화학공학소재연구정보센터
홈 로그인 로그아웃 연락처 사이트맵
Journal of Industrial and Engineering Chemistry, Vol.62, 341-351, June, 2018
DOI10.1016/j.jiec.2018.01.014  Export Citation
Construction of neurospheroids via surface modified concave microwells
GeonHui Lee1, Jaeho Lim2, JiSoo Park1, Wonseok Lee3, Dae Sung Yoon1, Soo Hyun Kim1, 4, Myung-Ki Kim1, †, Sang-Hoon Lee1, 2, and Dong-Hwee Kim1, †
  • 1KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
  • 2Department of Biomedical Engineering, Korea University, Seoul 02841, Republic of Korea
  • 3Department of Biomedical Engineering, Yonsei University, Wonju 26493, Republic of Korea
  • 4Center for Biomaterials, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
E-mail:,
Developing a three-dimensional (3D) neural tissue model is important to comprehensively understand neural development and neuronal degeneration associated with various neurological disorders such as axonopathy and neuronopathy. Here, a new microplatform suitable for constructing neuronal spheroids (neurospheroids) was developed by modulating cell.surface interactions. The inner surface of a polydimethylsiloxane (PDMS) concave microwell array extensively used in in vitro cell aggregation was modified with typical extracellular matrix (ECM) molecules or carbon nanotubes to control neural spheroid formation. Modulating neuronal cell-ECM interactions could tune 3D intercellular interactions and spheroidal functionality. Neurite outgrowth, a neuronal marker for complex interneuronal signaling, was found to be tightly regulated by cell-ECM interactions in a confined space. Furthermore, amyloid-β (Aβ)-induced axonopathy representing a pathological feature of neurodegenerative diseases in vivo was examined in this study to monitor the degeneration of neurite outgrowth and alteration of neuronal morphology in these neurospheroids. The proposed neural tissue model could be used to study various neurodegenerative diseases in the future.
Keywords:3D neural tissues;Cell-cell interactions;Cell-extracellular matrix interactions;Axonopathy
  1. Lu P, Jones L, Snyder E, Tuszynski M, Exp. Neurol., 181, 115 (2003)
  2. Song HJ, Stevens CF, Gage FH, Nat. Neurosci., 5, 438 (2002)
  3. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR, Cell, 143, 527 (2010)
  4. Lankford KL, DeMello FG, Klein WL, Proc. Natl. Acad. Sci. U. S. A., 85, 4567 (1988)
  5. Klambt C, Jacobs JR, Goodman CS, Cell, 64, 801 (1991)
  6. Meiri KF, Pfenninger KH, Willard MB, Proc. Natl. Acad. Sci. U. S. A., 83., 3537 (1986)
  7. Skene J, Jacobson RD, Snipes GJ, McGuire CB, Norden JJ, Freeman JA, Science, 233, 783 (1986)
  8. Choi YJ, Park J, Lee SH, Biomaterials, 34, 2938 (2013)
  9. Park J, Lee BK, Jeong GS, Hyun JK, Lee CJ, Lee SH, Lab Chip, 15, 141 (2015)
  10. McKee A, Kosik K, Kowall N, Ann. Neurol., 30, 156 (1991)
  11. Luckenbill-Edds L, Brain Res. Rev., 23, 1 (1997)
  12. Armstrong SJ, Wiberg M, Terenghi G, Kingham PJ, Tissue Eng., 13, 2863 (2007)
  13. Bixby JL, Lilien J, Reichardt LF, J. Cell Biol., 107, 353 (1988)
  14. Kang E, Jeong GS, Choi YY, Lee KH, Khademhosseini A, Lee SH, Nat. Mater., 10(11), 877 (2011)
  15. Kang K, Choi SE, Jang HS, Cho WK, Nam Y, Choi IS, Lee JS, Angew. Chem.-Int. Edit., 51, 2855 (2012)
  16. Koh HS, Yong T, Chan CK, Ramakrishna S, Biomaterials, 29, 3574 (2008)
  17. Nam Y, Branch DW, Wheeler BC, Biosens. Bioelectron., 22, 589 (2006)
  18. Taylor AM, Blurton-Jones M, Rhee SW, Cribbs DH, Cotman CW, Jeon NL, Nat. Methods, 2, 599 (2005)
  19. Koh H, Yong T, Chan C, Ramakrishna S, Biomaterials, 29, 3574 (2008)
  20. Sun W, Sun C, Zhao H, Lin H, Han Q, Wang J, Ma H, Chen B, Xiao Z, Dai J, PLoS ONE, 4, e6180 (2009)
  21. Rutka JT, Apodaca G, Stern R, Rosenblum M, J. Neurosurg., 69, 155 (1988)
  22. Kang K, Choi SE, Jang HS, Cho WK, Nam Y, Choi IS, Lee JS, Angew. Chem.-Int. Edit., 51, 2855 (2012)
  23. Tay A, Kunze A, Jun D, Hoek E, Di Carlo D, Small, 12, 3559 (2016)
  24. Koser DE, Thompson AJ, Foster SK, Dwivedy A, Pillai EK, Sheridan GK, Svoboda H, Viana M, da L, Costa F, Guck J, Nat. Neurosci., 19, 1592 (2016)
  25. Mattila PK, Lappalainen P, Nat. Rev. Mol. Cell Biol., 9, 446 (2008)
  26. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, Zahir N, Ming W, Weaver V, Janmey PA, Cell Motil. Cytoskeleton, 60, 24 (2005)
  27. Rutishauser U, Acheson A, Hall AK, Mann DM, Sunshine J, Science, 240, 53 (1988)
  28. Park JY, Lee DH, Lee EJ, Lee SH, Lab Chip, 9, 2043 (2009)
  29. Brunette D, Int. J. Oral Maxillofac. Implants, 3 (1988)
  30. Keselowsky BG, Collard DM, Garcia AJ, J. Biomed. Mater. Res. A, 66, 247 (2003)
  31. Ni Y, Hu H, Malarkey EB, Zhao B, Montana V, Haddon RC, Parpura V, J. Nanosci. Nanotechnol., 5, 1707 (2005)
  32. Yen SJ, Hsu WL, Chen YC, Su HC, Chang YC, Chen H, Yeh SR, Yew TR, Biosens. Bioelectron., 26, 4124 (2011)
  33. Higuchi M, Lee VM, Trojanowski JQ, Neuromolec. Med., 2, 131 (2002)
  34. Nordin-Andersson M, Forsby A, Heldring N, Dejongh J, Kjellstrand P, Walum E, Toxicol. In Vitro, 12, 557 (1998)
  35. Vickers JC, King AE, Woodhouse A, Kirkcaldie MT, Staal JA, McCormack GH, Blizzard CA, Musgrove RE, Mitew S, Liu Y, Chuckowree JA, Bibari O, Dickson TC, Brain Res. Bull., 80, 217 (2009)
  36. Saper C, Wainer B, German D, Neuroscience, 23, 389 (1987)
  37. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD, Exp. Neurol., 185, 232 (2004)
  38. Bjartmar C, Trapp BD, Curr. Opin. Neurol., 14, 271 (2001)
  39. Lee G, Lee J, Oh H, Lee S, PLOS ONE, 11, e01610 (2016)
  40. Lee GH, Lee JS, Lee GH, Joung WY, Kim SH, Lee SH, Park JY, Kim DH, Biofabrication, 10, 015001 (2017)
  41. Lee G, Jun Y, Jang H, Yoon J, Lee J, Hong M, Chung S, Kim DH, Lee S, Acta Biomater., 65, 185 (2018)
  42. Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, Ben-Hur T, Nat. Biotechnol., 19, 1134 (2001)
  43. Choi YJ, Park J, Lee SH, Biomaterials, 34, 2938 (2013)
  44. Choi YY, Chung BG, Lee DH, Khademhosseini A, Kim JH, Lee SH, Biomaterials, 31, 4296 (2010)
  45. da YN, Jeong GS, Lee SH, Biomaterials, 35, 8983 (2014)
  46. Wong SF, da YN, Choi YY, Kim DS, Chung BG, Lee SH, Biomaterials, 32, 8087 (2011)
  47. Aviles F, Cauich-Rodriguez J, Rodriguez-Gonzalez J, May-Pat A, Express Polym. Lett., 5, 766 (2011)
  48. Dunkers JP, Pakstis LM, Lee HJ, Matos MA, Cicerone MT, Polym. Mater. Sci. Eng., 99, 81 (2008)
  49. Chang JC, Brewer GJ, Wheeler BC, An Enhanced Microstamping Technique for Controlled Deposition of Proteins, IEEE,pp.126 2002.
  50. Byler DM, Susi H, Biopolymers, 25, 469 (1986)
  51. Fabian H, Mantele W, Handb. Vib. Spectrosc. (2002).
  52. Barth A, Biochim. Biophys. Acta (BBA)-Bioenerg., 1767, 1073 (2007)
  53. Lampin M, Warocquier-Clerout R, Legris C, Degrange M, Sigot-Luizard M, J. Biomed. Mater. Res., 36, 99 (1997)
  54. Gehlsen KR, Dillner L, Engvall E, Ruoslahti E, Science, 241, 1228 (1988)
  55. Khorasani M, Mirzadeh H, Irani S, Radiat. Phys. Chem., 77, 280 (2008)
  56. Schmechel D, Saunders A, Strittmatter W, Crain BJ, Hulette C, Joo S, Pericak-Vance MA, Goldgaber D, Roses A, Proc. Natl. Acad. Sci. U. S. A., 90, 9649 (1993)
  57. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Nature, 359, 322 (1992)
  58. Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD, Proc. Natl. Acad. Sci. U. S. A., 90, 8098 (1993)
  59. Yan SD, Chen X, Fu J, Chen M, Zhu HJ, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM, Nature, 382(6593), 685 (1996)
  60. Schmechel D, Saunders A, Strittmatter W, Crain BJ, Hulette C, Joo S, Pericak-Vance M, Goldgaber D, Roses A, Proc. Natl. Acad. Sci. U. S. A., 90, 9469 (1993)
  61. Kim HJ, Sugimori M, Nakafuku M, Svendsen CN, Exp. Neurol., 203, 394 (2007)
  62. Sucapane A, Cellot G, Prato M, Giugliano M, Parpura V, Ballerini L, J. Nanoneurosci., 1, 10 (2009)
  63. Pryzhkova MV, Stem Cells Transl. Med., 2, 376 (2013)
  64. Fabbro A, Bosi S, Ballerini L, Prato M, ACS Chem. Neurosci., 3, 611 (2012)
  65. Chen T, Yang J, Ren G, Yang Z, Zhang T, Toxicol. Lett., 217, 121 (2013)
  66. Gao L, Gan H, Meng Z, Gu R, Wu Z, Zhang L, Zhu X, Sun W, Li J, Zheng Y, Colloids Surf. B: Biointerfaces, 117, 398 (2014)
  67. Kim JH, Jekarl DW, Kim M, Oh EJ, Kim Y, Park IY, Shin JC, Int. J. Med. Sci., 11, 298 (2014)
  68. Bonde S, Berthing T, Madsen MH, Andersen TK, Buch-Manson N, Guo L, Li X, Badique F, Anselme K, Nygard J, ACS Appl. Mater. Interfaces, 5, 10510 (2013)
  69. Hu H, Ni Y, Montana V, Haddon RC, Parpura V, Nano Lett., 4, 507 (2004)
  70. Kim YH, Baek NS, Han YH, Chung MA, Jung SD, J. Neurosci. Methods, 202, 38 (2011)
  71. Kuddannaya S, Bao J, Zhang Y, ACS Appl. Mater. Interfaces, 7, 25529 (2015)
  72. Jeong GS, Chang JY, Park JS, Lee SA, Park D, Woo J, An H, Lee CJ, Lee SH, Molec. Brain, 8, 17 (2015)
  73. Park J, Lee BK, Jeong GS, Hyun JK, Lee CJ, Lee SH, Lab Chip, 15, 141 (2015)
  74. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH, Nat. Med., 4, 1313 (1998)
  75. Mahanthappa NK, Schwarting GA, Neuron, 10, 293 (1993)
  76. Duman RS, Malberg J, Nakagawa S, J. Pharmacol. Exp. Therap., 299, 401 (2001)