed Web of Science ®Google Scholar
• Rua R, McGavern DB. Advances in meningeal immunity. Trends Mol Med. 2018;24(6):542–559.
   PubMed Web of Science ®Google Scholar
• Banks WA. From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov. 2016 Apr 1;15(4):275–292.
   PubMed Web of Science ®Google Scholar
• Qi D, Lin H, Hu B, et al. A review on in vitro model of the blood-brain barrier (BBB) based on hCMEC/D3 cells. J Control Release. 2023 Jun 1;358:78–97. doi: 10.1016/j.jconrel.2023.04.020
   PubMed Web of Science ®Google Scholar
• Alexander A, Agrawal M, Uddin A, et al. Recent expansions of novel strategies towards the drug targeting into the brain. Int J Nanomedicine. 2019;14:5895–5909.
   PubMed Web of Science ®Google Scholar
• Brown TD, Nowak M, Bayles AV, et al. A microfluidic model of human brain (μHuB) for assessment of blood brain barrier. Bioeng Transl Med. 2019 May;4(2):e10126. doi: 10.1002/btm2.10126
   PubMed Web of Science ®Google Scholar
• Shawahna R, Decleves X, Scherrmann JM. 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. 2013 Jan;14(1):120–136.
   PubMed Web of Science ®Google Scholar
• Jagtiani E, Yeolekar M, Naik S, et al. In vitro blood brain barrier models: an overview. J Control Release. 2022 Mar 1;343:13–30. doi: 10.1016/j.jconrel.2022.01.011
   PubMed Web of Science ®Google Scholar
• Williams-Medina A, Deblock M, Janigro D. In vitro models of the blood–brain barrier: tools in translational medicine [Review]. Front Med Technol. 2021 Feb 15;2.
   Google Scholar
• Shah B, Dong X. Current status of in vitro models of the blood-brain barrier. Curr Drug Deliv. 2022;19(10):1034–1046. doi:10.2174/1567201819666220303102614
   PubMed Web of Science ®Google Scholar
• Dubey SK, Ram MS, Krishna KV, et al. Recent expansions on cellular models to uncover the scientific barriers towards drug development for alzheimer’s disease. Cell Mol Neurobiol. 2019 Mar;39(2):181–209. doi: 10.1007/s10571-019-00653-z
   PubMed Web of Science ®Google Scholar
• Agrawal M, Saraf S, Saraf S, et al. Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. J Control Release. 2020 May 10;321:372–415. doi: 10.1016/j.jconrel.2020.02.020
   PubMed Web of Science ®Google Scholar
• Aday S, Cecchelli R, Hallier-Vanuxeem D, et al. Stem cell-based human blood-brain barrier models for drug discovery and delivery. Trends Biotechnol. 2016 May;34(5):382–393. doi: 10.1016/j.tibtech.2016.01.001
   PubMed Web of Science ®Google Scholar
• Greene C, Hanley N, Campbell M. Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS. 2019 Jan 29;16(1):3.
   PubMed Web of Science ®Google Scholar
• Lochhead JJ, Yang J, Ronaldson PT, et al. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders. Front Physiol. 2020;11:914.
   PubMed Web of Science ®Google Scholar
• Xu L, Nirwane A, Yao Y. Basement membrane and blood-brain barrier. Stroke Vasc Neurol. 2019 Jul;4(2):78–82.
   PubMedGoogle Scholar
• Agrawal M, Tripathi DK, Saraf S, et al. Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J Control Release. 2017;260:61–77.
   PubMed Web of Science ®Google Scholar
• Armulik A, Genové G, Mäe M, et al. Pericytes regulate the blood–brain barrier. Nature. 2010 Nov 1;468(7323):557–561.
   PubMed Web of Science ®Google Scholar
• Díaz-Flores L, Gutiérrez R, Madrid JF, et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol. 2009 Jul;24(7):909–969. doi: 10.14670/HH-24.909
   PubMed Web of Science ®Google Scholar
• Reshma S, Megha KB, Amir S, et al. Blood brain barrier-on-a-chip to model neurological diseases. J Drug Delivery Sci Technol. 2023 Feb 1;80:104174. doi: 10.1016/j.jddst.2023.104174
   Web of Science ®Google Scholar
• Serlin Y, Shelef I, Knyazer B, et al. Anatomy and physiology of the blood–brain barrier. Semin Cell Dev Biol. 2015 Feb 1;38:2–6. doi: 10.1016/j.semcdb.2015.01.002
   PubMed Web of Science ®Google Scholar
• Gupta S, Dhanda S, Sandhir R. 2 - Anatomy and physiology of blood-brain barrier. In: Gao H, Gao X, editors. Brain targeted drug delivery system. United Kingdom: Academic Press; 2019. p. 7–31.
   Google Scholar
• Dhanda S, Sandhir R. Blood-brain barrier permeability is exacerbated in experimental model of hepatic encephalopathy via mmp-9 activation and downregulation of tight junction proteins. Mol Neurobiol. 2018 May;55(5):3642–3659.
   PubMed Web of Science ®Google Scholar
• Hanafy AS, Dietrich D, Fricker G, et al. Blood-brain barrier models: rationale for selection. Adv Drug Deliv Rev. 2021 Sept 1;176:113859. doi: 10.1016/j.addr.2021.113859
   PubMed Web of Science ®Google Scholar
• Terstappen GC, Meyer AH, Bell RD, et al. Strategies for delivering therapeutics across the blood–brain barrier. Nat Rev Drug Discov. 2021 May 1;20(5):362–383.
   PubMed Web of Science ®Google Scholar
• Clark DE. In silico prediction of blood–brain barrier permeation. Drug Discov Today. 2003 Oct 15;8(20):927–933.
   PubMed Web of Science ®Google Scholar
• Zhang -Y-Y, Liu H, Summerfield SG, et al. Integrating in silico and in vitro approaches to predict drug accessibility to the central nervous system. Mol Pharm. 2016 May 2;13(5):1540–1550.
   PubMedGoogle Scholar
• Helms HC, Abbott NJ, Burek M, 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. 2016 May;36(5):862–890. doi: 10.1177/0271678X16630991
   PubMed Web of Science ®Google Scholar
• Deli MA, Abrahám CS, Kataoka Y, et al. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol. 2005 Feb;25(1):59–127. doi: 10.1007/s10571-004-1377-8
   PubMed Web of Science ®Google Scholar
• Ulapane KR, On N, Kiptoo P, et al. Improving brain delivery of biomolecules via BBB modulation in mouse and rat: detection using MRI, NIRF, and mass spectrometry. Nanotheranostics. 2017;1(2):217–231. doi: 10.7150/ntno.19158
   PubMedGoogle Scholar
• Valic MS, Halim M, Schimmer P, et al. Guidelines for the experimental design of pharmacokinetic studies with nanomaterials in preclinical animal models. J Control Release. 2020 July 10;323:83–101. doi: 10.1016/j.jconrel.2020.04.002
   PubMed Web of Science ®Google Scholar
• Gonzales-Aloy E, Ahmed-Cox A, Tsoli M, et al. From cells to organoids: the evolution of blood-brain barrier technology for modelling drug delivery in brain cancer. Adv Drug Deliv Rev. 2023 May 1;196:114777. doi: 10.1016/j.addr.2023.114777
   PubMed Web of Science ®Google Scholar
• Kadry H, Noorani B, Cucullo L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020 Nov 18;17(1):69.
   PubMed Web of Science ®Google Scholar
• Nicolazzo JA, Charman SA, Charman WN. Methods to assess drug permeability across the blood-brain barrier. J Pharm Pharmacol. 2010;58(3):281–293.
   Google Scholar
• Lin Z, Jiang D, Liu D, et al. Noncontrast assessment of blood-brain barrier permeability to water: shorter acquisition, test-retest reproducibility, and comparison with contrast-based method. Magn Reson Med. 2021 Jul;86(1):143–156. doi: 10.1002/mrm.28687
   PubMed Web of Science ®Google Scholar
• Avdeef A, Deli MA, Neuhaus W. In vitro assays for assessing BBB permeability. Blood‐Brain Barrier Drug Disc. 2015;30:188–237.
   Google Scholar
• Noorani B, Chowdhury EA, Alqahtani F, et al. LC-MS/MS-based in vitro and in vivo investigation of blood-brain barrier integrity by simultaneous quantitation of mannitol and sucrose. Fluids Barriers CNS. 2020 Oct 14;17(1):61.
   PubMed Web of Science ®Google Scholar
• Kumar V, Lee JD, Coulson EJ, et al. A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models. J Neurochem. 2021 Aug;158(3):807–817. doi: 10.1111/jnc.15119
   PubMed Web of Science ®Google Scholar
• Kadir RRA, Alwjwaj M, Bayraktutan U. Establishment of an in vitro model of human blood-brain barrier to study the impact of ischemic injury. Methods Mol Biol. 2022;2492:143–155.
   PubMedGoogle Scholar
• Zhao W, Han L, Bae Y, et al. Lucifer yellow - a robust paracellular permeability marker in a cell model of the human blood-brain barrier. J Vis Exp. 2019 Aug;19(150):e58900.
   Google Scholar
• Ito R, Umehara K, Suzuki S, et al. A human immortalized cell-based blood–brain barrier triculture model: development and characterization as a promising tool for drug−brain permeability studies. Mol Pharm. 2019 Nov 4;16(11):4461–4471.
   PubMed Web of Science ®Google Scholar
• Sugiyama S, Sasaki T, Tanaka H, et al. The tight junction protein occludin modulates blood–brain barrier integrity and neurological function after ischemic stroke in mice. Sci Rep. 2023 Feb 18;13(1):2892.
   PubMed Web of Science ®Google Scholar
• Bauer H-C, Krizbai IA, Bauer H, et al. “You Shall Not Pass”—tight junctions of the blood brain barrier [Review]. Front Neurosci. 2014 December 3;8. doi: 10.3389/fnins.2014.00008
   PubMed Web of Science ®Google Scholar
• Lochhead JJ, Yang J, Ronaldson PT, et al. Structure, function, and regulation of the blood-brain barrier tight junction in central nervous system disorders [Review]. Front Physiol. 2020 August 6;11. doi: 10.3389/fphys.2020.00011
   PubMed Web of Science ®Google Scholar
• Sasson E, Anzi S, Bell B, et al. Nano-scale architecture of blood-brain barrier tight-junctions. eLife. 2021 Dec 24;10:e63253. doi: 10.7554/eLife.63253
   Google Scholar
• Srinivasan B, Kolli AR, Esch MB, et al. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015 Apr;20(2):107–126. doi: 10.1177/2211068214561025
   PubMedGoogle Scholar
• Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier.Adv Drug Deliv Rev. 1999 Apr 5;36(2–3):179–194. doi: 10.1016/S0169-409X(98)00085-4
   PubMed Web of Science ®Google Scholar
• Yan L, Moriarty RA, Stroka KM. Recent progress and new challenges in modeling of human pluripotent stem cell-derived blood-brain barrier. Theranostics. 2021;11(20):10148–10170.
   PubMed Web of Science ®Google Scholar
• Da Gama C S, Morin-Brureau M. Study of BBB dysregulation in neuropathogenicity using integrative human model of blood-brain barrier. Front Cell Neurosci. 2022;16:863836.
   PubMed Web of Science ®Google Scholar
• Brown LS, Foster CG, Courtney J-M, et al. Pericytes and neurovascular function in the healthy and diseased brain [mini review]. Front Cell Neurosci. 2019 June 28;13. doi: 10.3389/fncel.2019.00013
   PubMed Web of Science ®Google Scholar
• Bonkowski D, Katyshev V, Balabanov RD, et al. The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival. Fluids Barriers CNS. 2011 Jan 18;8(1).
   PubMedGoogle Scholar
• Cabezas R, Avila M, Gonzalez J, et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci. 2014;8:211.
   PubMed Web of Science ®Google Scholar
• Herland A, van der Meer AD, FitzGerald EA, et al. Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3d human blood-brain barrier on a chip. Plos One. 2016;11(3):e0150360. doi: 10.1371/journal.pone.0150360
   PubMed Web of Science ®Google Scholar
• Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006 Jan;7(1):41–53.
   PubMed Web of Science ®Google Scholar
• Yamaguchi T, Nishijima M, Kawabata K. Inhibition of glycogen synthase kinase 3ß enhances functions of induced pluripotent stem cell-derived brain microvascular endothelial cells in the blood-brain barrier. Biol Pharm Bull. 2022;45(10):1525–1530.
   PubMed Web of Science ®Google Scholar
• Nicolicht-Amorim P, Delgado-Garcia LM, Nakamura TKE, et al. Simple and efficient protocol to isolate and culture brain microvascular endothelial cells from newborn mice [Original Research]. Front Cell Neurosci. 2022 October 13;16. doi: 10.3389/fncel.2022.949412
   PubMed Web of Science ®Google Scholar
• Thomsen LB, Burkhart A, Moos T. A triple culture model of the blood-brain barrier using porcine brain endothelial cells, astrocytes and pericytes. Plos One. 2015;10(8):e0134765.
   PubMed Web of Science ®Google Scholar
• Yang J, Aschner M. Developmental aspects of blood–brain barrier (BBB) and rat brain endothelial (RBE4) cells as in vitro model for studies on chlorpyrifos transport. Neuro Toxicol. 2003 Aug 1;24(4):741–745.
   Google Scholar
• Gomez-Zepeda D, Perrière N, Glacial F, et al. Functional and targeted proteomics characterization of a human primary endothelial cell model of the blood-brain barrier (BBB) for drug permeability studies. Toxicol Appl Pharmacol. 2023 Apr 15;465:116456. doi: 10.1016/j.taap.2023.116456
   PubMed Web of Science ®Google Scholar
• Moya ELJ, Lombardo SM, Vandenhaute E, et al. Interaction of surfactant coated PLGA nanoparticles with in vitro human brain-like endothelial cells. Int J Pharm. 2022 Jun 10;621:121780. doi: 10.1016/j.ijpharm.2022.121780
   PubMed Web of Science ®Google Scholar
• Friedrich A, George RL, Bridges CC, et al. Transport of choline and its relationship to the expression of the organic cation transporters in a rat brain microvessel endothelial cell line (RBE4). Biochim Biophys Acta - Biomembr. 2001 Jun 6;1512(2):299–307.
   PubMed Web of Science ®Google Scholar
• Ning Y, Chen S, Li X, et al. Cholesterol, LDL, and 25-hydroxycholesterol regulate expression of the steroidogenic acute regulatory protein in microvascular endothelial cell line (Bend.3). Biochem Biophys Res Commun. 2006 Apr 21;342(4):1249–1256.
   PubMed Web of Science ®Google Scholar
• Yang S, Mei S, Jin H, et al. Identification of two immortalized cell lines, ECV304 and bEnd3, for in vitro permeability studies of blood-brain barrier. PLoS One. 2017;12(10):e0187017. doi: 10.1371/journal.pone.0187017
   PubMed Web of Science ®Google Scholar
• Neuhaus W, Lauer R, Oelzant S, et al. A novel flow based hollow-fiber blood–brain barrier in vitro model with immortalised cell line PBMEC/C1–2. J Biotechnol. 2006 Aug 20;125(1):127–141.
   PubMed Web of Science ®Google Scholar
• Adriani G, Ma D, Pavesi A, et al. A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. Lab Chip. 2017 Jan 31;17(3):448–459.
   PubMed Web of Science ®Google Scholar
• Cucullo L, Hossain M, Puvenna V, et al. The role of shear stress in blood-brain barrier endothelial physiology. BMC Neurosci. 2011 May 11;12(1):40.
   PubMedGoogle Scholar
• Cucullo L, McAllister MS, Kight K, et al. A new dynamic in vitro model for the multidimensional study of astrocyte–endothelial cell interactions at the blood–brain barrier. Brain Res. 2002 Oct 04;951(2):243–254.
   PubMed Web of Science ®Google Scholar
• Wagmann L, Gampfer TM, Meyer MRJA, et al. Recent trends in drugs of abuse metabolism studies for mass spectrometry–based analytical screening procedures. Anal Bioanal Chem Abbreviated as per journal style in globally. 2021;413:5551–5559.
   PubMed Web of Science ®Google Scholar
• Shah B, Dong XJCdd. Current status of in vitro models of the blood-brain barrier. Curr Drug Deliv. 2022.
   PubMed Web of Science ®Google Scholar
• Jeliazkova-Mecheva VV, Bobilya D. A porcine astrocyte/endothelial cell co-culture model of the blood–brain barrier. Brain Res Protoc Abbreviated as per journal style. 2003;12(2):91–98.
   PubMed Web of Science ®Google Scholar
• Wolff A, Antfolk M, Brodin B, et al. In vitro blood–brain barrier models—an overview of established models and new microfluidic approaches. J Pharmacl Sci abbreviated. 2015;104(9):2727–2746. doi: 10.1002/jps.24329
   PubMed Web of Science ®Google Scholar
• Nakagawa S, Deli MA, Kawaguchi H, et al. A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2009;54(3–4):253–263. doi: 10.1016/j.neuint.2008.12.002
   PubMed Web of Science ®Google Scholar
• SJTB-BBB N, Protocols R. Blood-brain barrier permeability using tracers and immunohistochemistry. Blood’Brain Barrier: Biology and Research Protocols. 2003;133–144.
   Google Scholar
• Piantino M, Louis F, Shigemoto-Mogami Y, et al. Brain microvascular endothelial cells derived from human induced pluripotent stem cells as in vitro model for assessing blood-brain barrier transferrin receptor-mediated transcytosis. Mater Today Bio. 2022 Mar 1;14:100232. doi: 10.1016/j.mtbio.2022.100232
   PubMedGoogle Scholar
• Perrière N, Demeuse P, Garcia E, et al. Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem. 2005 Apr;93(2):279–289. doi: 10.1111/j.1471-4159.2004.03020.x
   PubMed Web of Science ®Google Scholar
• Bernas MJ, Cardoso FL, Daley SK, et al. Establishment of primary cultures of human brain microvascular endothelial cells: a new and simplified method to obtain cells for an in vitro model of the blood-brain barrier. Nat Protoc. 2010;5(7):1265. doi: 10.1038/nprot.2010.76
   PubMed Web of Science ®Google Scholar
• Pong S, Karmacharya R, Sofman M, et al. The role of brain microvascular endothelial cell and blood-brain barrier dysfunction in schizophrenia. Compl Psych. 2020;6(1–2):30–46. doi: 10.1159/000511552
   PubMedGoogle Scholar
• Nishihara H, Perriot S, Gastfriend BD, et al. Intrinsic blood–brain barrier dysfunction contributes to multiple sclerosis pathogenesis. Brain: J Neurol. 2022;145(12):4334–4348. doi: 10.1093/brain/awac019
   Google Scholar
• Förster C, Burek M, Romero IA, et al. Differential effects of hydrocortisone and TNFα on tight junction proteins in an in vitro model of the human blood–brain barrier. J Physiol. 2008;586(7):1937–1949. doi: 10.1113/jphysiol.2007.146852
   PubMed Web of Science ®Google Scholar
• Łukasiewicz S, Błasiak E, Szczepanowicz K, et al. The interaction of clozapine loaded nanocapsules with the hCMEC/D3 cells – In vitro model of blood brain barrier. Colloids Surf, B. 2017;159:200–210. doi: 10.1016/j.colsurfb.2017.07.053
   PubMed Web of Science ®Google Scholar
• Hinkel S, Mattern K, Dietzel A, et al. Parametric investigation of static and dynamic cell culture conditions and their impact on hCMEC/D3 barrier properties. Int J Pharmac. 2019;566:434–444.
   PubMed Web of Science ®Google Scholar
• Cucullo L, Couraud P-O, Weksler B, et al. Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies. J Cereb Blood Flow Metab. 2008;28(2):312–328. doi: 10.1038/sj.jcbfm.9600525
   PubMed Web of Science ®Google Scholar
• Tricinci O, De Pasquale D, Marino A, et al. A 3D biohybrid real‐scale model of the brain cancer microenvironment for advanced in vitro testing. Adv Mate Technol. 2020;5(10):2000540. doi: 10.1002/admt.202000540
   PubMed Web of Science ®Google Scholar
• Adil MS, Prjpbm S. Protocols. Endothelial permeability assays in vitro. Meth Molecu Biol (Clifton, NJ). 2021;2367:177–191.
   PubMedGoogle Scholar
• Deepika D, Kumar S, Bravo N, et al. Chlorpyrifos, permethrin and cyfluthrin effect on cell survival, permeability, and tight junction in an in-vitro model of the human blood-brain barrier (BBB). Neurotoxicology. 2022;93:152–162.
   PubMed Web of Science ®Google Scholar
• Garberg P, Ball M, Borg N, et al. In vitro models for the blood–brain barrier. Toxicol vitro. 2005;19(3):299–334. doi: 10.1016/j.tiv.2004.06.011
   PubMed Web of Science ®Google Scholar
• Avdeef A. How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood–brain barrier permeability? Eur J Pharm Sci. 2011;43(3):109–124.
   PubMed Web of Science ®Google Scholar
• Burek M, Salvador E, Cyjj F. Generation of an immortalized murine brain microvascular endothelial cell line as an in vitro blood brain barrier model. J Visualized Exp. 2012(66):e4022.
   Google Scholar
• Molino Y, Jabès F, Lacassagne E, et al. Setting-up an in vitro model of rat blood-brain barrier (BBB): a focus on BBB impermeability and receptor-mediated transport. J Visualized Exp. 2014(88):e51278.
   Google Scholar
• Bowman PD, Ennis SR, Rarey KE, et al. Brain microvessel endothelial cells in tissue culture: a model for study of blood‐brain barrier permeability. Ann Neurol. 1983;14(4):396–402. doi: 10.1002/ana.410140403
   PubMed Web of Science ®Google Scholar
• Vandenhaute E, Dehouck L, Boucau M-C, et al. Modelling the neurovascular unit and the blood-brain barrier with the unique function of pericytes. Curr Neurovascu Res. 2011;8(4):258–269. doi: 10.2174/156720211798121016
   PubMed Web of Science ®Google Scholar
• Mischeck U, Meyer J, H-JJC G, et al. Characterization of γ-glutamyl transpeptidase activity of cultured endothelial cells from porcine brain capillaries. Cell and Tissue Res. 1989;256(1):221–226. doi: 10.1007/BF00224737
   PubMed Web of Science ®Google Scholar
• Patabendige A, Skinner RA, NJJBr A. Establishment of a simplified in vitro porcine blood–brain barrier model with high transendothelial electrical resistance. Brain Res. 2013;1521:1–15.
   PubMed Web of Science ®Google Scholar
• Thomsen LB, Burkhart A, TJPo M. A triple culture model of the blood-brain barrier using porcine brain endothelial cells, astrocytes and pericytes. Plos one. 2015;10(8):e0134765.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li CS, Ye Y, et al. Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability. Drug Metab Dispos. 2006;34(11):1935–1943. doi: 10.1124/dmd.105.006437.
   PubMed Web of Science ®Google Scholar
• Zhang Y-L, Wang J, Zhang Z-N, et al. The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer’s disease. Neural Regener Res. 2022;17(11):2355.
   PubMedGoogle Scholar
• Pirchl M, Marksteiner J, CJNr H. Effects of acidosis on brain capillary endothelial cells and cholinergic neurons: relevance to vascular dementia and Alzheimer’s disease. Neurol Res. 2006;28(6):657–664.
   PubMed Web of Science ®Google Scholar
• Puscas I, Bernard-Patrzynski F, Jutras M, et al. IVIVC assessment of two mouse brain endothelial cell models for drug screening. Pharmaceutics. 2019;11(11):587. doi: 10.3390/pharmaceutics11110587
   PubMed Web of Science ®Google Scholar
• Jamieson JJ, Searson PC, Gerecht S. Engineering the human blood-brain barrier in vitro. J Biol Eng. 2017;11(1):37.
   PubMedGoogle Scholar
• Canfield SG, Stebbins MJ, Morales BS, et al. An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells. J Neurochem. 2017 Mar;140(6):874–888. doi: 10.1111/jnc.13923
   PubMed Web of Science ®Google Scholar
• Mantle JL, Min L, Lee KH. Minimum transendothelial electrical resistance thresholds for the study of small and large molecule drug transport in a human in vitro blood-brain barrier model. Mol Pharm. 2016 Dec 5;13(12):4191–4198.
   PubMedGoogle Scholar
• Ballabh P, Braun A, Fau - Nedergaard M, et al. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16(1):969–9961.
   Web of Science ®Google Scholar
• Sano Y, Shimizu F, Abe M, 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. 2010 Nov;225(2):519–528. doi: 10.1002/jcp.22232
   PubMed Web of Science ®Google Scholar
• Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv. 2003 Mar;3(2):90–105, 51.
   PubMedGoogle Scholar
• Weiss N, Miller F, Cazaubon S, et al. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta. 2009 Apr;1788(4):842–857. doi: 10.1016/j.bbamem.2008.10.022
   PubMed Web of Science ®Google Scholar
• Kokubu Y, Yamaguchi T, Kawabata K. In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells. Biochem Biophys Res Commun. 2017 Apr 29;486(2):577–583.
   PubMed Web of Science ®Google Scholar
• Syvänen S, Lindhe O, Palner M, et al. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos. 2009 Mar;37(3):635–643. doi: 10.1124/dmd.108.024745
   PubMed Web of Science ®Google Scholar
• Cecchelli R, Berezowski V, Lundquist S, et al. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov. 2007 Aug;6(8):650–661. doi: 10.1038/nrd2368
   PubMed Web of Science ®Google Scholar
• Weksler BB, Subileau EA, Perrière N, et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. Faseb J. 2005 Nov;19(13):1872–1874. doi: 10.1096/fj.04-3458fje
   PubMed Web of Science ®Google Scholar
• Lippmann ES, Azarin SM, Kay JE, et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol. 2012 Aug;30(8):783–791. doi: 10.1038/nbt.2247
   PubMed Web of Science ®Google Scholar
• Appelt-Menzel A, Cubukova A, Günther K, 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 Reports. 2017 Apr 11;8(4):894–906.
   PubMed Web of Science ®Google Scholar
• Faley SL, Neal EH, Wang JX, et al. iPSC-derived brain endothelium exhibits stable, long-term barrier function in perfused hydrogel scaffolds. Stem Cell Reports. 2019 Mar 5;12(3):474–487.
   PubMed Web of Science ®Google Scholar
• Linville RM, DeStefano JG, Sklar MB, et al. Human iPSC-derived blood-brain barrier microvessels: validation of barrier function and endothelial cell behavior. Biomaterials. 2019 Jan;190-191:24–37.
   PubMed Web of Science ®Google Scholar
• Lippmann ES, Azarin SM, Palecek SP, et al. Commentary on human pluripotent stem cell-based blood-brain barrier models. Fluids Barriers CNS. 2020 Oct 19;17(1):64.
   PubMed Web of Science ®Google Scholar
• Bicker J, Alves G, Fortuna A, et al. A new PAMPA model using an in-house brain lipid extract for screening the blood-brain barrier permeability of drug candidates. Int J Pharm. 2016 Mar 30;501(1–2):102–111.
   PubMedGoogle Scholar
• Russo G, Grumetto L, Szucs R, et al. Determination of in vitro and in silico indexes for the modeling of blood-brain barrier partitioning of drugs via micellar and immobilized artificial membrane liquid chromatography. J Med Chem. 2017 May 11;60(9):3739–3754.
   PubMed Web of Science ®Google Scholar
• Radan M, Djikic T, Obradovic D, et al. Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates. Eur J Pharm Sci. 2022 Jan 1;168:106056. doi: 10.1016/j.ejps.2021.106056
   PubMed Web of Science ®Google Scholar
• Simon A, Darcsi A, Kéry Á, et al. Blood-brain barrier permeability study of ginger constituents. J Pharm Biomed Anal. 2020 Jan 5;177:112820. doi: 10.1016/j.jpba.2019.112820
   PubMed Web of Science ®Google Scholar
• Wilhelm I, Krizbai IA. In vitro models of the blood-brain barrier for the study of drug delivery to the brain. Mol Pharm. 2014 Jul 7;11(7):1949–1963.
   PubMedGoogle Scholar
• Siddharthan V, Kim YV, Liu S, et al. Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res. 2007 May 25;1147:39–50. doi: 10.1016/j.brainres.2007.02.029
   PubMed Web of Science ®Google Scholar
• Bagchi S, Lahooti B, Chhibber T, et al. In vitro models of central nervous system barriers for blood-brain barrier permeation studies. Nanomedicines for Brain Drug Delivery. 2021;235–253.
   Google Scholar
• Sivandzade F, Cucullo L. In-vitro blood-brain barrier modeling: a review of modern and fast-advancing technologies. J Cereb Blood Flow Metab. 2018 Oct;38(10):1667–1681.
   PubMed Web of Science ®Google Scholar
• Andjelkovic AV, Stamatovic SM, Phillips CM, et al. Modeling blood–brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms. Fluids Barriers CNS. 2020 July 16;17(1):44.
   PubMed Web of Science ®Google Scholar
• Bussolari SR, Dewey CF Jr, Gimbrone MA Jr. Apparatus for subjecting living cells to fluid shear stress. Rev Sci Instrum. 1982 Dec;53(12):1851–1854.
   PubMed Web of Science ®Google Scholar
• Cucullo L, Marchi N, Hossain M, et al. A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system. J Cereb Blood Flow Metab. 2011 Feb;31(2):767–777. doi: 10.1038/jcbfm.2010.162
   PubMed Web of Science ®Google Scholar
• Sreekanthreddy P, Gromnicova R, Davies H, et al. A three-dimensional model of the human blood-brain barrier to analyse the transport of nanoparticles and astrocyte/endothelial interactions. F1000Res. 2015;4:1279.
   PubMedGoogle Scholar
• Ferro MP, Heilshorn SC, Owens RM. Materials for blood brain barrier modeling in vitro. Mater Sci Eng R Rep. 2020 Apr 1;140:100522. doi: 10.1016/j.mser.2019.100522
   PubMed Web of Science ®Google Scholar
• Urich E, Patsch C, Aigner S, et al. Multicellular self-assembled spheroidal model of the blood brain barrier. Sci Rep. 2013;3:1500.
   PubMed Web of Science ®Google Scholar
• Kim J, Koo B-K, Knoblich JA. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol. 2020 Oct 01;21(10):571–584.
   PubMed Web of Science ®Google Scholar
• Lancaster MA, Renner M, Martin C-A, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013 Sept 1;501(7467):373–379.
   PubMed Web of Science ®Google Scholar
• Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014 Oct 1;9(10):2329–2340.
   PubMed Web of Science ®Google Scholar
• Ahn Y, J-H A, Yang H-J, et al. Human blood vessel organoids penetrate human cerebral organoids and form a vessel-like system. Cells. 2021;10(8):2036. doi: 10.3390/cells10082036
   PubMed Web of Science ®Google Scholar
• Ham O, Jin YB, Kim J, et al. Blood vessel formation in cerebral organoids formed from human embryonic stem cells. Biochem Biophys Res Commun. 2020 Jan 1;521(1):84–90.
   PubMed Web of Science ®Google Scholar
• Liebner S, Dijkhuizen RM, Reiss Y, et al. Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol. 2018 Mar 1;135(3):311–336.
   PubMed Web of Science ®Google Scholar
• Khalil A, Elfert A, Ghanem S, et al. The role of metabolomics in hepatocellular carcinoma. Egypt Liver J. 2021;11.
   PubMedGoogle Scholar
• Zhou WM, Yan YY, Guo QR, et al. Microfluidics applications for high-throughput single cell sequencing. J Nanobiotechnology. 2021 Oct 11;19(1):312.
   PubMed Web of Science ®Google Scholar
• Žvirblytė J, Mažutis L. Microfluidics for cancer biomarker discovery, research, and clinical application. Adv Exp Med Biol. 2022;1379:499–524.
   PubMedGoogle Scholar
• Li M, Zhu M, Huang R, et al. Blood–brain barrier microfluidic chips and their applications. Organs-on-a-Chip. 2023 Dec 1;5:100027. doi: 10.1016/j.ooc.2023.100027
   Google Scholar
• Hajal C, Offeddu GS, Shin Y, et al. Engineered human blood–brain barrier microfluidic model for vascular permeability analyses. Nat Protoc. 2022 Jan 1;17(1):95–128.
   PubMed Web of Science ®Google Scholar
• Banks WA. The blood–brain barrier as an endocrine tissue. Nat Rev Endocrinol. 2019 Aug 1;15(8):444–455.
   PubMed Web of Science ®Google Scholar
• Bickel U. Modeling blood-brain barrier permeability to solutes and drugs in vivo. Pharmaceutics. 2022 Aug 15;14(8):1696.
   PubMed Web of Science ®Google Scholar
• Murata Y, Neuhoff S, Rostami-Hodjegan A, et al. In vitro to in vivo extrapolation linked to physiologically based pharmacokinetic models for assessing the brain drug disposition. Aaps J. 2022 Jan 13;24(1):28.
   PubMed Web of Science ®Google Scholar
• Prashanth A, Donaghy H, Stoner SP, et al. Are in vitro human blood-brain-tumor-barriers suitable replacements for in vivo models of brain permeability for novel therapeutics? Cancers (Basel). 2021 Feb 25;13(5). doi: 10.3390/cancers13050955
   PubMed Web of Science ®Google Scholar
• Wang YI, Abaci HE, Shuler ML. Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng. 2017 Jan;114(1):184–194.
   PubMed Web of Science ®Google Scholar
• Sharma C, Woo H, Kim SR. Addressing Blood-Brain Barrier Impairment in Alzheimer’s Disease. Biomedicines. 2022 Mar 22;10(4):742.
   PubMed Web of Science ®Google Scholar
• Barisano G, Montagne A, Kisler K, et al. Blood-brain barrier link to human cognitive impairment and Alzheimer’s Disease. Nat Cardiovasc Res. 2022 Feb;1(2):108–115. doi: 10.1038/s44161-021-00014-4
   PubMedGoogle Scholar
• Zhang Y, Nozohouri S, Abbruscato TJ. In vivo evaluation of BBB integrity in the post-stroke brain. Methods Mol Biol. 2023;2616:191–203.
   PubMedGoogle Scholar
• Miny L, Maisonneuve BGC, Quadrio I, et al. Modeling neurodegenerative diseases using in vitro compartmentalized microfluidic devices [review]. Front Bioeng Biotechnol. 2022 Jun 24;10:10.
   Web of Science ®Google Scholar
• Mata A, Fleischman AJ, Roy S. Characterization of polydimethylsiloxane (PDMS) properties for biomedical micro/nanosystems. Biomed Microdevices. 2005 Dec 1;7(4):281–293.
   PubMed Web of Science ®Google Scholar
• Friend J, Yeo L. Fabrication of microfluidic devices using polydimethylsiloxane. Biomicrofluidics. 2010;4(2). DOI:10.1063/1.3259624
   Web of Science ®Google Scholar
• Menon NV, Chuah YJ, Cao B, et al. A microfluidic co-culture system to monitor tumor-stromal interactions on a chip. Biomicrofluidics. 2014;8(6). doi: 10.1063/1.4903762
   PubMed Web of Science ®Google Scholar
• Du G, Fang Q, den Toonder JM. Microfluidics for cell-based high throughput screening platforms - A review. Anal Chim Acta. 2016 Jan 15;903:36–50. doi: 10.1016/j.aca.2015.11.023
   PubMed Web of Science ®Google Scholar
• Wan AMD, Devadas D, Young EWK. Recycled polymethylmethacrylate (PMMA) microfluidic devices. Sens Actuators B Chem. 2017 Dec 1;253:738–744. doi: 10.1016/j.snb.2017.07.011
   Web of Science ®Google Scholar
• Chen X, Liu C, Muok L, et al. Dynamic 3D on-chip BBB model design, development, and applications in neurological diseases. Cells. 2021;10(11):3183. doi: 10.3390/cells10113183
   PubMed Web of Science ®Google Scholar
• Koenig L, Ramme AP, Faust D, et al. A human stem cell-derived brain-liver chip for assessing blood-brain-barrier permeation of pharmaceutical drugs. Cells. 2022;11(20):3295. doi: 10.3390/cells11203295
   PubMed Web of Science ®Google Scholar
• Wevers NR, Nair AL, Fowke TM, et al. Modeling ischemic stroke in a triculture neurovascular unit on-a-chip. Fluids Barriers CNS. 2021 Dec 14;18(1):59.
   PubMed Web of Science ®Google Scholar
• Pamies D, Barreras P, Block K, et al. A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity. Altex. 2017;34(3):362–376. doi: 10.14573/altex.1609122
   PubMedGoogle Scholar
• Pediaditakis I, Kodella KR, Manatakis DV, et al. A microengineered Brain-Chip to model neuroinflammation in humans. iScience. 2022 Aug 19;25(8):104813.
   PubMed Web of Science ®Google Scholar
• Peng B, Hao S, Tong Z, et al., Blood–brain barrier (BBB)-on-a-chip: a promising breakthrough in brain disease research [10.1039/D2LC00305H]. Lab Chip. 2022; 22(19): 3579–3602. doi: 10.1039/D2LC00305H
   PubMed Web of Science ®Google Scholar
• Shao X, Gao D, Chen Y, et al. Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening. Anal Chim Acta. 2016 Aug 31;934:186–193. doi: 10.1016/j.aca.2016.06.028
   PubMed Web of Science ®Google Scholar
• Yue H, Xie K, Ji X, et al. Vascularized neural constructs for ex-vivo reconstitution of blood-brain barrier function. Biomaterials. 2020 July 01;245:119980. doi: 10.1016/j.biomaterials.2020.119980
   PubMed Web of Science ®Google Scholar
• van der Helm MW, van der Meer AD, Eijkel JCT, et al. Microfluidic organ-on-chip technology for blood-brain barrier research. Tissue Barriers. 2016 Jan-Mar;4(1):e1142493. doi: 10.1080/21688370.2016.1142493
   PubMed Web of Science ®Google Scholar
• Lee IK, Wang CC, Lin MC, et al. Effective strategies to prevent coronavirus disease-2019 (COVID-19) outbreak in hospital. J Hosp Infect. 2020 Mar 3;105:102–103. doi: 10.1016/j.jhin.2020.02.022
   PubMed Web of Science ®Google Scholar
• Wevers NR, Kasi DG, Gray T, et al. A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS. 2018 Aug 31;15(1):23.
   PubMedGoogle Scholar