Skip to main content

Advertisement

SpringerLink
Log in

Microphysiological Human Brain and Neural Systems-on-a-Chip: Potential Alternatives to Small Animal Models and Emerging Platforms for Drug Discovery and Personalized Medicine

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Translational challenges associated with reductionist modeling approaches, as well as ethical concerns and economic implications of small animal testing, drive the need for developing microphysiological neural systems for modeling human neurological diseases, disorders, and injuries. Here, we provide a comprehensive review of microphysiological brain and neural systems-on-a-chip (NSCs) for modeling higher order trajectories in the human nervous system. Societal, economic, and national security impacts of neurological diseases, disorders, and injuries are highlighted to identify critical NSC application spaces. Hierarchical design and manufacturing of NSCs are discussed with distinction for surface- and bulk-based systems. Three broad NSC classes are identified and reviewed: microfluidic NSCs, compartmentalized NSCs, and hydrogel NSCs. Emerging areas and future directions are highlighted, including the application of 3D printing to design and manufacturing of next-generation NSCs, the use of stem cells for constructing patient-specific NSCs, and the application of human NSCs to ‘personalized neurology’. Technical hurdles and remaining challenges are discussed. This review identifies the state-of-the-art design methodologies, manufacturing approaches, and performance capabilities of NSCs. This work suggests NSCs appear poised to revolutionize the modeling of human neurological diseases, disorders, and injuries.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Thurman, D. J., Alverson, C., Dunn, K. A., Guerrero, J., & Sniezek, J. E. (1999). Traumatic brain injury in the United States: A public health perspective. The Journal of Head Trauma Rehibilitation, 14, 602–615.

    Article  CAS  Google Scholar 

  2. Menken, M., Munsat, T. L., & Toole, J. F. (2000). The global burden of disease study: Implications for neurology. Archives of Neurology, 57, 418–420.

    Article  CAS  PubMed  Google Scholar 

  3. Kochanek, K. D., Murry, S. L., Xu, J., & Tejada-Vera, B. (2016). Deaths: Final data for 2014. National Vital Statistics Report, 64, 1–121.

    Google Scholar 

  4. Health, United States. (2015). With special feature on racial and ethnic health disparities. Hyattsville, MD: National Center for Health Statistics.

    Google Scholar 

  5. Alzheimer's Association (2011). Alzheimer’s disease facts and figures. http://www.alz.org/downloads/Facts_Figures_2011.pdf. Accessed 2/7/16, 2017.

  6. Ma, V. Y., Chan, L., & Carruthers, K. J. (2014). The incidence, prevalence, costs and impact on disability of common conditions requiring rehabilitation in the US: Stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Archive of Physical Medicine and Rehabilitation, 95, 986–995.

    Article  Google Scholar 

  7. Kehoe, S., Zhang, X., & Boyd, D. (2012). FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy. Injury, 43, 553–572.

    Article  CAS  PubMed  Google Scholar 

  8. DiMasi, J. A., Hansen, R. W., & Grabowski, H. G. (2003). The price of innovation: New estimates of drug development costs. Journal of Health Economics, 22, 151–185.

    Article  PubMed  Google Scholar 

  9. Difede, J., & Barchas, J. D. (2010). Psychiatric and neurologic aspects of war: An overview and perspective. Annals of the New York Academy of Sciences, 1208, 1–9.

    Article  PubMed  Google Scholar 

  10. Murray, C., King, G., Lopez, A., Tomijima, N., & Krug, E. (2002). Armed conflict as a public health problem. BMJ, 324, 346–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. Nature, 451, 716–719.

    Article  CAS  PubMed  Google Scholar 

  12. Macedonia C, Zamisch M, Judy J, Ling G. (2012) DARPA challenge: developing new technologies for brain and spinal injuries. Proceedings of SPIE 8371, 8371 0I.

  13. Pampaloni, F., Reynaud, E. G., & Stelzer, E. H. (2007). The third dimension bridges the gap between cell culture and live tissue. Nature Reviews. Molecular Cell Biology, 8, 839–845.

    Article  CAS  PubMed  Google Scholar 

  14. Breslin, S., & O’Driscoll, L. (2013). Three-dimensional cell culture: The missing link in drug discovery. Drug Discovery Today, 18, 240–249.

    Article  CAS  PubMed  Google Scholar 

  15. van Duinen, V., Trietsch, S. J., Joore, J., Vulto, P., & Hankemeier, T. (2015). Microfluidic 3D cell culture: From tools to tissue models. Current Opinion in Biotechnology, 35, 118–126.

    Article  PubMed  CAS  Google Scholar 

  16. Fennema, E., Rivron, N., Rouwkema, J., van Blitterswijk, C., & de Boer, J. (2013). Spheroid culture as a tool for creating 3D complex tissues. Trends in Biotechnology, 31, 108–115.

    Article  CAS  PubMed  Google Scholar 

  17. Laurent, J., Frongia, C., Cazales, M., Mondesert, O., Ducommun, B., & Lobjois, V. (2013). Multicellular tumor spheroid models to explore cell cycle checkpoints in 3D. BMC Cancer, 13, 73.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Perestrelo, A. R., Águas, A. C., Rainer, A., & Forte, G. (2015). Microfluidic organ/body-on-a-chip devices at the convergence of biology and microengineering. Sensors, 15, 31142–31170.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Esch, E. W., Bahinski, A., & Huh, D. (2015). Organs-on-chips at the frontiers of drug discovery. Nature Reviews Drug Discovery, 14, 248–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pamies, D., Hartung, T., & Hogberg, H. T. (2014). Biological and medical applications of a brain-on-a-chip. Experimental Biology and Medicine, 239, 1096–1107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Johnson, B. N., Lancaster, K. Z., Hogue, I. B., et al. (2016). 3D printed nervous system on a chip. Lab on a Chip, 16, 1393–1400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Taylor, A. M., Blurton-Jones, M., Rhee, S. W., Cribbs, D. H., Cotman, C. W., & Jeon, N. L. (2005). A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nature Methods, 2, 599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Han, A., Park, J., Li, J., & Kim, S. (2014). Microfluidic systems for axonal growth and regeneration research. Neural Regeneration Research, 9, 1703–1705.

    PubMed  PubMed Central  Google Scholar 

  24. Lee, K. H., Lee, K. H., Lee, J., et al. (2014). Integration of microfluidic chip with biomimetic hydrogel for 3D controlling and monitoring of cell alignment and migration. Journal of Biomedical Materials Research Part A, 102, 1164–1172.

    Article  PubMed  CAS  Google Scholar 

  25. Chung, B. G., Flanagan, L. A., Rhee, S. W., et al. (2005). Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab on a Chip, 5, 401–406.

    Article  CAS  PubMed  Google Scholar 

  26. Huh, D., Matthews, B. D., Mammoto, A., Montoya-Zavala, M., Hsin, H. Y., & Ingber, D. E. (2010). Reconstituting organ-level lung functions on a chip. Science, 328, 1662–1668.

    Article  CAS  PubMed  Google Scholar 

  27. Southam, K. A., King, A. E., Blizzard, C. A., McCormack, G. H., & Dickson, T. C. (2013). Microfluidic primary culture model of the lower motor neuron–neuromuscular junction circuit. Journal of Neuroscience Methods, 218, 164–169.

    Article  PubMed  Google Scholar 

  28. Millet, L. J., Stewart, M. E., Nuzzo, R. G., & Gillette, M. U. (2010). Guiding neuron development with planar surface gradients of substrate cues deposited using microfluidic devices. Lab on a Chip, 10, 1525–1535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Madou, M. J. (2011). Manufacturing techniques for microfabrication and nanotechnology. Boca Raton: CRC Press.

    Google Scholar 

  30. Madou, M. J. (2002). Fundamentals of microfabrication: The science of miniaturization. Boca Raton: CRC Press.

    Google Scholar 

  31. Sackmann, E. K., Fulton, A. L., & Beebe, D. J. (2014). The present and future role of microfluidics in biomedical research. Nature, 507, 181–189.

    Article  CAS  PubMed  Google Scholar 

  32. Hynd, M. R., Frampton, J. P., Dowell-Mesfin, N., Turner, J. N., & Shain, W. (2007). Directed cell growth on protein-functionalized hydrogel surfaces. Journal of Neuroscience Methods, 162, 255–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hahn, M. S., Taite, L. J., Moon, J. J., Rowland, M. C., Ruffino, K. A., & West, J. L. (2006). Photolithographic patterning of polyethylene glycol hydrogels. Biomaterials, 27, 2519–2524.

    Article  CAS  PubMed  Google Scholar 

  34. Luo, Y., & Shoichet, M. S. (2004). A photolabile hydrogel for guided three-dimensional cell growth and migration. Nature Materials, 3, 249–253.

    Article  CAS  PubMed  Google Scholar 

  35. Hahn, M. S., Miller, J. S., & West, J. L. (2006). Three-dimensional biochemical and biomechanical patterning of hydrogels for guiding cell behavior. Advanced Materials, 18, 2679–2684.

    Article  CAS  Google Scholar 

  36. Wong, K. V., & Hernandez, A. (2012). A review of additive manufacturing. ISRN Mechanical Engineering, 2012, 208760.

    Article  Google Scholar 

  37. Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32, 773–785.

    Article  CAS  PubMed  Google Scholar 

  38. Booth, R., & Kim, H. (2012). Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab on a Chip, 12, 1784–1792.

    Article  CAS  PubMed  Google Scholar 

  39. Griep, L., Wolbers, F., De Wagenaar, B., et al. (2013). BBB on chip: Microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. Biomedical Microdevices, 15, 145–150.

    Article  CAS  PubMed  Google Scholar 

  40. Prabhakarpandian, B., Shen, M.-C., Nichols, J. B., et al. (2013). SyM-BBB: A microfluidic blood brain barrier model. Lab on a Chip, 13, 1093–1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Queval, A., Ghattamaneni, N. R., Perrault, C. M., et al. (2010). Chamber and microfluidic probe for microperfusion of organotypic brain slices. Lab on a Chip, 10, 326–334.

    Article  CAS  PubMed  Google Scholar 

  42. Park, J., Lee, B. K., Jeong, G. S., Hyun, J. K., Lee, C. J., & 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 on a Chip, 15, 141–150.

    Article  CAS  PubMed  Google Scholar 

  43. Musick, K., Khatami, D., & Wheeler, B. C. (2009). Three-dimensional micro-electrode array for recording dissociated neuronal cultures. Lab on a Chip, 9, 2036–2042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Whitesides, G. M. (2006). The origins and the future of microfluidics. Nature, 442, 368–373.

    Article  CAS  PubMed  Google Scholar 

  45. Sia, S. K., & Whitesides, G. M. (2003). Microfluidic devices fabricated in poly (dimethylsiloxane) for biological studies. Electrophoresis, 24, 3563–3576.

    Article  CAS  PubMed  Google Scholar 

  46. Au, A. K., Huynh, W., Horowitz, L. F., & Folch, A. (2016). 3D-printed microfluidics. Angewandte Chemie, International Edition, 55, 3862–3881.

    Article  CAS  Google Scholar 

  47. Ho, C. M. B., Ng, S. H., Li, K. H. H., & Yoon, Y.-J. (2015). 3D printed microfluidics for biological applications. Lab on a Chip, 15, 3627–3637.

    Article  CAS  PubMed  Google Scholar 

  48. Kitson, P. J., Rosnes, M. H., Sans, V., Dragone, V., & Cronin, L. (2012). Configurable 3D-printed millifluidic and microfluidic ‘lab on a chip’reactionware devices. Lab on a Chip, 12, 3267–3271.

    Article  CAS  PubMed  Google Scholar 

  49. Lozano, R., Stevens, L., Thompson, B. C., et al. (2015). 3D printing of layered brain-like structures using peptide modified gellan gum substrates. Biomaterials, 67, 264–273.

    Article  CAS  PubMed  Google Scholar 

  50. Dworak, B. J., & Wheeler, B. C. (2009). Novel MEA platform with PDMS microtunnels enables the detection of action potential propagation from isolated axons in culture. Lab on a Chip, 9, 404–410.

    Article  CAS  PubMed  Google Scholar 

  51. Rowe, L., Almasri, M., Lee, K., et al. (2007). Active 3-D microscaffold system with fluid perfusion for culturing in vitro neuronal networks. Lab on a Chip, 7, 475–482.

    Article  CAS  PubMed  Google Scholar 

  52. Kanagasabapathi, T. T., Franco, M., Barone, R. A., Martinoia, S., Wadman, W. J., & Decré, M. M. (2013). Selective pharmacological manipulation of cortical–thalamic co-cultures in a dual-compartment device. Journal of Neuroscience Methods, 214, 1–8.

    Article  PubMed  Google Scholar 

  53. Kanagasabapathi, T. T., Massobrio, P., Barone, R. A., et al. (2012). Functional connectivity and dynamics of cortical–thalamic networks co-cultured in a dual compartment device. Journal of Neural Engineering, 9, 036010.

    Article  PubMed  Google Scholar 

  54. Bianco, F., Tonna, N., Lovchik, R. D., et al. (2012). Overflow microfluidic networks: Application to the biochemical analysis of brain cell interactions in complex neuroinflammatory scenarios. Analytical Chemistry, 84, 9833–9840.

    Article  CAS  PubMed  Google Scholar 

  55. Park, J. Y., Kim, S.-K., Woo, D.-H., Lee, E.-J., Kim, J.-H., & Lee, S.-H. (2009). Differentiation of neural progenitor cells in a microfluidic Chip-generated cytokine gradient. Stem Cells, 27, 2646–2654.

    Article  CAS  PubMed  Google Scholar 

  56. Tourovskaia, A., Figueroa-Masot, X., & Folch, A. (2005). Differentiation-on-a-chip: A microfluidic platform for long-term cell culture studies. Lab on a Chip, 5, 14–19.

    Article  CAS  PubMed  Google Scholar 

  57. Blake, A., Pearce, T., Rao, N., Johnson, S., & Williams, J. (2007). Multilayer PDMS microfluidic chamber for controlling brain slice microenvironment. Lab on a Chip, 7, 842–849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Deosarkar, S. P., Prabhakarpandian, B., Wang, B., Sheffield, J. B., Krynska, B., & Kiani, M. F. (2015). A novel dynamic neonatal blood-brain barrier on a Chip. PloS One, 10, e0142725.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. 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, 2253–2282.

    Article  CAS  PubMed  Google Scholar 

  60. Morgan, J. P., Delnero, P. F., Zheng, Y., et al. (2013). Formation of microvascular networks in vitro. Nature Protocols, 8, 1820–1836.

    Article  PubMed  CAS  Google Scholar 

  61. Park, J., Kim, S., Park, S. I., Choe, Y., Li, J., & Han, A. (2014). A microchip for quantitative analysis of CNS axon growth under localized biomolecular treatments. Journal of Neuroscience Methods, 221, 166–174.

    Article  PubMed  Google Scholar 

  62. Hosie, K. A., King, A. E., Blizzard, C. A., Vickers, J. C., & Dickson, T. C. (2012). Chronic excitotoxin-induced axon degeneration in a compartmented neuronal culture model. ASN Neuro, 4, AN20110031.

    Article  CAS  Google Scholar 

  63. Park, J. W., Vahidi, B., Taylor, A. M., Rhee, S. W., & Jeon, N. L. (2006). Microfluidic culture platform for neuroscience research. Nat Protocols, 1, 2128–2136.

    Article  CAS  PubMed  Google Scholar 

  64. Song, H. L., Shim, S., Kim, D. H., et al. (2014). β-amyloid is transmitted via neuronal connections along axonal membranes. Annals of Neurology, 75, 88–97.

    Article  CAS  PubMed  Google Scholar 

  65. Taylor, A. M., Dieterich, D. C., Ito, H. T., Kim, S. A., & Schuman, E. M. (2010). Microfluidic local perfusion chambers for the visualization and manipulation of synapses. Neuron, 66, 57–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bang, S., Na, S., Jang, J. M., Kim, J., & Jeon, N. L. (2015). Engineering-aligned 3D neural circuit in microfluidic device. Advanced Healthcare Materials, 5, 159–166.

    Article  PubMed  CAS  Google Scholar 

  67. Stoothoff, W., Jones, P. B., Spires-Jones, T. L., et al. (2009). Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. Journal of Neurochemistry, 111, 417–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, W. W., Goodhouse, J., Jeon, N. L., & Enquist, L. (2008). A microfluidic chamber for analysis of neuron-to-cell spread and axonal transport of an alpha-herpesvirus. PloS One, 3, e2382.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Peyrin, J.-M., Deleglise, B., Saias, L., et al. (2011). Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers. Lab on a Chip, 11, 3663–3673.

    Article  CAS  PubMed  Google Scholar 

  70. Ionescu, A., Zahavi, E. E., Gradus, T., Ben-Yaakov, K., & Perlson, E. (2016). Compartmental microfluidic system for studying muscle–neuron communication and neuromuscular junction maintenance. European Journal of Cell Biology, 95, 69–88.

    Article  CAS  PubMed  Google Scholar 

  71. Berdichevsky, Y., Staley, K. J., & Yarmush, M. L. (2010). Building and manipulating neural pathways with microfluidics. Lab on a Chip, 10, 999–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shin, Y., Yang, K., Han, S., et al. (2014). Reconstituting vascular microenvironment of neural stem cell niche in three-dimensional extracellular matrix. Advanced Healthcare Materials, 3, 1457–1464.

    Article  CAS  PubMed  Google Scholar 

  73. Ch'ng, T., & Enquist, L. (2005). Neuron-to-cell spread of pseudorabies virus in a compartmented neuronal culture system. Journal of Virology, 79, 10875–10889.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Park, J., Koito, H., Li, J., & Han, A. (2012). Multi-compartment neuron–glia co-culture platform for localized CNS axon–glia interaction study. Lab on a Chip, 12, 3296–3304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Taylor, M. P., Kobiler, O., & Enquist, L. W. (2012). Alphaherpesvirus axon-to-cell spread involves limited virion transmission. Proceeding of National Academy of Science United State of America, 109, 17046–17051.

    Article  CAS  Google Scholar 

  76. Deleglise, B., Magnifico, S., Duplus, E., et al. (2014). β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network. Acta Neuropathologica Communications, 2, 145.

    PubMed  PubMed Central  Google Scholar 

  77. Siddique, R., Vyas, A., Thakor, N., & Brushart, T. M. (2014). A two-compartment organotypic model of mammalian peripheral nerve repair. Journal of Neuroscience Methods, 232, 84–92.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Koyuncu, O. O., Perlman, D. H., & Enquist, L. W. (2013). Efficient retrograde transport of pseudorabies virus within neurons requires local protein synthesis in axons. Cell Host & Microbe, 13, 54–66.

    Article  CAS  Google Scholar 

  79. Irons, H. R., Cullen, D. K., Shapiro, N. P., Lambert, N. A., Lee, R. H., & LaPlaca, M. C. (2008). Three-dimensional neural constructs: A novel platform for neurophysiological investigation. Journal of Neural Engineering, 5, 333.

    Article  PubMed  Google Scholar 

  80. Gu, Q., Tomaskovic-Crook, E., Lozano, R., et al. (2016). Functional 3D neural mini-tissues from printed gel-based bioink and human neural stem cells. Advanced Healthcare Materials, 5, 1429–1438.

    Article  CAS  PubMed  Google Scholar 

  81. Kolesky, D. B., Truby, R. L., Gladman, A. S., Busbee, T. A., Homan, K. A., & Lewis, J. A. (2014). 3D Bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Advanced Materials, 26, 3124–3130.

    Article  CAS  PubMed  Google Scholar 

  82. Selkoe, D. J. (1997). Alzheimer's disease--genotypes, phenotype, and treatments. Science, 275, 630–631.

    Article  CAS  PubMed  Google Scholar 

  83. Kunze, A., Meissner, R., Brando, S., & Renaud, P. (2011). Co-pathological connected primary neurons in a microfluidic device for alzheimer studies. Biotechnology and Bioengineering, 108, 2241–2245.

    Article  CAS  PubMed  Google Scholar 

  84. Choi, Y. J., Park, J., & Lee, S.-H. (2013). Size-controllable networked neurospheres as a 3D neuronal tissue model for Alzheimer's disease studies. Biomaterials, 34, 2938–2946.

    Article  CAS  PubMed  Google Scholar 

  85. O'Brien, J. C., Jones, V. W., Porter, M. D., Mosher, C. L., & Henderson, E. (2000). Immunosensing platforms using spontaneously adsorbed antibody fragments on gold. Analytical Chemistry, 72, 703–710.

    Article  PubMed  CAS  Google Scholar 

  86. Lotharius, J., & Brundin, P. (2002). Pathogenesis of Parkinson's disease: Dopamine, vesicles and α-synuclein. Nature Reviews. Neuroscience, 3, 932–942.

    Article  CAS  PubMed  Google Scholar 

  87. Lu, X., Kim-Han, J. S., Harmon, S., Sakiyama-Elbert, S. E., & O'Malley, K. L. (2014). The parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons. Molecular Neurodegeneration, 9, 17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Ghannad-Rezaie, M., Wang, X., Mishra, B., Collins, C., & Chronis, N. (2012). Microfluidic chips for in vivo imaging of cellular responses to neural injury in drosophila larvae. PloS One, 7, e29869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yin, B.-S., Li, M., Liu, B.-M., Wang, S.-Y., & Zhang, W.-G. (2015). An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration. Experimental and Therapeutic Medicine, 9, 154–158.

    CAS  PubMed  Google Scholar 

  90. Rengier, F., Mehndiratta, A., Tengg-Kobligk, H., et al. (2010). 3D printing based on imaging data: Review of medical applications. International Journal of Computer Assisted Radiology Surgery, 5, 335–341.

    Article  CAS  PubMed  Google Scholar 

  91. Johnson, B. N., Lancaster, K. Z., Zhen, G., et al. (2015). 3D printed anatomical nerve regeneration pathways. Advanced Functional Materials, 25, 6205–6217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Smith, A., Long, C., Pirozzi, K., & Hickman, J. (2013). A functional system for high-content screening of neuromuscular junctions in vitro. Technology, 1, 37–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yeon, J. H., Na, D., Choi, K., Ryu, S.-W., Choi, C., & Park, J.-K. (2012). Reliable permeability assay system in a microfluidic device mimicking cerebral vasculatures. Biomedical Microdevices, 14, 1141–1148.

    Article  CAS  PubMed  Google Scholar 

  94. Hamburg, M. A., & Collins, F. S. (2010). The path to personalized medicine. NEJM, 363, 301–304.

    Article  CAS  PubMed  Google Scholar 

  95. Murphy, S. V., Atala, A. (2016). Regenerative medicine technology: On-a-Chip applications for disease modeling, Drug Discovery and Personalized Medicine. Boca Raton: CRC Press.

  96. Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.

    Article  CAS  PubMed  Google Scholar 

  97. Rooney, G. E., Goodwin, A. F., Depeille, P., et al. (2016). Human iPS cell-derived neurons uncover the impact of increased Ras signaling in Costello syndrome. The Journal of Neuroscience, 36, 142–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sung, K. E., Su, X., Berthier, E., Pehlke, C., Friedl, A., & Beebe, D. J. (2013). Understanding the impact of 2D and 3D fibroblast cultures on in vitro breast cancer models. PloS One, 8, e76373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Baharvand, H., Hashemi, S. M., Ashtiani, S. K., & Farrokhi, A. (2006). Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. The International Journal of Developmental Biology, 50, 645–652.

    Article  CAS  PubMed  Google Scholar 

  100. DelNero, P., Lane, M., Verbridge, S. S., et al. (2015). 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways. Biomaterials, 55, 110–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Smith, K. M., & Kates, J. A. (1996). Regulatory hurdles in bringing an in vitro diagnostic device to market. Clinical Chemistry, 42, 1556–1557.

    CAS  PubMed  Google Scholar 

  102. Coquinco, A., Kojic, L., Wen, W., et al. (2014). A microfluidic based in vitro model of synaptic competition. Molecular and Cellular Neurosciences, 60, 43–52.

    Article  CAS  PubMed  Google Scholar 

  103. Lu, X., Kim-Han, J. S., O’Malley, K. L., & Sakiyama-Elbert, S. E. (2012). A microdevice platform for visualizing mitochondrial transport in aligned dopaminergic axons. Journal of Neuroscience Methods, 209, 35–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Park, J., Koito, H., Li, J., & Han, A. (2009). Microfluidic compartmentalized co-culture platform for CNS axon myelination research. Biomedical Microdevices, 11, 1145–1153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tong, Z., Seira, O., Casas, C., et al. (2014). Engineering a functional neuro-muscular junction model in a chip. RSC Advances, 4, 54788–54797.

    Article  CAS  Google Scholar 

  106. Zahavi, E. E., Ionescu, A., Gluska, S., Gradus, T., Ben-Yaakov, K., & Perlson, E. (2015). A compartmentalized microfluidic neuromuscular co-culture system reveals spatial aspects of GDNF functions. Journal of Cell Science, 128, 1241–1252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Suzuki, I., & Yasuda, K. (2007). Constructive formation and connection of aligned micropatterned neural networks by stepwise photothermal etching during cultivation. Japanese Journal of Applied Physics, 46, 6398.

    Article  CAS  Google Scholar 

  108. Suzuki, I., Sugio, Y., Jimbo, Y., & Yasuda, K. (2004). Individual-cell-based electrophysiological measurement of a topographically controlled neuronal network pattern using agarose architecture with a multi-electrode array. Japanese Journal of Applied Physics, 43, L403.

    Article  CAS  Google Scholar 

  109. Suzuki, I., Sugio, Y., Jimbo, Y., & Yasuda, K. (2005). Stepwise pattern modification of neuronal network in photo-thermally-etched agarose architecture on multi-electrode array chip for individual-cell-based electrophysiological measurement. Lab on a Chip, 5, 241–247.

    Article  CAS  PubMed  Google Scholar 

  110. Odawara, A., Gotoh, M., & Suzuki, I. (2013). Control of neural network patterning using collagen gel photothermal etching. Lab on a Chip, 13, 2040–2046.

    Article  CAS  PubMed  Google Scholar 

  111. Horn-Ranney, E. L., Curley, J. L., Catig, G. C., Huval, R. M., & Moore, M. J. (2013). Structural and molecular micropatterning of dual hydrogel constructs for neural growth models using photochemical strategies. Biomedical Microdevices, 15, 49–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Curley, J. L., Catig, G. C., Horn-Ranney, E. L., & Moore, M. J. (2014). Sensory axon guidance with semaphorin 6A and nerve growth factor in a biomimetic choice point model. Biofabrication, 6, 035026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Huval, R. M., Miller, O. H., Curley, J. L., Fan, Y., Hall, B. J., & Moore, M. J. (2015). Microengineered peripheral nerve-on-a-chip for preclinical physiological testing. Lab on a Chip, 15, 2221–2232.

    Article  CAS  PubMed  Google Scholar 

  114. Tang-Schomer, M. D., White, J. D., Tien, L. W., et al. (2014). Bioengineered functional brain-like cortical tissue. Proceedings of National Academy of Science of the United State of America, 111, 13811–13816.

    Article  CAS  Google Scholar 

  115. Bettencourt, L. M., Stephens, G. J., Ham, M. I., & Gross, G. W. (2007). Functional structure of cortical neuronal networks grown in vitro. Physical Review E, 75, 021915.

    Article  CAS  Google Scholar 

  116. Brewer, G. J., Boehler, M. D., Ide, A. N., & Wheeler, B. C. (2009). Chronic electrical stimulation of cultured hippocampal networks increases spontaneous spike rates. Journal of Neuroscience Methods, 184, 104–109.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Cadotte, A. J., DeMarse, T. B., He, P., & Ding, M. (2008). Causal measures of structure and plasticity in simulated and living neural networks. PloS One, 3, e3355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Dimoka, A., Courellis, S. H., Gholmieh, G. I., Marmarelis, V. Z., & Berger, T. W. (2008). Modeling the nonlinear properties of the in vitro hippocampal perforant path-dentate system using multielectrode array technology. IEEE Transactions on Biomedical Engineering, 55, 693–702.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Fromherz, P., & Stett, A. (1995). Silicon-neuron junction: Capacitive stimulation of an individual neuron on a silicon chip. Physical Review Letters, 75, 1670.

    Article  CAS  PubMed  Google Scholar 

  120. Gross, G. W., Harsch, A., Rhoades, B. K., & Göpel, W. (1997). Odor, drug and toxin analysis with neuronal networks in vitro: Extracellular array recording of network responses. Biosensors & Bioelectronics, 12, 373–393.

    Article  CAS  Google Scholar 

  121. Hofmann, F., & Bading, H. (2006). Long term recordings with microelectrode arrays: Studies of transcription-dependent neuronal plasticity and axonal regeneration. Journal of Physiology, Paris, 99, 125–132.

    Article  CAS  PubMed  Google Scholar 

  122. Hutzler, M., & Fromherz, P. (2004). Silicon chip with capacitors and transistors for interfacing organotypic brain slice of rat hippocampus. The European Journal of Neuroscience, 19, 2231–2238.

    Article  PubMed  Google Scholar 

  123. Hutzler, M., Lambacher, A., Eversmann, B., Jenkner, M., Thewes, R., & Fromherz, P. (2006). High-resolution multitransistor array recording of electrical field potentials in cultured brain slices. Journal of Neurophysiology, 96, 1638–1645.

    Article  CAS  PubMed  Google Scholar 

  124. Patolsky, F., Timko, B. P., Yu, G., et al. (2006). Detection, stimulation, and inhibition of neuronal signals with high-density nanowire transistor arrays. Science, 313, 1100–1104.

    Article  CAS  PubMed  Google Scholar 

  125. Pine, J. (1980). Recording action potentials from cultured neurons with extracellular microcircuit electrodes. Journal of Neuroscience Methods, 2, 19–31.

    Article  CAS  PubMed  Google Scholar 

  126. Qing, Q., Pal, S. K., Tian, B., et al. (2010). Nanowire transistor arrays for mapping neural circuits in acute brain slices. Proceedings of National Academy of Science of the United State of America, 107, 1882–1887.

    Article  CAS  Google Scholar 

  127. Achyuta, A. K. H., Conway, A. J., Crouse, R. B., et al. (2013). A modular approach to create a neurovascular unit-on-a-chip. Lab on a Chip, 13, 542–553.

    Article  CAS  PubMed  Google Scholar 

  128. Zhang, K., Chou, C.-K., Xia, X., Hung, M.-C., & Qin, L. (2014). Block-cell-printing for live single-cell printing. Proceedings of National Academy of Science of the United State of America, 111, 2948–2953.

    Article  CAS  Google Scholar 

  129. Chronis, N., Zimmer, M., & Bargmann, C. I. (2007). Microfluidics for in vivo imaging of neuronal and behavioral activity in Caenorhabditis elegans. Nature Methods, 4, 727–731.

    Article  CAS  PubMed  Google Scholar 

  130. Majumdar, D., Gao, Y., Li, D., & Webb, D. J. (2011). Co-culture of neurons and glia in a novel microfluidic platform. Journal of Neuroscience Methods, 196, 38–44.

    Article  PubMed  Google Scholar 

  131. Tang, Y. T., Mendez, J. M., Theriot, J. J., et al. (2014). Minimum conditions for the induction of cortical spreading depression in brain slices. Journal of Neurophysiology, 112, 2572–2579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The presented work was supported by the National Science Foundation (NSF) grant number NSF CBET-1650601 and the National Institutes of Health (NIH) grant numb ers NIH R01NS082851-01A1 and NIH R01NS036692.

Author information

Authors and Affiliations

  1. Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA, 24061, USA

    Alexander P. Haring & Blake N. Johnson

  2. Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA, 24061, USA

    Alexander P. Haring & Blake N. Johnson

  3. Glial Biology in Health, Disease, and Cancer Center, Virginia Tech Carilion Research Institute, Roanoke, VA, 24016, USA

    Harald Sontheimer

  4. School of Neuroscience, Virginia Tech, Blacksburg, VA, 24061, USA

    Harald Sontheimer & Blake N. Johnson

  5. Department of Materials Science and Engineering, Virginia Tech, Blacksburg, VA, 24061, USA

    Blake N. Johnson

Authors
  1. Alexander P. Haring
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harald Sontheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Blake N. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Blake N. Johnson.

Ethics declarations

Conflict of Interest

No competing financial interests exist.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haring, A.P., Sontheimer, H. & Johnson, B.N. 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 and Rep 13, 381–406 (2017). https://doi.org/10.1007/s12015-017-9738-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-017-9738-0

Keywords

Search

Navigation