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Microfluidic Brain-on-a-Chip: Perspectives for Mimicking Neural System Disorders

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Abstract

Neurodegenerative diseases (NDDs) include more than 600 types of nervous system disorders in humans that impact tens of millions of people worldwide. Estimates by the World Health Organization (WHO) suggest NDDs will increase by nearly 50% by 2030. Hence, development of advanced models for research on NDDs is needed to explore new therapeutic strategies and explore the pathogenesis of these disorders. Different approaches have been deployed in order to investigate nervous system disorders, including two-and three-dimensional (2D and 3D) cell cultures and animal models. However, these models have limitations, such as lacking cellular tension, fluid shear stress, and compression analysis; thus, studying the biochemical effects of therapeutic molecules on the biophysiological interactions of cells, tissues, and organs is problematic. The microfluidic “organ-on-a-chip” is an inexpensive and rapid analytical technology to create an effective tool for manipulation, monitoring, and assessment of cells, and investigating drug discovery, which enables the culture of various cells in a small amount of fluid (10−9 to 10−18 L). Thus, these chips have the ability to overcome the mentioned restrictions of 2D and 3D cell cultures, as well as animal models. Stem cells (SCs), particularly neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) have the capability to give rise to various neural system cells. Hence, microfluidic organ-on-a-chip and SCs can be used as potential research tools to study the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders. Accordingly, in the present review, we discuss the latest progress in microfluidic brain-on-a-chip as a powerful and advanced technology that can be used in basic studies to investigate normal and abnormal functions of the nervous system.

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Abbreviations

2D:

two-dimensional

3D:

three-dimensional

AD:

Alzheimer’s disease

ADME:

adsorption, distribution, metabolism, excretion

ALT:

amyotrophic lateral sclerosis

ASTs:

astrocytes

BBB:

blood–brain barrier

BECs:

brain endothelial cells

bFGF:

basic fibroblast growth factor

BMECs:

brain microvascular endothelial cells

BRAIN:

Brain Research through Advancing Innovative Neurotechnologies

CD:

cluster of differentiation

CNS:

central nervous system

CTIP2:

chicken ovalbumin upstream promoter transcription factor-interacting protein 2

DARPA:

Defense Advanced Research Projects Agency

DCX:

doublecortin

DOX:

doxorubicin

ECM:

extracellular matrix

ECs:

endothelial cells

EGCs:

embryonic germ cells

EGFR:

epidermal growth factor receptor

EGFR:

epidermal growth factor

ESCs:

embryonic stem cells

FDA:

Food and Drug Administration

FITC:

fluorescein isothiocyanate

FOXG1:

forkhead box protein G1

GBM:

glioblastoma multiforme

G-CSF:

granulocyte colony-stimulating factor

GFAP:

glial fibrillary acidic protein

hBMVECs:

human brain microvascular endothelial cells

HBP:

Human Brain Project

HD:

Huntington’s disease

hiPSCs:

human-induced pluripotent stem cells

HUVEC:

human umbilical vein endothelial cells

ISL1:

insulin gene enhancer protein 1

ITSS:

insulin-transferrin–sodium selenite supplement

IL-6:

interleukin-6

KROX20:

early growth response 2 (egr2)

LOC:

laboratory-on-a-chip

LPS:

lipopolysaccharide

MS:

multiple sclerosis

NCATS:

National Center for Advancing Translational Sciences

NDDs:

neurodegenerative diseases

NIH:

National Institutes of Health

NPCs:

neural progenitor cells

NSCs:

neural stem cells

NSF:

National Science Foundation

NG2:

neuron glial antigen 2

NSPCs:

neural stem/progenitor cells

NVC:

neurovascular chip

PD:

Parkinson’s disease

PAX2/6:

paired box gene 2/6

PDMS:

polydimethylsiloxane

PEGDA:

poly(ethylene) glycol diacrylate

Pgp:

P-glycoprotein

PNS:

peripheral nervous system

PTEF:

polytetrafluoroethylene

PTEN:

phosphatase and tensin homolog

RT-PCR:

real-time polymerase chain reaction

SCs:

stem cells

SCZ:

schizophrenia

SEM:

scanning electron microscopy

SOX2:

sex determining region Y-box 2

SSEA:

stage-specific embryonic antigen

TBI:

traumatic brain injury

TBR1:

T-box brain 1

TEER:

trans-endothelial electrical resistance

TNF-α:

tumor necrosis factor-alpha

TUJ1:

neuron-specific class III beta-tubulin

TUNEL:

terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling

ZO-1:

zonula occludens-1; GFP, green fluorescent protein; human cerebral microvascular endothelial cell, hCMEC/D3; human umbilical veinendothelial cell, HUVEC.

References

  1. Heemels MT (2016) Neurodegenerative diseases. Nature 539(7628):179. https://doi.org/10.1038/539179a

    Article  PubMed  Google Scholar 

  2. Matilla-Duenas A, Corral-Juan M, Rodriguez-Palmero Seuma A, Vilas D, Ispierto L, Morais S, Sequeiros J, Alonso I et al (2017) Rare neurodegenerative diseases: clinical and genetic update. Adv Exp Med Biol 1031:443–496. https://doi.org/10.1007/978-3-319-67144-4_25

  3. McColgan P, Tabrizi SJ (2018) Huntington's disease: a clinical review. Eur J Neurol 25(1):24–34. https://doi.org/10.1111/ene.13413

    Article  CAS  PubMed  Google Scholar 

  4. Trovato Salinaro A, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, Ontario ML, Tomasello M et al (2018) Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer's disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms. Immun Ageing 15:8. https://doi.org/10.1186/s12979-017-0108-1

  5. Marsh SE, Blurton-Jones M (2017) Neural stem cell therapy for neurodegenerative disorders: the role of neurotrophic support. Neurochem Int 106:94–100. https://doi.org/10.1016/j.neuint.2017.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Noble W, Burns MP (2010) Challenges in neurodegeneration research. Front Psychiatry 1:7. https://doi.org/10.3389/fpsyt.2010.00007

    Article  PubMed  PubMed Central  Google Scholar 

  7. Reardon S (2014) Brain-mapping projects to join forces. Nature:18

  8. Samuel A, Levine H, Blagoev KB (2013) Scientific priorities for the BRAIN initiative. Nat Methods 10(8):713–714. https://doi.org/10.1038/nmeth.2565

    Article  CAS  PubMed  Google Scholar 

  9. Logroscino G, Capozzo R, Tortelli R, Marin B (2016) Current issues in randomized clinical trials of neurodegenerative disorders at enrolment and reporting: diagnosis, recruitment, representativeness of patients, ethnicity, and quality of reporting. In: The right therapy for neurological disorders, vol 39. Karger Publishers, pp. 24–36. https://doi.org/10.1159/000445410

  10. Vagaska B, Ferretti P (2017) Toward modeling the human nervous system in a dish: recent progress and outstanding challenges. Regen Med 12(1):15–23

    Article  CAS  PubMed  Google Scholar 

  11. Bracken MB (2009) Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med 102(3):120–122

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mak IW, Evaniew N, Ghert M (2014) Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 6(2):114–118

    PubMed  PubMed Central  Google Scholar 

  13. Karimi M, Zare H, Bakhshian Nik A, Yazdani N, Hamrang M, Mohamed E, Sahandi Zangabad P, Moosavi Basri SM et al (2016) Nanotechnology in diagnosis and treatment of coronary artery disease. Nanomedicine (London) 11(5):513–530. https://doi.org/10.2217/nnm.16.3

  14. Malekzad H, Mirshekari H, Sahandi Zangabad P, Moosavi Basri SM, Baniasadi F, Sharifi Aghdam M, Karimi M, Hamblin MR (2018) Plant protein-based hydrophobic fine and ultrafine carrier particles in drug delivery systems. Crit Rev Biotechnol 38(1):47–67. https://doi.org/10.1080/07388551.2017.1312267

    Article  CAS  PubMed  Google Scholar 

  15. Sambale F, Lavrentieva A, Stahl F, Blume C, Stiesch M, Kasper C, Bahnemann D, Scheper T (2015) Three dimensional spheroid cell culture for nanoparticle safety testing. J Biotechnol 205:120–129. https://doi.org/10.1016/j.jbiotec.2015.01.001

    Article  CAS  PubMed  Google Scholar 

  16. Kapałczyńska M, Kolenda T, Przybyła W, Zajączkowska M, Teresiak A, Filas V, Ibbs M, Bliźniak R et al (2018) 2D and 3D cell cultures—a comparison of different types of cancer cell cultures. Arch Med Sci 14(4):910. https://doi.org/10.5114/aoms.2016.63743

  17. Fang Y, Eglen RM (2017) Three-dimensional cell cultures in drug discovery and development. SLAS Discov 22(5):456–472. https://doi.org/10.1177/1087057117696795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hoarau-Véchot J, Rafii A, Touboul C, Pasquier J (2018) Halfway between 2D and animal models: are 3D cultures the ideal tool to study cancer–microenvironment interactions? Int J Mol Sci 19(1):181

    Article  CAS  PubMed Central  Google Scholar 

  19. Jabbarzadegan M, Rajayi H, Mofazzal Jahromi MA, Yeganeh H, Yousefi M, Muhammad Hassan Z, Majidi J (2017) Application of arteether-loaded polyurethane nanomicelles to induce immune response in breast cancer model. Artif Cells Nanomed Biotechnol 45(4):808–816. https://doi.org/10.1080/21691401.2016.1178131

    Article  CAS  PubMed  Google Scholar 

  20. Farjadian F, Moghoofei M, Mirkiani S, Ghasemi A, Rabiee N, Hadifar S, Beyzavi A, Karimi M, Hamblin MR (2018) Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: set the bugs to work? Biotechnology Advances

  21. Garreta E, Oria R, Tarantino C, Pla-Roca M, Prado P, Fernández-Avilés F, Campistol JM, Samitier J et al (2017) Tissue engineering by decellularization and 3D bioprinting. Mater Today 20(4):166–178. https://doi.org/10.1016/j.mattod.2016.12.005

  22. Hong N, Yang GH, Lee J, Kim G (2018) 3D bioprinting and its in vivo applications. J Biomed Mater Res B Appl Biomater 106(1):444–459. https://doi.org/10.1002/jbm.b.33826

    Article  CAS  PubMed  Google Scholar 

  23. Karimi M, M Moosavi Basri S, Vossoughi M, S Pakchin P, Mirshekari H, R Hamblin M (2016) Redox-sensitive smart nanosystems for drug and gene delivery. Curr Org Chem 20(28):2949–2959

    Article  CAS  Google Scholar 

  24. Tsutsui K, Taira M, Sakata H (2005) Neural mechanisms of three-dimensional vision. Neurosci Res 51(3):221–229. https://doi.org/10.1016/j.neures.2004.11.006

    Article  PubMed  Google Scholar 

  25. Dutta D, Heo I, Clevers H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23(5):393–410. https://doi.org/10.1016/j.molmed.2017.02.007

    Article  CAS  PubMed  Google Scholar 

  26. Wang Z, Wang SN, Xu TY, Miao ZW, Su DF, Miao CY (2017) Organoid technology for brain and therapeutics research. CNS Neurosci Ther 23(10):771–778. https://doi.org/10.1111/cns.12754

    Article  PubMed  PubMed Central  Google Scholar 

  27. Willyard C (2015) The boom in mini stomachs, brains, breasts, kidneys and more. Nature 523(7562):520–522. https://doi.org/10.1038/523520a

    Article  CAS  PubMed  Google Scholar 

  28. Aebersold MJ, Dermutz H, Forró C, Weydert S, Thompson-Steckel G, Vörös J, Demkó L (2016) “Brains on a chip”: towards engineered neural networks. TrAC Trends Anal Chem 78:60–69

    Article  CAS  Google Scholar 

  29. Park J, Wetzel I, Dreau D, Cho H (2018) 3D miniaturization of human organs for drug discovery. Adv healthc Mater 7(2). https://doi.org/10.1002/adhm.201700551

  30. Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotechnol 32(8):760–772. https://doi.org/10.1038/nbt.2989

    Article  CAS  PubMed  Google Scholar 

  31. Jahromi MAM, Zangabad PS, Basri SMM, Zangabad KS, Ghamarypour A, Aref AR, Karimi M, Hamblin MR (2017) Nanomedicine and advanced technologies for burns: preventing infection and facilitating wound healing. Advanced Drug Delivery Reviews

  32. Gjorevski N, Nelson CM (2010) The mechanics of development: models and methods for tissue morphogenesis. Birth Defects Res C Embryo Today 90(3):193–202. https://doi.org/10.1002/bdrc.20185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mammoto T, Ingber DE (2010) Mechanical control of tissue and organ development. Development 137(9):1407–1420. https://doi.org/10.1242/dev.024166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Auluck PK, Chan HE, Trojanowski JQ, Lee VM-Y, Bonini NM (2002) Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295(5556):865–868

    Article  CAS  PubMed  Google Scholar 

  35. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ et al (2017) Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544(7650):367–371

  36. Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci 92(20):9368–9372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Park J, Lee BK, Jeong GS, Hyun JK, Lee CJ, Lee S-H (2015) Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer's disease. Lab Chip 15(1):141–150

    Article  CAS  PubMed  Google Scholar 

  38. Li M, Izpisua Belmonte JC (2019) Organoids—preclinical models of human disease. N Engl J Med 380(6):569–579. https://doi.org/10.1056/NEJMra1806175

    Article  PubMed  Google Scholar 

  39. El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442(7101):403–411

    Article  CAS  PubMed  Google Scholar 

  40. Esch EW, Bahinski A, Huh D (2015) Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov 14(4):248–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kilic O, Pamies D, Lavell E, Schiapparelli P, Feng Y, Hartung T, Bal-Price A, Hogberg HT et al (2016) Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis. Lab Chip 16(21):4152–4162

  42. Liu Y, Gill E, Shery Huang YY (2017) Microfluidic on-chip biomimicry for 3D cell culture: a fit-for-purpose investigation from the end user standpoint. Future Sci OA 3(2):FSO173. https://doi.org/10.4155/fsoa-2016-0084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Perez-Toralla K, Mottet G, Tulukcuoglu-Guneri E, Champ J, Bidard FC, Pierga JY, Klijanienko J, Draskovic I et al (2017) FISH-in-CHIPS: a microfluidic platform for molecular typing of cancer cells. Methods Mol Biol 1547:211–220. https://doi.org/10.1007/978-1-4939-6734-6_16

  44. Temiz Y, Lovchik RD, Kaigala GV, Delamarche E (2015) Lab-on-a-chip devices: how to close and plug the lab? Microelectron Eng 132:156–175

    Article  CAS  Google Scholar 

  45. Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373. https://doi.org/10.1038/nature05058

    Article  CAS  PubMed  Google Scholar 

  46. Zheng F, Fu F, Cheng Y, Wang C, Zhao Y, Gu Z (2016) Organ-on-a-chip systems: microengineering to biomimic living systems. Small 12(17):2253–2282. https://doi.org/10.1002/smll.201503208

    Article  CAS  PubMed  Google Scholar 

  47. Logun M, Zhao W, Mao L, Karumbaiah L (2018) Microfluidics in malignant glioma research and precision medicine. Adv Biosyst 2(5):1700221

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sosa-Hernández JE, Villalba-Rodríguez AM, Romero-Castillo KD, Aguilar-Aguila-Isaías MA, García-Reyes IE, Hernández-Antonio A, Ahmed I, Sharma A et al (2018) Organs-on-a-chip module: a review from the development and applications perspective. Micromachines 9(10):536

  49. Yu Y, Shang L, Guo J, Wang J, Zhao Y (2018) Design of capillary microfluidics for spinning cell-laden microfibers. Nat Protoc:1

  50. Sosa-Hernandez JE, Villalba-Rodriguez AM, Romero-Castillo KD, Aguilar-Aguila-Isaias MA, Garcia-Reyes IE, Hernandez-Antonio A, Ahmed I, Sharma A et al (2018) Organs-on-a-chip module: a review from the development and applications perspective. Micromachines (Basel) 9(10). https://doi.org/10.3390/mi9100536

  51. Haring AP, Sontheimer H, Johnson BN (2017) Microphysiological human brain and neural systems-on-a-chip: potential alternatives to small animal models and emerging platforms for drug discovery and personalized medicine. Stem Cell Rev 13(3):381–406. https://doi.org/10.1007/s12015-017-9738-0

    Article  CAS  PubMed Central  Google Scholar 

  52. Qin D, Xia Y, Whitesides GM (2010) Soft lithography for micro- and nanoscale patterning. Nat Protoc 5(3):491–502

    Article  CAS  PubMed  Google Scholar 

  53. Whitesides GM, Ostuni E, Takayama S, Jiang X, Ingber DE (2001) Soft lithography in biology and biochemistry. Annu Rev Biomed Eng 3(1):335–373

    Article  CAS  PubMed  Google Scholar 

  54. Xia Y, Whitesides GM (1998) Soft lithography. Angew Chem Int Ed 37(5):550–575

    Article  CAS  Google Scholar 

  55. Huh D, Kim HJ, Fraser JP, Shea DE, Khan M, Bahinski A, Hamilton GA, Ingber DE (2013) Microfabrication of human organs-on-chips. Nat Protoc 8(11):2135–2157. https://doi.org/10.1038/nprot.2013.137

    Article  CAS  PubMed  Google Scholar 

  56. Mancera-Andrade EI, Parsaeimehr A, Arevalo-Gallegos A, Ascencio-Favela G, Parra Saldivar R (2018) Microfluidics technology for drug delivery: a review. Front Biosci (Elite Ed) 10:74–91

    Google Scholar 

  57. Miccoli B, Braeken D, Ethan Li Y-C (2018) Brain-on-a-chip devices for drug screening and disease modeling applications. Curr Pharm Des

  58. Musick K, Khatami D, Wheeler BC (2009) Three-dimensional micro-electrode array for recording dissociated neuronal cultures. Lab Chip 9(14):2036–2042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Queval A, Ghattamaneni NR, Perrault CM, Gill R, Mirzaei M, McKinney RA, Juncker D (2010) Chamber and microfluidic probe for microperfusion of organotypic brain slices. Lab Chip 10(3):326–334

    Article  CAS  PubMed  Google Scholar 

  60. Reardon S (2015) Scientists seek ‘Homo chippiens. Nature 518(7539):285–286

    Article  CAS  PubMed  Google Scholar 

  61. Baker M (2011) Tissue models: a living system on a chip. Nature 471(7340):661–665. https://doi.org/10.1038/471661a

    Article  CAS  PubMed  Google Scholar 

  62. Reardon S (2015) Organs-on-chips’ go mainstream. Nature 523(7560):266. https://doi.org/10.1038/523266a

    Article  CAS  PubMed  Google Scholar 

  63. Zhang B, Korolj A, Lai BFL, Radisic M (2018) Advances in organ-on-a-chip engineering. Nat Rev Mater:1

  64. Park J, Kim S, Park SI, Choe Y, Li J, Han A (2014) A microchip for quantitative analysis of CNS axon growth under localized biomolecular treatments. J Neurosci Methods 221:166–174

    Article  PubMed  Google Scholar 

  65. Lu X, Kim-Han JS, O’Malley KL, Sakiyama-Elbert SE (2012) A microdevice platform for visualizing mitochondrial transport in aligned dopaminergic axons. J Neurosci Methods 209(1):35–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moreno EL, Hachi S, Hemmer K, Trietsch SJ, Baumuratov AS, Hankemeier T, Vulto P, Schwamborn JC et al (2015) Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. Lab Chip 15(11):2419–2428

  67. Achyuta AKH, Conway AJ, Crouse RB, Bannister EC, Lee RN, Katnik CP, Behensky AA, Cuevas J et al (2013) A modular approach to create a neurovascular unit-on-a-chip. Lab Chip 13(4):542–553

  68. Wang Y, Ma J, Li N, Wang L, Shen L, Sun Y, Wang Y, Zhao J et al (2017) Microfluidic engineering of neural stem cell niches for fate determination. Biomicrofluidics 11(1):014106. https://doi.org/10.1063/1.4974902

  69. 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(3):448–459

    Article  CAS  PubMed  Google Scholar 

  70. Brown JA, Codreanu SG, Shi M, Sherrod SD, Markov DA, Neely MD, Britt CM, Hoilett OS et al (2016) Metabolic consequences of inflammatory disruption of the blood–brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 13(1):306

  71. Griep L, Wolbers F, De Wagenaar B, ter Braak PM, Weksler B, Romero IA, Couraud P, Vermes I et al (2013) BBB on chip: microfluidic platform to mechanically and biochemically modulate blood–brain barrier function. Biomed Microdevices 15(1):145–150

  72. Herland A, van der Meer AD, FitzGerald EA, Park T-E, 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(3):e0150360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sellgren KL, Hawkins BT, Grego S (2015) An optically transparent membrane supports shear stress studies in a three-dimensional microfluidic neurovascular unit model. Biomicrofluidics 9(6):061102

    Article  PubMed  PubMed Central  Google Scholar 

  74. 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(1):184–194

    Article  CAS  PubMed  Google Scholar 

  75. Ruiz A, Joshi P, Mastrangelo R, Francolini M, Verderio C, Matteoli M (2014) Testing Aβ toxicity on primary CNS cultures using drug-screening microfluidic chips. Lab Chip 14(15):2860–2866

    Article  CAS  PubMed  Google Scholar 

  76. Fan Y, Nguyen DT, Akay Y, Xu F, Akay M (2016) Engineering a brain cancer chip for high-throughput drug screening. Sci Rep 6:25062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sun J, Masterman-Smith MD, Graham NA, Jiao J, Mottahedeh J, Laks DR, Ohashi M, DeJesus J et al (2010) A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. Cancer Res 70(15):6128–6138

  78. Hidalgo San Jose L, Stephens P, Song B, Barrow D (2018) Microfluidic encapsulation supports stem cell viability, proliferation, and neuronal differentiation. Tissue Eng Part C Methods 24:158–170. https://doi.org/10.1089/ten.TEC.2017.0368

    Article  CAS  PubMed  Google Scholar 

  79. Wang Y, Wang L, Guo Y, Zhu Y, Qin J (2018) Engineering stem cell-derived 3D brain organoids in a perfusable organ-on-a-chip system. RSC Adv 8(3):1677–1685

    Article  CAS  Google Scholar 

  80. Wang Y, Wang L, Zhu Y, Qin J (2018) Human brain organoid-on-a-chip to model prenatal nicotine exposure. Lab Chip 18(6):851–860. https://doi.org/10.1039/c7lc01084b

    Article  CAS  PubMed  Google Scholar 

  81. MacKerron C, Robertson G, Zagnoni M, Bushell TJ (2017) A microfluidic platform for the characterisation of CNS active compounds. Sci Rep 7(1):15692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Osaki T, Sivathanu V, Kamm RD (2018) Engineered 3D vascular and neuronal networks in a microfluidic platform. Sci Rep 8(1):5168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sandlin ZD, Shou M, Shackman JG, Kennedy RT (2005) Microfluidic electrophoresis chip coupled to microdialysis for in vivo monitoring of amino acid neurotransmitters. Anal Chem 77(23):7702–7708

    Article  CAS  PubMed  Google Scholar 

  84. Kelava I, Lancaster MA (2016) Stem cell models of human brain development. Cell Stem Cell 18(6):736–748. https://doi.org/10.1016/j.stem.2016.05.022

    Article  CAS  PubMed  Google Scholar 

  85. Qian T, Shusta EV, Palecek SP (2015) Advances in microfluidic platforms for analyzing and regulating human pluripotent stem cells. Curr Opin Genet Dev 34:54–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang J, Wei X, Zeng R, Xu F, Li X (2017) Stem cell culture and differentiation in microfluidic devices toward organ-on-a-chip. Future Sci OA 3(2):FSO187. https://doi.org/10.4155/fsoa-2016-0091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mammoto A, Mammoto T, Ingber DE (2012) Mechanosensitive mechanisms in transcriptional regulation. J Cell Sci 125 (Pt 13:3061–3073. https://doi.org/10.1242/jcs.093005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Adegbola A, Bury LA, Fu C, Zhang M, Wynshaw-Boris A (2017) Concise review: induced pluripotent stem cell models for neuropsychiatric diseases. Stem Cells Transl Med 6(12):2062–2070. https://doi.org/10.1002/sctm.17-0150

    Article  PubMed  PubMed Central  Google Scholar 

  89. Alvarez CV, Garcia-Lavandeira M, Garcia-Rendueles ME, Diaz-Rodriguez E, Garcia-Rendueles AR, Perez-Romero S, Vila TV, Rodrigues JS et al (2012) Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells. J Mol Endocrinol 49(2):R89–R111. https://doi.org/10.1530/JME-12-0072

  90. De Filippis L, Zalfa C, Ferrari D (2017) Neural stem cells and human induced pluripotent stem cells to model rare CNS diseases. CNS Neurol Disord Drug Targets 16(8):915–926. https://doi.org/10.2174/1871527316666170615121753

    Article  CAS  PubMed  Google Scholar 

  91. Fong ELS, Yu H (2017) Organs-on-chips: filtration enabled by differentiation. Nat Biomed Eng 1(5):0074

    Article  Google Scholar 

  92. Kornblum HI (2007) Introduction to neural stem cells. Stroke 38(2 Suppl):810–816. https://doi.org/10.1161/01.STR.0000255757.12198.0f

    Article  PubMed  Google Scholar 

  93. Wang Y, Zhao C, Hou Z, Yang Y, Bi Y, Wang H, Zhang Y, Gao S (2018) Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naive state. Elife 7. https://doi.org/10.7554/eLife.29518

  94. Wang S, Wu J, Liu GH (2018) First stem cell transplantation to regenerate human lung. Protein Cell 9(3):244–245. https://doi.org/10.1007/s13238-017-0498-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Karimi M, Bahrami S, Mirshekari H, Basri SM, Nik AB, Aref AR, Akbari M, Hamblin MR (2016) Microfluidic systems for stem cell-based neural tissue engineering. Lab Chip 16(14):2551–2571. https://doi.org/10.1039/c6lc00489j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pamies D, Hartung T, Hogberg HT (2014) Biological and medical applications of a brain-on-a-chip. Exp Biol Med (Maywood) 239(9):1096–1107. https://doi.org/10.1177/1535370214537738

    Article  CAS  Google Scholar 

  97. Prajumwongs P, Weeranantanapan O, Jaroonwitchawan T, Noisa P (2016) Human embryonic stem cells: a model for the study of neural development and neurological diseases. Stem Cells Int 2016:2958210. https://doi.org/10.1155/2016/2958210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Takayama Y, Kida YS (2016) In vitro reconstruction of neuronal networks derived from human iPS cells using microfabricated devices. PLoS One 11(2):e0148559. https://doi.org/10.1371/journal.pone.0148559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lupo G, Nisi PS, Esteve P, Paul YL, Novo CL, Sidders B, Khan MA, Biagioni S et al (2018) Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. Aging Cell 17. https://doi.org/10.1111/acel.12745

  100. Shu P, Fu H, Zhao X, Wu C, Ruan X, Zeng Y, Liu W, Wang M et al (2017) MicroRNA-214 modulates neural progenitor cell differentiation by targeting quaking during cerebral cortex development. Sci Rep 7(1):8014. https://doi.org/10.1038/s41598-017-08450-8

  101. Jäkel S, Dimou L (2017) Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci 11:24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sacco R, Cacci E, Novarino G (2018) Neural stem cells in neuropsychiatric disorders. Curr Opin Neurobiol 48:131–138. https://doi.org/10.1016/j.conb.2017.12.005

    Article  CAS  PubMed  Google Scholar 

  103. Wang Z, Luo Y, Chen L, Liang W (2017) Safety of neural stem cell transplantation in patients with severe traumatic brain injury. Exp Ther Med 13(6):3613–3618. https://doi.org/10.3892/etm.2017.4423

    Article  PubMed  PubMed Central  Google Scholar 

  104. Kim WT, Ryu CJ (2017) Cancer stem cell surface markers on normal stem cells. BMB Rep 50(6):285–298

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kopach O, Rybachuk O, Krotov V, Kyryk V, Voitenko N, Pivneva T (2018) Maturation of neural stem cells and integration into hippocampal circuits: functional study in post-ischemia in situ. J Cell Sci 131:jcs. 210989

    Article  CAS  Google Scholar 

  106. Jessberger S (2016) Stem cell-mediated regeneration of the adult brain. Transfus Med Hemother 43(5):321–326. https://doi.org/10.1159/000447646

    Article  PubMed  PubMed Central  Google Scholar 

  107. Wang B, Jedlicka S, Cheng X (2014) Maintenance and neuronal cell differentiation of neural stem cells C17. 2 correlated to medium availability sets design criteria in microfluidic systems. PLoS One 9(10):e109815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Barros CS, Franco SJ, Müller U (2011) Extracellular matrix: functions in the nervous system. Cold Spring Harb Perspect Biol 3(1):a005108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bonneh-Barkay D, Wiley CA (2009) Brain extracellular matrix in neurodegeneration. Brain Pathol 19(4):573–585

    Article  CAS  PubMed  Google Scholar 

  110. Lepelletier FX, Mann D, Robinson A, Pinteaux E, Boutin H (2017) Early changes in extracellular matrix in Alzheimer's disease. Neuropathol Appl Neurobiol 43(2):167–182

    Article  CAS  PubMed  Google Scholar 

  111. Berretta S (2012) Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 62(3):1584–1597

    Article  CAS  PubMed  Google Scholar 

  112. Leslie SK, Kinney RC, Schwartz Z, Boyan BD (2017) Microencapsulation of stem cells for therapy. In: Cell Microencapsulation. Springer, pp. 251–259

  113. Vitrac A, Cloëz-Tayarani I (2018) Induced pluripotent stem cells as a tool to study brain circuits in autism-related disorders. Stem Cell Res Ther 9(1):226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Koo Y, Hawkins BT, Yun Y (2018) Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening. Sci Rep 8(1):2841. https://doi.org/10.1038/s41598-018-20876-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parr CJC, Yamanaka S, Saito H (2017) An update on stem cell biology and engineering for brain development. Mol Psychiatry 22(6):808–819. https://doi.org/10.1038/mp.2017.66

    Article  CAS  PubMed  Google Scholar 

  116. Qian X, Jacob F, Song MM, Nguyen HN, Song H, Ming GL (2018) Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc 13(3):565–580. https://doi.org/10.1038/nprot.2017.152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hartley BJ, Brennand KJ (2017) Neural organoids for disease phenotyping, drug screening and developmental biology studies. Neurochem Int 106:85–93. https://doi.org/10.1016/j.neuint.2016.10.004

    Article  CAS  PubMed  Google Scholar 

  118. Hunsberger JG, Efthymiou AG, Malik N, Behl M, Mead IL, Zeng X, Simeonov A, Rao M (2015) Induced pluripotent stem cell models to enable in vitro models for screening in the central nervous system. Stem Cells Dev 24(16):1852–1864. https://doi.org/10.1089/scd.2014.0531

    Article  PubMed  PubMed Central  Google Scholar 

  119. Tong G, Izquierdo P, Raashid RA (2017) Human induced pluripotent stem cells and the modelling of Alzheimer's disease: the human brain outside the dish. Open Neurol J 11:27–38. https://doi.org/10.2174/1874205X01711010027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wei T-Y, Fu Y, Chang K-H, Lin K-J, Lu Y-J, Cheng C-M (2017) Point-of-care devices using disease biomarkers to diagnose neurodegenerative disorders. Trends Biotechnol

  121. Fyfe I (2018) Alzheimer disease: epigenetics links ageing with Alzheimer disease. Nat Rev Neurol. https://doi.org/10.1038/nrneurol.2018.36

  122. Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS et al (2011) Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 13(6):597–605. https://doi.org/10.1097/GIM.0b013e31821d69b8

  123. De Felice FG, Munoz DP (2016) Opportunities and challenges in developing relevant animal models for Alzheimer’s disease. Ageing Res Rev 26:112–114

    Article  PubMed  Google Scholar 

  124. Talbot K (2002) Motor neurone disease. Postgrad Med J 78(923):513–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Abbott NJ (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 36(3):437–449

    Article  CAS  PubMed  Google Scholar 

  126. Yamamizu K, Iwasaki M, Takakubo H, Sakamoto T, Ikuno T, Miyoshi M, Kondo T, Nakao Y et al (2017) In vitro modeling of blood–brain barrier with human iPSC-derived endothelial cells, pericytes, neurons, and astrocytes via notch signaling. Stem Cell Reports 8(3):634–647. https://doi.org/10.1016/j.stemcr.2017.01.023

  127. Daneman R (2012) The blood–brain barrier in health and disease. Ann Neurol 72(5):648–672

    Article  CAS  PubMed  Google Scholar 

  128. Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13

    Article  CAS  PubMed  Google Scholar 

  129. Chernykh I, Yakusheva E, Shulkin A (2015) P-Glycoprotein expression in blood–brain barrier in bilateral occlusion of the common carotid artery. Nauchnye vedomosti Belgorodskogo gosudarstvennogo universiteta Seriya: Medicina Farmaciya 29(4):91–95

    Google Scholar 

  130. van der Helm MW, van der Meer AD, Eijkel JC, van den Berg A, Segerink LI (2016) Microfluidic organ-on-chip technology for blood–brain barrier research. Tissue barriers 4(1):e1142493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wolff A, Antfolk M, Brodin B, Tenje M (2015) In vitro blood–brain barrier models—an overview of established models and new microfluidic approaches. J Pharm Sci 104(9):2727–2746

    Article  CAS  PubMed  Google Scholar 

  132. Huh D, Torisawa Y-s, Hamilton GA, Kim HJ, Ingber DE (2012) Microengineered physiological biomimicry: organs-on-chips. Lab Chip 12(12):2156–2164

    Article  CAS  PubMed  Google Scholar 

  133. Perrin S (2014) Preclinical research: make mouse studies work. Nature 507(7493):423–425

    Article  PubMed  Google Scholar 

  134. Alcendor DJ, Block FE 3rd, Cliffel DE, Daniels JS, Ellacott KL, Goodwin CR, Hofmeister LH, Li D et al (2013) Neurovascular unit on a chip: implications for translational applications. Stem Cell Res Ther 4(Suppl 1):S18. https://doi.org/10.1186/scrt379

  135. Adriani G, Ma D, Pavesi A, Goh E, Kamm R (2015) Modeling the blood–brain barrier in a 3D triple co-culture microfluidic system. In: Engineering in medicine and biology society (EMBC), 2015 37th annual international conference of the IEEE. IEEE, pp. 338–341

  136. Bergink V, Gibney SM, Drexhage HA (2014) Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry 75(4):324–331

    Article  CAS  PubMed  Google Scholar 

  137. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2(3):258–270

    Article  PubMed  PubMed Central  Google Scholar 

  138. Yesil-Celiktas O, Hassan S, Miri AK, Maharjan S, Al-kharboosh R, Quiñones-Hinojosa A, Zhang YS (2018) Mimicking human pathophysiology in organ-on-chip devices. Adv Biosyst 2:1800109. https://doi.org/10.1002/adbi.201800109

    Article  Google Scholar 

  139. Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS, Polverini PJ, Mooney DJ (2007) Engineering tumors with 3D scaffolds. Nat Methods 4(10):855–860

    Article  CAS  PubMed  Google Scholar 

  140. Unger C, Kramer N, Walzl A, Scherzer M, Hengstschläger M, Dolznig H (2014) Modeling human carcinomas: physiologically relevant 3D models to improve anti-cancer drug development. Adv Drug Deliv Rev 79:50–67

    Article  CAS  PubMed  Google Scholar 

  141. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. https://doi.org/10.1038/nature12517

  142. Pickl M, Ries C (2009) Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. Oncogene 28(3):461–468

    Article  CAS  PubMed  Google Scholar 

  143. Tanner K, Gottesman MM (2015) Beyond 3D culture models of cancer. Sci Transl Med 7(283):283ps289–283ps289

    Article  Google Scholar 

  144. Cosson S, Lutolf M (2014) Hydrogel microfluidics for the patterning of pluripotent stem cells. Sci Rep 4

  145. Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC (2010) Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials 31(32):8494–8506

    Article  CAS  PubMed  Google Scholar 

  146. Laquintana V, Trapani A, Denora N, Wang F, Gallo JM, Trapani G (2009) New strategies to deliver anticancer drugs to brain tumors. Expert Opinion On Drug Delivery 6(10):1017–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Altemus M, Leung B, Morikawa A, Dziubinski M, Castro M, Merajver S (2016) Novel microfluidic blood–brain niche to study breast cancer metastasis to the brain. AACR

  148. Keng PY, Chen S, Ding H, Sadeghi S, Shah GJ, Dooraghi A, Phelps ME, Satyamurthy N et al (2012) Micro-chemical synthesis of molecular probes on an electronic microfluidic device. Proc Natl Acad Sci U S A 109(3):690–695. https://doi.org/10.1073/pnas.1117566109

  149. Low LA, Tagle DA (2017) Organs-on-chips: progress, challenges, and future directions. Exp Biol Med 242(16):1573–1578

    Article  CAS  Google Scholar 

  150. Haehnel V, Khan FZ, Mutschke G, Cierpka C, Uhlemann M, Fritsch I (2019) Combining magnetic forces for contactless manipulation of fluids in microelectrode-microfluidic systems. Sci Rep 9(1):5103. https://doi.org/10.1038/s41598-019-41284-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Obien MEJ, Deligkaris K, Bullmann T, Bakkum DJ, Frey U (2015) Revealing neuronal function through microelectrode array recordings. Front Neurosci 8:423

    Article  PubMed  PubMed Central  Google Scholar 

  152. Kane KIW, Moreno EL, Hachi S, Walter M, Jarazo J, Oliveira MAP, Hankemeier T, Vulto P et al (2019) Automated microfluidic cell culture of stem cell derived dopaminergic neurons. Sci Rep 9(1):1796. https://doi.org/10.1038/s41598-018-34828-3

  153. Kim S, Kim W, Lim S, Jeon JS (2017) Vasculature-on-a-chip for in vitro disease models. Bioengineering (Basel) 4(1). https://doi.org/10.3390/bioengineering4010008

  154. Sontheimer-Phelps A, Hassell BA, Ingber DE (2019) Modelling cancer in microfluidic human organs-on-chips. Nat Rev Cancer 19(2):65–81. https://doi.org/10.1038/s41568-018-0104-6

    Article  CAS  PubMed  Google Scholar 

  155. Blinder YJ, Freiman A, Raindel N, Mooney DJ, Levenberg S (2015) Vasculogenic dynamics in 3D engineered tissue constructs. Sci Rep 5:17840. https://doi.org/10.1038/srep17840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang X, Sun Q, Pei J (2018) Microfluidic-based 3D engineered microvascular networks and their applications in vascularized microtumor models. Micromachines (Basel) 9(10). https://doi.org/10.3390/mi9100493

  157. Lee SH, Sung JH (2017) Microtechnology-based multi-organ models. Bioengineering (Basel) 4(2). https://doi.org/10.3390/bioengineering4020046

  158. Lee SH, Ha SK, Choi I, Choi N, Park TH, Sung JH (2016) Microtechnology-based organ systems and whole-body models for drug screening. Biotechnol J 11(6):746–756. https://doi.org/10.1002/biot.201500551

    Article  CAS  PubMed  Google Scholar 

  159. An F, Qu Y, Liu X, Zhong R, Luo Y (2015) Organ-on-a-chip: new platform for biological analysis. Anal Chem Insights 10:39–45. https://doi.org/10.4137/ACI.S28905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Karimi M, Zangabad PS, Mehdizadeh F, Malekzad H, Ghasemi A, Bahrami S, Zare H, Moghoofei M et al (2017) Nanocaged platforms: modification, drug delivery and nanotoxicity. Opening synthetic cages to release the tiger. Nanoscale 9(4):1356–1392. https://doi.org/10.1039/c6nr07315h

  161. Kimura H, Sakai Y, Fujii T (2018) Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab Pharmacokinet 33(1):43–48. https://doi.org/10.1016/j.dmpk.2017.11.003

    Article  CAS  PubMed  Google Scholar 

  162. Lee SH, Sung JH (2018) Organ-on-a-chip technology for reproducing multiorgan physiology. Adv healthc Mater 7(2). https://doi.org/10.1002/adhm.201700419

  163. Yum K, Hong SG, Healy KE, Lee LP (2014) Physiologically relevant organs on chips. Biotechnol J 9(1):16–27. https://doi.org/10.1002/biot.201300187

    Article  CAS  PubMed  Google Scholar 

  164. Perestrelo AR, Águas AC, Rainer A, Forte G (2015) Microfluidic organ/body-on-a-chip devices at the convergence of biology and microengineering. Sensors 15(12):31142–31170

    Article  PubMed  PubMed Central  Google Scholar 

  165. Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR et al (2017) Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Sci Rep 7(1):8837. https://doi.org/10.1038/s41598-017-08879-x

  166. Sung JH, Esch MB, Prot J-M, Long CJ, Smith A, Hickman JJ, Shuler ML (2013) Microfabricated mammalian organ systems and their integration into models of whole animals and humans. Lab Chip 13(7):1201–1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

M.R.H. was supported by US NIH Grants R01AI050875 and R21AI121700.

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Author notes

  1. Mirza Ali Mofazzal Jahromi and Amir Abdoli contributed equally to this work.

Authors and Affiliations

  1. Department of Advanced Medical Sciences & Technologies, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran

    Mirza Ali Mofazzal Jahromi

  2. Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran

    Mirza Ali Mofazzal Jahromi, Amir Abdoli & Mohammad Rahmanian

  3. Department of Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran

    Amir Abdoli

  4. Zoonoses Research Center, Jahrom University of Medical Sciences, Jahrom, Iran

    Amir Abdoli

  5. Department of Anesthesiology, Critical Care, and Pain Medicine, Jahrom University of Medical Sciences, Jahrom, Iran

    Mohammad Rahmanian

  6. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Hassan Bardania

  7. Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mehrdad Bayandori & Mahdi Karimi

  8. Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Mehrdad Bayandori & Mahdi Karimi

  9. Civil & Environmental Engineering Department, Shahid Beheshti University, Tehran, Iran

    Seyed Masoud Moosavi Basri

  10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Alireza Kalbasi

  11. Department of Cancer Biology, Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School, Boston, MA, 02215, USA

    Amir Reza Aref

  12. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mahdi Karimi

  13. Research Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mahdi Karimi

  14. Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Mahdi Karimi & Michael R Hamblin

  15. Department of Dermatology, Harvard Medical School, Boston, MA, USA

    Michael R Hamblin

  16. Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA

    Michael R Hamblin

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  1. Mirza Ali Mofazzal Jahromi
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Correspondence to Mahdi Karimi or Michael R Hamblin.

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BeWell Global Inc., Wan Chai, Hong Kong.

Hologenix Inc., Santa Monica, CA.

LumiThera Inc., Poulsbo, WA.

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Bright Photomedicine, Sao Paulo, Brazil.

Quantum Dynamics LLC, Cambridge, MA.

Global Photon Inc., Bee Cave, TX.

Medical Coherence, Boston MA.

NeuroThera, Newark DE.

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Mofazzal Jahromi, M.A., Abdoli, A., Rahmanian, M. et al. Microfluidic Brain-on-a-Chip: Perspectives for Mimicking Neural System Disorders. Mol Neurobiol 56, 8489–8512 (2019). https://doi.org/10.1007/s12035-019-01653-2

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