1932

Abstract

The blood–brain barrier (BBB) is one of the most selective endothelial barriers. An understanding of its cellular, morphological, and biological properties in health and disease is necessary to develop therapeutics that can be transported from blood to brain. In vivo models have provided some insight into these features and transport mechanisms adopted at the brain, yet they have failed as a robust platform for the translation of results into clinical outcomes. In this article, we provide a general overview of major BBB features and describe various models that have been designed to replicate this barrier and neurological pathologies linked with the BBB. We propose several key parameters and design characteristics that can be employed to engineer physiologically relevant models of the blood–brain interface and highlight the need for a consensus in the measurement of fundamental properties of this barrier.

[Erratum, Closure]

An erratum has been published for this article:
Erratum: Biology and Models of the Blood–Brain Barrier
Loading

Article metrics loading...

/content/journals/10.1146/annurev-bioeng-082120-042814
2021-07-13
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/bioeng/23/1/annurev-bioeng-082120-042814.html?itemId=/content/journals/10.1146/annurev-bioeng-082120-042814&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Stern L, Gautier R 1921. Récherches sur le liquide céphalo-rachidien. I. Les rapports entre le liquide céphalo-rachidien et la circulation sanguine. Arch. Int. Physiol. 17:138–92
    [Google Scholar]
  2. 2. 
    Ehrlich P 1885. Das Sauerstoff-Bedürfniss des Organismus: Eine farbenanalytische Studie Berlin: Hirschwald
  3. 3. 
    Spatz H 1934. Die Bedeutung der vitalen Färbung für die Lehre vom Stoffaustausch zwischen dem Zentralnervensystem und dem übrigen Körper. Arch. Psychiatrie Nervenkrankh. 101:267–358
    [Google Scholar]
  4. 4. 
    Reese TS, Karnovsky MJ 1967. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34:207–17
    [Google Scholar]
  5. 5. 
    Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD et al. 2014. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front. Neurosci. 8:404
    [Google Scholar]
  6. 6. 
    Risau W 1997. Mechanisms of angiogenesis. Nature 386:671–74
    [Google Scholar]
  7. 7. 
    Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA 2009. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. PNAS 106:641–46
    [Google Scholar]
  8. 8. 
    Lindahl P, Johansson BR, Levéen P, Betsholtz C 1997. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–45
    [Google Scholar]
  9. 9. 
    Mizee MR, Wooldrik D, Lakeman KAM, van het Hof B, Drexhage JAR et al. 2013. Retinoic acid induces blood-brain barrier development. J. Neurosci. 33:1660–71
    [Google Scholar]
  10. 10. 
    Hupe M, Li MX, Kneitz S, Davydova D, Yokota C et al. 2017. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Sci. Signal. 10:eaag2476
    [Google Scholar]
  11. 11. 
    Levison SW, de Vellis J, Goldman JE 2005. Astrocyte development. Developmental Neurobiology MS Rao, M Jacobson197–222 New York: Springer. 4th ed.
    [Google Scholar]
  12. 12. 
    Ormestad M, Astorga J, Carlsson P 2004. Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes. Dev. Dyn. 229:328–33
    [Google Scholar]
  13. 13. 
    Yamamoto S, Muramatsu M, Azuma E, Ikutani M, Nagai Y et al. 2017. A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS. Sci. Rep. 7:3855
    [Google Scholar]
  14. 14. 
    Dore-Duffy P, Cleary K 2011. Morphology and properties of pericytes. The Blood–Brain and Other Neural Barriers S Nag49–68 New York: Humana
    [Google Scholar]
  15. 15. 
    Nag S 2011. Morphology and properties of astrocytes. Methods Mol. Biol. 686:69–100
    [Google Scholar]
  16. 16. 
    Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E et al. 2010. Pericytes regulate the blood-brain barrier. Nature 468:557–61
    [Google Scholar]
  17. 17. 
    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A et al. 2014. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60
    [Google Scholar]
  18. 18. 
    Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J 2015. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87:95–110
    [Google Scholar]
  19. 19. 
    Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D 2016. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19:1619–27
    [Google Scholar]
  20. 20. 
    Chow BW, Nuñez V, Kaplan L, Granger AJ, Bistrong K et al. 2020. Caveolae in CNS arterioles mediate neurovascular coupling. Nature 579:106–10
    [Google Scholar]
  21. 21. 
    Alarcon-Martinez L, Villafranca-Baughman D, Quintero H, Kacerovsky JB, Dotigny F et al. 2020. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 585:91–95
    [Google Scholar]
  22. 22. 
    Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H et al. 2019. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat. Commun. 10:5816
    [Google Scholar]
  23. 23. 
    Hanisch UK, Kettenmann H 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10:1387–94
    [Google Scholar]
  24. 24. 
    Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA et al. 2003. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6:43–50
    [Google Scholar]
  25. 25. 
    Li YN, Pan R, Qin XJ, Yang WL, Qi Z et al. 2014. Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J. Neurochem. 129:120–29
    [Google Scholar]
  26. 26. 
    Charabati M, Rabanel JM, Ramassamy C, Prat A 2020. Overcoming the brain barriers: from immune cells to nanoparticles. Trends Pharmacol. Sci. 41:42–54
    [Google Scholar]
  27. 27. 
    Weiss N, Miller F, Cazaubon S, Couraud PO 2009. The blood-brain barrier in brain homeostasis and neurological diseases. Biochem. Biophys. Acta Biomembr. 1788:842–57
    [Google Scholar]
  28. 28. 
    Rodriguez-Baeza A, Reina-De La Torre F, Ortega-Sanchez M, Sahuquillo-Barris J 1998. Perivascular structures in corrosion casts of the human central nervous system: a confocal laser and scanning electron microscope study. Anat. Rec. 252:176–84
    [Google Scholar]
  29. 29. 
    Campisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD 2018. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 180:117–29
    [Google Scholar]
  30. 30. 
    Cipolla MJ 2016. The Cerebral Circulation San Rafael, CA: Morgan & Claypool 2nd ed. Colloq. Ser. Integr. Syst. Physiol. Mol. Funct.
  31. 31. 
    Follain G, Osmani N, Azevedo AS, Allio G, Mercier L et al. 2018. Hemodynamic forces tune the arrest, adhesion, and extravasation of circulating tumor cells. Dev. Cell 45:33–52
    [Google Scholar]
  32. 32. 
    Destefano JG, Jamieson JJ, Linville RM, Searson PC 2018. Benchmarking in vitro tissue-engineered blood–brain barrier models. Fluids Barriers CNS 15:32
    [Google Scholar]
  33. 33. 
    Zarrinkoob L, Ambarki K, Wahlin A, Birgander R, Carlberg B et al. 2016. Aging alters the dampening of pulsatile blood flow in cerebral arteries. J. Cereb. Blood Flow Metab. 36:1519–27
    [Google Scholar]
  34. 34. 
    Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM 2012. Increased cerebral arterial pulsatility in patients with leukoaraiosis: Arterial stiffness enhances transmission of aortic pulsatility. Stroke 43:2631–36
    [Google Scholar]
  35. 35. 
    Jessen NA, Munk ASF, Lundgaard I, Nedergaard M 2015. The glymphatic system: a beginner's guide. Neurochem. Res. 40:2583–99
    [Google Scholar]
  36. 36. 
    Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A et al. 2017. Blood-brain barrier permeability is regulated by lipid transport–dependent suppression of caveolae-mediated transcytosis. Neuron 94:581–94
    [Google Scholar]
  37. 37. 
    Hajal C, Campisi M, Mattu C, Chiono V, Kamm RD 2018. In vitro models of molecular and nano-particle transport across the blood-brain barrier. Biomicrofluidics 12:042213
    [Google Scholar]
  38. 38. 
    Barar J, Rafi MA, Pourseif MM, Omidi Y 2016. Blood-brain barrier transport machineries and targeted therapy of brain diseases. BioImpacts 6:225–48
    [Google Scholar]
  39. 39. 
    Rapoport SI 2000. Osmotic opening of the blood-brain barrier. Cell. Mol. Neurobiol. 20:217–30
    [Google Scholar]
  40. 40. 
    Yuan W, Lv Y, Zeng M, Fu BM 2009. Non-invasive measurement of solute permeability in cerebral microvessels of the rat. Microvasc. Res. 77:166–73
    [Google Scholar]
  41. 41. 
    Shi L, Zeng M, Sun Y, Fu BM 2014. Quantification of blood-brain barrier solute permeability and brain transport by multiphoton microscopy. J. Biomech. Eng. 136:031005
    [Google Scholar]
  42. 42. 
    Schaaf MB, Houbaert D, Meçe O, Agostinis P 2019. Autophagy in endothelial cells and tumor angiogenesis. Cell Death Differ. 26:665–79
    [Google Scholar]
  43. 43. 
    Pieper C, Pieloch P, Galla HJ 2013. Pericytes support neutrophil transmigration via interleukin-8 across a porcine co-culture model of the blood-brain barrier. Brain Res. 1524:1–11
    [Google Scholar]
  44. 44. 
    Fazakas C, Wilhelm I, Nagyoszi P, Farkas AE, Haskó J et al. 2011. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLOS ONE 6:e20758
    [Google Scholar]
  45. 45. 
    Offeddu GS, Possenti L, Loessberg-Zahl JT, Zunino P, Roberts J et al. 2019. Application of transmural flow across in vitro microvasculature enables direct sampling of interstitial therapeutic molecule distribution. Small 15:1902393
    [Google Scholar]
  46. 46. 
    Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ 2010. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37:13–25
    [Google Scholar]
  47. 47. 
    Banks WA 2009. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 9:S3
    [Google Scholar]
  48. 48. 
    Butt AM, Jones HC, Abbott NJ 1990. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J. Physiol. 429:47–62
    [Google Scholar]
  49. 49. 
    Sharabi S, Bresler Y, Ravid O, Shemesh C, Atrakchi D et al. 2019. Transient blood–brain barrier disruption is induced by low pulsed electrical fields in vitro: an analysis of permeability and trans-endothelial electric resistivity. Drug Deliv. 26:459–69
    [Google Scholar]
  50. 50. 
    Elbrecht DH, Long CJ, Hickman JJ 2016. Transepithelial/endothelial electrical resistance (TEER) theory and applications for microfluidic body-on-a-chip devices. J. Rare Dis. Res. Treat. Open 1:46–52
    [Google Scholar]
  51. 51. 
    Deosarkar SP, Prabhakarpandian B, Wang B, Sheffield JB, Krynska B, Kiani MF 2015. A novel dynamic neonatal blood-brain barrier on a chip. PLOS ONE 10:e0142725
    [Google Scholar]
  52. 52. 
    Crone C, Olesen SP 1982. Electrical resistance of brain microvascular endothelium. Brain Res. 241:49–55
    [Google Scholar]
  53. 53. 
    Wiranowska M, Wilson TC, Beneze KS, Prockop LD 1988. A mouse model for the study of blood-brain barrier permeability. J. Neurosci. Methods 26:105–9
    [Google Scholar]
  54. 54. 
    Rapoport SI, Bachman DS, Thompson HK 1972. Chronic effects of osmotic opening of the blood-brain barrier in the monkey. Science 176:1243–44
    [Google Scholar]
  55. 55. 
    Sohet F, Daneman R 2013. Genetic mouse models to study blood-brain barrier development and function. Fluids Barriers CNS 10:1
    [Google Scholar]
  56. 56. 
    Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ 2015. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20:107–26
    [Google Scholar]
  57. 57. 
    Crone C, Christensen O 1981. Electrical resistance of a capillary endothelium. J. Gen. Physiol. 77:349–71
    [Google Scholar]
  58. 58. 
    Helms HC, Abbott NJ, Burek M, Cecchelli R, Couraud PO et al. 2015. 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. 36:862–90
    [Google Scholar]
  59. 59. 
    Lacombe O, Videau O, Chevillon D, Guyot AC, Contreras C et al. 2011. In vitro primary human and animal cell-based blood–brain barrier models as a screening tool in drug discovery. Mol. Pharm. 8:651–63
    [Google Scholar]
  60. 60. 
    Gaston JD, Bischel LL, Fitzgerald LA, Cusick KD, Ringeisen BR, Pirlo RK 2017. Gene expression changes in long-term in vitro human blood-brain barrier models and their dependence on a Transwell scaffold material. J. Healthc. Eng. 2017:5740975
    [Google Scholar]
  61. 61. 
    Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M et al. 2007. Modelling of the blood–brain barrier in drug discovery and development. Nat. Rev. Drug Discov. 6:650–61
    [Google Scholar]
  62. 62. 
    Bertassoni LE, Cecconi M, Manoharan V, Nikkhah M, Hjortnaes J et al. 2014. Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs. Lab Chip 14:2202–11
    [Google Scholar]
  63. 63. 
    Offeddu GS, Haase K, Gillrie MR, Li R, Morozova O et al. 2019. An on-chip model of protein paracellular and transcellular permeability in the microcirculation. Biomaterials 212:115–25
    [Google Scholar]
  64. 64. 
    Watanabe T, Dohgu S, Takata F, Nishioku T, Nakashima A et al. 2013. Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4. Biol. Pharm. Bull. 36:492–95
    [Google Scholar]
  65. 65. 
    Rist RJ, Romero IA, Chan MW, Couraud PO, Roux F, Abbott NJ 1997. 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
    [Google Scholar]
  66. 66. 
    Eigenmann DE, Xue G, Kim KS, Moses AV, Hamburger M, Oufir M 2013. 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
    [Google Scholar]
  67. 67. 
    Wevers NR, Kasi DG, Gray T, Wilschut KJ, Smith B et al. 2018. A perfused human blood–brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS 15:23
    [Google Scholar]
  68. 68. 
    Poller B, Gutmann H, Krähenbühl S, Weksler B, Romero I et al. 2008. The human brain endothelial cell line hCMEC/D3 as a human blood-brain barrier model for drug transport studies. J. Neurochem. 107:1358–68
    [Google Scholar]
  69. 69. 
    Xu M, He J, Zhang C, Xu J, Wang Y 2019. Strategies for derivation of endothelial lineages from human stem cells. Stem Cell Res. Ther. 10:200
    [Google Scholar]
  70. 70. 
    Lippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK et al. 2012. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat. Biotechnol. 30:783–91
    [Google Scholar]
  71. 71. 
    Orlova VV, Van Den Hil FE, Petrus-Reurer S, Drabsch Y, Ten Dijke P, Mummery CL 2014. Generation, expansion and functional analysis of endothelial cells and pericytes derived from human pluripotent stem cells. Nat. Protoc. 9:1514–31
    [Google Scholar]
  72. 72. 
    Weidenfeller C, Svendsen CN, Shusta EV 2007. Differentiating embryonic neural progenitor cells induce blood-brain barrier properties. J. Neurochem. 101:555–65
    [Google Scholar]
  73. 73. 
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–72
    [Google Scholar]
  74. 74. 
    Qian T, Hernday SE, Bao X, Olson WR, Panzer SE et al. 2019. Directed differentiation of human pluripotent stem cells to podocytes under defined conditions. Sci. Rep. 9:48–50
    [Google Scholar]
  75. 75. 
    Park TE, Mustafaoglu N, Herland A, Hasselkus R, Mannix R et al. 2019. Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat. Commun. 10:2621
    [Google Scholar]
  76. 76. 
    Workman MJ, Svendsen CN 2020. Recent advances in human iPSC-derived models of the blood–brain barrier. Fluids Barriers CNS 17:30
    [Google Scholar]
  77. 77. 
    Linville RM, DeStefano JG, Sklar MB, Xu Z, Farrell AM et al. 2019. Human iPSC-derived blood-brain barrier microvessels: validation of barrier function and endothelial cell behavior. Biomaterials 190/191:24–37
    [Google Scholar]
  78. 78. 
    Vatine GD, Al-Ahmad A, Barriga BK, Svendsen S, Salim A et al. 2017. Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell 20:831–43
    [Google Scholar]
  79. 79. 
    Delsing L, Herland A, Falk A, Hicks R, Synnergren J, Zetterberg H 2020. Models of the blood-brain barrier using iPSC-derived cells. Mol. Cell. Neurosci. 705:103533
    [Google Scholar]
  80. 80. 
    Lu TM, Redmond D, Magdeldin T, Nguyen DHT, Snead A et al. 2019. Human induced pluripotent stem cell–derived neuroectodermal epithelial cells mistaken for blood-brain barrier–forming endothelial cells. bioRxiv 699173 https://doi.org/10.1101/699173
    [Crossref] [Google Scholar]
  81. 81. 
    Stone NL, England TJ, O'Sullivan SE 2019. A novel Transwell blood brain barrier model using primary human cells. Front. Cell. Neurosci. 13:230
    [Google Scholar]
  82. 82. 
    Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK et al. 2019. Human iPSC-derived blood-brain barrier chips enable disease modeling and personalized medicine applications. Cell Stem Cell 24:995–1005
    [Google Scholar]
  83. 83. 
    Marino A, Tricinci O, Battaglini M, Filippeschi C, Mattoli V et al. 2018. A 3D real-scale, biomimetic, and biohybrid model of the blood-brain barrier fabricated through two-photon lithography. Small 14:1702959
    [Google Scholar]
  84. 84. 
    Herland A, Van Der Meer AD, FitzGerald EA, Park TE, Sleeboom JJ, Ingber DE 2016. Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood-brain barrier on a chip. PLOS ONE 11:e0150360
    [Google Scholar]
  85. 85. 
    Lee S, Chung M, Lee S, Jeon NL 2020. 3D brain angiogenesis model to reconstitute functional human blood–brain barrier in vitro. Biotechnol. Bioeng. 117:748–62
    [Google Scholar]
  86. 86. 
    Bowman PD, Ennis SR, Rarey KE, Lorris Betz A, Goldstein GW 1983. Brain microvessel endothelial cells in tissue culture: a model for study of blood–brain barrier permeability. Ann. Neurol. 14:396–402
    [Google Scholar]
  87. 87. 
    Rauh J, Meyer J, Beuckmann C, Galla HJ 1992. Development of an in vitro cell culture system to mimic the blood-brain barrier. Prog. Brain Res. 91:117–21
    [Google Scholar]
  88. 88. 
    Shafaie S, Hutter V, Brown MB, Cook MT, Chau DY 2017. Influence of surface geometry on the culture of human cell lines: a comparative study using flat, round-bottom and v-shaped 96 well plates. PLOS ONE 12:e0186799
    [Google Scholar]
  89. 89. 
    Dehouck M, Meresse S, Delorme P, Fruchart J, Cecchelli R 1990. An easier, reproducible, and mass-production method to study the blood–brain barrier in vitro. J. Neurochem. 54:1798–801
    [Google Scholar]
  90. 90. 
    Bischel LL, Coneski PN, Lundin JG, Wu PK, Giller CB et al. 2016. Electrospun gelatin biopapers as substrate for in vitro bilayer models of blood-brain barrier tissue. J. Biomed. Mater. Res. A 104:901–9
    [Google Scholar]
  91. 91. 
    Sip CG, Bhattacharjee N, Folch A 2014. Microfluidic Transwell inserts for generation of tissue culture–friendly gradients in well plates. Lab Chip 14:302–14
    [Google Scholar]
  92. 92. 
    Wang X, Xu B, Xiang M, Yang X, Liu Y et al. 2020. Advances on fluid shear stress regulating blood-brain barrier. Microvasc. Res. 128:103930
    [Google Scholar]
  93. 93. 
    Zhang B, Korolj A, Lai BFL, Radisic M 2018. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3:257–78
    [Google Scholar]
  94. 94. 
    Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR et al. 2017. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci. Rep. 7:42296
    [Google Scholar]
  95. 95. 
    Novak R, Ingram M, Marquez S, Das D, Delahanty A et al. 2020. Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nat. Biomed. Eng. 4:407–20
    [Google Scholar]
  96. 96. 
    Herland A, Maoz BM, Das D, Somayaji MR, Prantil-Baun R et al. 2020. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat. Biomed. Eng. 4:421–36
    [Google Scholar]
  97. 97. 
    Junaid A, Mashaghi A, Hankemeier T, Vulto P 2017. An end-user perspective on organ-on-a-chip: assays and usability aspects. Curr. Opin. Biomed. Eng. 1:15–22
    [Google Scholar]
  98. 98. 
    Esch EW, Bahinski A, Huh D 2015. Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14:248–60
    [Google Scholar]
  99. 99. 
    Odijk M, Van Der Meer AD, Levner D, Kim HJ, Van Der Helm MW et al. 2015. Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems. Lab Chip 15:745–52
    [Google Scholar]
  100. 100. 
    Brown TD, Nowak M, Bayles AV, Prabhakarpandian B, Karande P et al. 2019. A microfluidic model of human brain (μHuB) for assessment of blood brain barrier. Bioeng. Transl. Med. 4:e10126
    [Google Scholar]
  101. 101. 
    Maoz BM, Herland A, FitzGerald EA, Grevesse T, Vidoudez C et al. 2018. A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells. Nat. Biotechnol. 36:865–74
    [Google Scholar]
  102. 102. 
    Herland A, Maoz BM, FitzGerald EA, Grevesse T, Vidoudez C et al. 2020. Proteomic and metabolomic characterization of human neurovascular unit cells in response to methamphetamine. Adv. Biosyst. 4:1900230
    [Google Scholar]
  103. 103. 
    Probst C, Schneider S, Loskill P 2018. High-throughput organ-on-a-chip systems: current status and remaining challenges. Curr. Opin. Biomed. Eng. 6:33–41
    [Google Scholar]
  104. 104. 
    Ahn SI, Sei YJ, Park HJ, Kim J, Ryu Y et al. 2020. Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms. Nat. Commun. 11:175
    [Google Scholar]
  105. 105. 
    Xu H, Li Z, Yu Y, Sizdahkhani S, Ho WS et al. 2016. A dynamic in vivo–like organotypic blood-brain barrier model to probe metastatic brain tumors. Sci. Rep. 6:36670
    [Google Scholar]
  106. 106. 
    Katt ME, Linville RM, Mayo LN, Xu ZS, Searson PC 2018. Functional brain-specific microvessels from iPSC-derived human brain microvascular endothelial cells: the role of matrix composition on monolayer formation. Fluids Barriers CNS 15:7
    [Google Scholar]
  107. 107. 
    Rauti R, Renous N, Maoz BM 2019. Mimicking the brain extracellular matrix in vitro: a review of current methodologies and challenges. Isr. J. Chem. 60:1141–51
    [Google Scholar]
  108. 108. 
    Brown JA, Pensabene V, Markov DA, Allwardt V, Neely MD et al. 2015. Recreating blood-brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics 9:054124
    [Google Scholar]
  109. 109. 
    Adriani G, Ma D, Pavesi A, Kamm RD, Goh EL 2017. A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier. Lab Chip 17:448–59
    [Google Scholar]
  110. 110. 
    Ruoslahti E 1996. Brain extracellular matrix. Glycobiology 6:489–92
    [Google Scholar]
  111. 111. 
    Peak CW, Cross L, Singh A, Gaharwar AK 2015. Microscale technologies for engineering complex tissue structures. Microscale Technologies for Cell Engineering A Singh, AK Gaharwar3–25 New York: Springer
    [Google Scholar]
  112. 112. 
    Chen MB, Whisler JA, Fröse J, Yu C, Shin Y, Kamm RD 2017. On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics. Nat. Protoc. 12:865–80
    [Google Scholar]
  113. 113. 
    Bang S, Lee SR, Ko J, Son K, Tahk D et al. 2017. A low permeability microfluidic blood-brain barrier platform with direct contact between perfusable vascular network and astrocytes. Sci. Rep. 7:8083
    [Google Scholar]
  114. 114. 
    Wang YI, Abaci HE, Shuler ML 2017. Microfluidic blood–brain barrier model provides in vivo–like barrier properties for drug permeability screening. Biotechnol. Bioeng. 114:184–94
    [Google Scholar]
  115. 115. 
    Qian X, Song H, Ming GL 2019. Brain organoids: advances, applications and challenges. Development 146:dev166074
    [Google Scholar]
  116. 116. 
    Raja WK, Mungenast AE, Lin YT, Ko T, Abdurrob F et al. 2016. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer's disease phenotypes. PLOS ONE 11:e0161969
    [Google Scholar]
  117. 117. 
    Pham MT, Pollock KM, Rose MD, Cary WA, Stewart HR et al. 2018. Generation of human vascularized brain organoids. NeuroReport 29:588–93
    [Google Scholar]
  118. 118. 
    Cakir B, Xiang Y, Tanaka Y, Kural MH, Parent M et al. 2019. Engineering of human brain organoids with a functional vascular-like system. Nat. Methods 16:1169–75
    [Google Scholar]
  119. 119. 
    Homan KA, Gupta N, Kroll KT, Kolesky DB, Skylar-Scott M et al. 2019. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16:255–62
    [Google Scholar]
  120. 120. 
    Yue K, Trujillo-de Santiago G, Alvarez MM, Tamayol A, Annabi N, Khademhosseini A 2015. Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials 73:254–71
    [Google Scholar]
  121. 121. 
    Zhang Z, Jin Y, Yin J, Xu C, Xiong R et al. 2018. Evaluation of bioink printability for bioprinting applications. Appl. Phys. Rev. 5:041304
    [Google Scholar]
  122. 122. 
    Bajaj P, Schweller RM, Khademhosseini A, West JL, Bashir R 2014. 3D biofabrication strategies for tissue engineering and regenerative medicine. Annu. Rev. Biomed. Eng. 16:247–76
    [Google Scholar]
  123. 123. 
    Yi HG, Jeong YH, Kim Y, Choi YJ, Moon HE et al. 2019. A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy. Nat. Biomed. Eng. 3:509–19
    [Google Scholar]
  124. 124. 
    Chen N, Zhu K, Zhang YS, Yan S, Pan T et al. 2019. Hydrogel bioink with multilayered interfaces improves dispersibility of encapsulated cells in extrusion bioprinting. ACS Appl. Mater. Interfaces 11:30585–95
    [Google Scholar]
  125. 125. 
    Grifno GN, Farrell AM, Linville RM, Arevalo D, Kim JH et al. 2019. Tissue-engineered blood-brain barrier models via directed differentiation of human induced pluripotent stem cells. Sci. Rep. 9:13957
    [Google Scholar]
  126. 126. 
    Yang L, Shridhar SV, Gerwitz M, Soman P 2016. An in vitro vascular chip using 3D printing-enabled hydrogel casting. Biofabrication 8:035015
    [Google Scholar]
  127. 127. 
    Pi Q, Maharjan S, Yan X, Liu X, Singh B et al. 2018. Digitally tunable microfluidic bioprinting of multilayered cannular tissues. Adv. Mater. 30:1706913
    [Google Scholar]
  128. 128. 
    Lee JB, Kim DH, Yoon JK, Park DB, Kim HS et al. 2020. Microchannel network hydrogel induced ischemic blood perfusion connection. Nat. Commun. 11:615
    [Google Scholar]
  129. 129. 
    Rosenberg GA 2012. Neurological diseases in relation to the blood–brain barrier. J. Cereb. Blood Flow Metab. 32:1139–51
    [Google Scholar]
  130. 130. 
    Sweeney MD, Sagare AP, Zlokovic BV 2018. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14:133–50
    [Google Scholar]
  131. 131. 
    Mackic JB, Stins M, McComb JG, Calero M, Ghiso J et al. 1998. Human blood-brain barrier receptors for Alzheimer's amyloid-β 1-40 asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Investig. 102:734–43
    [Google Scholar]
  132. 132. 
    Robert J, Button EB, Yuen B, Gilmour M, Kang K et al. 2017. Clearance of β-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife 6:e29595
    [Google Scholar]
  133. 133. 
    Shin Y, Choi SH, Kim E, Bylykbashi E, Kim JA et al. 2019. Blood–brain barrier dysfunction in a 3D in vitro model of Alzheimer's disease. Adv. Sci. 6:1900962
    [Google Scholar]
  134. 134. 
    Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L et al. 2020. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat. Med. 26:952–63
    [Google Scholar]
  135. 135. 
    Yang C, Hawkins KE, Doré S, Candelario-Jalil E 2019. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am. J. Physiol. Cell Physiol. 316:C135–53
    [Google Scholar]
  136. 136. 
    Xiong Y, Mahmood A, Chopp M 2013. Animal models of traumatic brain injury. Nat. Rev. Neurosci. 14:128–42
    [Google Scholar]
  137. 137. 
    Chen T, Dai SH, Li X, Luo P, Zhu J et al. 2018. Sirt1–Sirt3 axis regulates human blood–brain barrier permeability in response to ischemia. Redox Biol. 14:229–36
    [Google Scholar]
  138. 138. 
    Chaitanya GV, Minagar A, Alexander JS 2014. Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia. Cell Commun. Signal. 12:7
    [Google Scholar]
  139. 139. 
    Plummer S, Wallace S, Ball G, Lloyd R, Schiapparelli P et al. 2019. A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine. Sci. Rep. 9:1407
    [Google Scholar]
  140. 140. 
    Ngo MT, Harley BA 2019. Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel. Biomaterials 198:122–34
    [Google Scholar]
  141. 141. 
    Ozturk MS, Lee VK, Zou H, Friedel RH, Intes X, Dai G 2020. High-resolution tomographic analysis of in vitro 3D glioblastoma tumor model under long-term drug treatment. Sci. Adv. 6:eaay7513
    [Google Scholar]
  142. 142. 
    Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR et al. 2009. Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–9
    [Google Scholar]
  143. 143. 
    Chaudhuri JD 2000. Blood brain barrier and infection. Med. Sci. Monit. 6:1213–22
    [Google Scholar]
  144. 144. 
    Baig AM, Khaleeq A, Ali U, Syeda H 2020. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 11:995–98
    [Google Scholar]
  145. 145. 
    Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, McGary H, Razmpour R et al. 2020. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood–brain barrier. bioRxiv 150912 https://doi.org/10.1101/2020.06.15.150912
    [Crossref] [Google Scholar]
  146. 146. 
    Shimizu F, Nishihara H, Kanda T 2018. Blood–brain barrier dysfunction in immuno-mediated neurological diseases. Immunol. Med. 41:120–28
    [Google Scholar]
  147. 147. 
    Jacobs BM 2014. Stemming the hype: What can we learn from iPSC models of Parkinson's disease and how can we learn it?. J. Parkinson's Dis. 4:15–27
    [Google Scholar]
  148. 148. 
    Lim RG, Quan C, Reyes-Ortiz AM, Lutz SE, Kedaigle AJ et al. 2017. Huntington's disease iPSC-derived brain microvascular endothelial cells reveal WNT-mediated angiogenic and blood-brain barrier deficits. Cell Rep. 19:1365–77
    [Google Scholar]
  149. 149. 
    Shityakov S, Förster CY 2018. Computational simulation and modeling of the blood–brain barrier pathology. Histochem. Cell Biol. 149:451–59
    [Google Scholar]
  150. 150. 
    Adhikari U, Goliaei A, Berkowitz ML 2016. Nanobubbles, cavitation, shock waves and traumatic brain injury. Phys. Chem. Chem. Phys. 18:32638–52
    [Google Scholar]
/content/journals/10.1146/annurev-bioeng-082120-042814
Loading
/content/journals/10.1146/annurev-bioeng-082120-042814
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error