Advertisement

Biomedical Microdevices

, Volume 14, Issue 4, pp 779–789 | Cite as

Micro/nanoscale technologies for the development of hormone-expressing islet-like cell clusters

  • Daniel Gallego-Perez
  • Natalia Higuita-Castro
  • Rashmeet K. Reen
  • Marcela Palacio-Ochoa
  • Sadhana Sharma
  • L. James Lee
  • John J. Lannutti
  • Derek J. Hansford
  • Keith J. GoochEmail author
Article

Abstract

Insulin-expressing islet-like cell clusters derived from precursor cells have significant potential in the treatment of type-I diabetes. Given that cluster size and uniformity are known to influence islet cell behavior, the ability to effectively control these parameters could find applications in the development of anti-diabetic therapies. In this work, we combined micro and nanofabrication techniques to build a biodegradable platform capable of supporting the formation of islet-like structures from pancreatic precursors. Soft lithography and electrospinning were used to create arrays of microwells (150–500 μm diameter) structurally interfaced with a porous sheet of micro/nanoscale polyblend fibers (∼0.5–10 μm in cross-sectional size), upon which human pancreatic ductal epithelial cells anchored and assembled into insulin-expressing 3D clusters. The microwells effectively regulated the spatial distribution of the cells on the platform, as well as cluster size, shape and homogeneity. Average cluster cross-sectional area (∼14000–17500 μm2) varied in proportion to the microwell dimensions, and mean circularity values remained above 0.7 for all microwell sizes. In comparison, clustering on control surfaces (fibers without microwells or tissue culture plastic) resulted in irregularly shaped/sized cell aggregates. Immunoreactivity for insulin, C-peptide and glucagon was detected on both the platform and control surfaces; however, intracellular levels of C-peptide/cell were ∼60 % higher on the platform.

Keywords

Diabetes Soft lithography Electrospinning Precursor cell 

Notes

Acknowledgments

The authors would like to thank the staff of the Ohio Nanotech West Laboratory for technical assistance, and Dr. Herbert Bresler for his helpful suggestions during the early phases of the work. Human islet-derived precursor cells were kindly donated by Dr. Gershengorn’s lab (NIH). This work was supported with funds from the Juvenile Diabetes Research Foundation (Grant No. 5-2009-511), the National Science Foundation (Grants No. EEC-0425626 and No. CMMI-0928739), and AFOSR MURI (Grant No. F49620-03-1-0421).

Supplementary material

10544_2012_9657_MOESM1_ESM.docx (1.8 mb)
ESM 1 (DOCX 1860 kb)
10544_2012_9657_MOESM2_ESM.docx (991 kb)
ESM 2 (DOCX 990 kb)
10544_2012_9657_MOESM3_ESM.docx (290 kb)
ESM 3 (DOCX 289 kb)
10544_2012_9657_MOESM4_ESM.docx (706 kb)
ESM 4 (DOCX 706 kb)
10544_2012_9657_MOESM5_ESM.docx (14 kb)
ESM 5 (DOCX 14 kb)
ESM 6

(WMV 3013 kb)

References

  1. D.R. Albrecht, G.H. Underhill, T.B. Wassermann, S.L. Sah, S.N. Bhatia, Nat. Methods 3, 369 (2006)CrossRefGoogle Scholar
  2. S. Assady, G. Maor, M. Amit, J. Itskovitz-Eldor, K.L. Skorecki, M. Tzukerman, Diabetes 50, 1691 (2000)CrossRefGoogle Scholar
  3. C.L. Bauwens, R. Peerani, S. Niebruegge, K.A. Woodhouse, E. Kumacheva, M. Husain, P.W. Zandstra, Stem Cells 26, 2300 (2008)CrossRefGoogle Scholar
  4. G.M. Beattie, J.S. Rubin, M.I. Mally, T. Otonkoski, A. Hayek, Diabetes 45, 1223 (1996)CrossRefGoogle Scholar
  5. G.M. Beattie, A.M. Montgomery, A.D. Lopez, E. Hao, B. Perez, M.L. Just, J.R. Lakey, M.E. Hart, A. Hayek, Diabetes 51, 3435 (2002)CrossRefGoogle Scholar
  6. J. Beck, R. Angus, B. Madsen, D. Britt, B. Vernon, K.T. Nguyen, Tissue Eng. 13, 589 (2007)CrossRefGoogle Scholar
  7. A.B. Bernard, C. Lin, K.S. Anseth, Tissue Eng. C 18 (2012). doi: 10.1089/ten.tec.2011.0504
  8. S. Bonner-Weir, M. Taneja, G.C. Weir, K. Tatarkiewicz, K.H. Song, A. Sharma, J.J. O’Neil, Proc. Natl. Acad. Sci. USA 97, 7999 (2000)CrossRefGoogle Scholar
  9. M.I. Boretti, K.J. Gooch, Tissue Eng. 12, 939 (2006)CrossRefGoogle Scholar
  10. M.I. Boretti, K.J. Gooch, Tissue Eng. 14, 1927 (2008)CrossRefGoogle Scholar
  11. H.C. Brereton, M.J. Carvell, H. Asare-Anane, G. Roberts, M.R. Christie, S.J. Persaud, P.M. Jones, Biochem. Biophys. Res. Commun. 344, 995 (2006)CrossRefGoogle Scholar
  12. P.O. Carlsson, F. Palm, A. Andersson, P. Liss, Diabetes 50, 489 (2001)CrossRefGoogle Scholar
  13. Y.Y. Choi, B.G. Chung, D.H. Lee, A. Khademhosseini, J.H. Kim, S.H. Lee, Biomaterials 31, 4296 (2010)CrossRefGoogle Scholar
  14. R.J. Daly, Biochem. J. 382, 13 (2004)CrossRefGoogle Scholar
  15. J. Daoud, M. Petropavlovskaia, L. Rosenberg, M. Tabrizian, Biomaterials 31, 1676 (2010)CrossRefGoogle Scholar
  16. S.C. Daxini, J.W. Nichol, A.L. Sieminski, G. Smith, K.J. Gooch, V.P. Shastri, Biorheology 43, 45 (2006)Google Scholar
  17. S. Efrat, Adv. Drug. Deliv. Rev. 60, 114 (2008)CrossRefGoogle Scholar
  18. N. Ferrell, D. Hansford, Macromol. Rapid Commun. 28, 966 (2007)CrossRefGoogle Scholar
  19. N. Ferrell, D. Gallego-Perez, N. Higuita-Castro, R.T. Butler, R.K. Reen, K.J. Gooch, D.J. Hansford, Anal. Chem. 82, 2380 (2010)CrossRefGoogle Scholar
  20. C.A. Fraker, S. Alvarez, P. Papadopoulos, J. Giraldo, W. Gu, C. Ricordi, L. Inverardi, J. Dominguez-Bendala, Stem Cells 25, 3155 (2007)CrossRefGoogle Scholar
  21. J. Fukuda, A. Khademhosseini, Y. Yeo, X. Yang, J. Yeh, G. Eng, J. Blumling, C.F. Wang, D.S. Kohane, R. Langer, Biomaterials 27, 5259 (2006)CrossRefGoogle Scholar
  22. D. Gallego-Perez, N. Higuita-Castro, S. Sharma, R.K. Reen, A.F. Palmer, K.J. Gooch, L.J. Lee, J.J. Lannutti, D.J. Hansford, Lab Chip 10, 775 (2010)CrossRefGoogle Scholar
  23. M.C. Gershengorn, A.A. Hardikar, C. Wei, E. Geras-Raaka, B. Marcus-Samuels, B.M. Raaka, Science 306, 2261 (2004)CrossRefGoogle Scholar
  24. R. Glicklis, J.C. Merchuk, S. Cohen, Biotechnol. Bioeng. 86, 672 (2004)CrossRefGoogle Scholar
  25. P. Grant, Prim Care Diabetes 4, 69 (2010)CrossRefGoogle Scholar
  26. J. Gunn, M. Zhang, Trends Biotechnol. 29, 189 (2010)CrossRefGoogle Scholar
  27. J.F. Habener, Pediatr. Diabetes 5, 29 (2004)CrossRefGoogle Scholar
  28. T.L. Halvorsen, G.M. Beattie, A.D. Lopez, A. Hayek, F. Levine, J. Endocrinol. 166, 103 (2000)CrossRefGoogle Scholar
  29. A.A. Hardikar, B. Marcus-Samuels, E. Geras-Raaka, B.M. Raaka, M.C. Gershengorn, Proc. Natl. Acad. Sci. USA 100, 7117 (2003)CrossRefGoogle Scholar
  30. S. Heydarkhan-Hagvall, K. Schenke-Layland, A.P. Dhanasopon, F. Rofail, H. Smith, B.M. Wu, R. Shemin, R.E. Beygui, W.R. MacLellan, Biomaterials 29, 2907 (2008)CrossRefGoogle Scholar
  31. D.J. Hill, Rev. Endocr. Metab. Disord. 6, 229 (2005)CrossRefGoogle Scholar
  32. Y. Hori, I.C. Rulifson, B.C. Tsai, J.J. Heit, J.D. Cahoy, S.K. Kim, Proc. Natl. Acad. Sci. USA 99, 16105 (2002)CrossRefGoogle Scholar
  33. H. Hui, C. Wright, R. Perfetti, Diabetes 50, 785 (2001)CrossRefGoogle Scholar
  34. A.C. Hulst, H.J.H. Hens, R.M. Buitelaar, J. Tramper, Biotechnol. Tech. 3, 199 (1989)CrossRefGoogle Scholar
  35. Y.S. Hwang, B.G. Chung, D. Ortmann, N. Hattori, H.C. Moeller, A. Khademhosseini, Proc. Natl. Acad. Sci. USA 106, 16978 (2009)CrossRefGoogle Scholar
  36. B.W. Kahan, L.M. Jacobson, D.A. Hullett, J.M. Ochoada, T.D. Oberley, K.M. Lang, J.S. Odorico, Diabetes 52, 2016 (2003)CrossRefGoogle Scholar
  37. J.M. Karp, J. Yeh, G. Eng, J. Fukuda, J. Blumling, K.Y. Suh, J. Cheng, A. Mahdavi, J. Borenstein, R. Langer, A. Khademhosseini, Lab Chip 7, 786 (2007)CrossRefGoogle Scholar
  38. J.M. Kelm, M. Fussenegger, Trends Biotechnol. 22, 195 (2004)CrossRefGoogle Scholar
  39. M. Khalil, A. Shariat-Panahi, R. Tootle, T. Ryder, P. McCloskey, E. Roberts, H. Hodgson, C. Selden, J. Hepatol. 34, 68 (2001)CrossRefGoogle Scholar
  40. V.I. Khaoustov, G.J. Darlington, H.E. Soriano, B. Krishnan, D. Risin, N.R. Pellis, B. Yoffe, In Vitro Cell Dev. Biol. Anim. 35, 501 (1999)CrossRefGoogle Scholar
  41. S.F. Khattak, K.S. Chin, S.R. Bhatia, S.C. Roberts, Biotechnol. Bioeng. 96, 156 (2007)CrossRefGoogle Scholar
  42. J. Lannutti, D. Reneker, T. Ma, D. Tomasko, D. Farson, Mater. Sci. Eng. C 27, 504 (2007)CrossRefGoogle Scholar
  43. R. Lehmann, R.A. Zuellig, P. Kugelmeier, P.B. Baenninger, W. Moritz, A. Perren, P.A. Clavien, M. Weber, G.A. Spinas, Diabetes 56, 594 (2007)CrossRefGoogle Scholar
  44. D. Li, Y. Xia, Adv. Mater. 16, 1151 (2004)CrossRefGoogle Scholar
  45. R.H. Li, D.H. Altreuter, F.T. Gentile, Biotechnol. Bioeng. 50, 365 (1996)CrossRefGoogle Scholar
  46. S.H. Lim, H.Q. Mao, Adv. Drug Deliv. Rev. 61, 1084 (2009)CrossRefGoogle Scholar
  47. M. Lovett, K. Lee, A. Edwards, D.L. Kaplan, Tissue Eng. Part B Rev. 15, 353 (2009)CrossRefGoogle Scholar
  48. N. Lumelsky, O. Blondel, P. Laeng, I. Velasco, R. Ravin, R. McKay, Science 292, 1389 (2001)CrossRefGoogle Scholar
  49. M.J. Luther, A. Hauge-Evans, K.L.A. Souza, A. Jörns, S. Lenzen, S.J. Persaud, P.M. Jones, Biochem. Biophys. Res. Commun. 343, 99 (2006)CrossRefGoogle Scholar
  50. A.D. Mendelsohn, D.A. Bernards, R.D. Lowe, T.A. Desai, Langmuir 26, 9943 (2010)CrossRefGoogle Scholar
  51. K. Minami, H. Okano, A. Okumachi, S. Seino, J. Biol. Chem. 283, 13753 (2008)CrossRefGoogle Scholar
  52. X. Mo, Q. Li, L.W. Yi-Lui, B. Zheng, C.H. Kang, B. Nugraha, Z. Yue, R.R. Jia, H.X. Fu, D. Choudhury, T. Arooz, J. Yan, C.T. Lim, S. Shen, C.H. Tan, H. Yu, Biomaterials 31, 7455 (2010)CrossRefGoogle Scholar
  53. H.C. Moeller, M.K. Mian, S. Shrivastava, B.G. Chung, A. Khademhosseini, Biomaterials 29, 752 (2008)CrossRefGoogle Scholar
  54. N. Nakajima-Nagata, T. Sakurai, T. Mitaka, T. Katakai, E. Yamato, J. Miyazaki, Y. Tabata, M. Sugai, A. Shimizu, Biochem. Biophys. Res. Commun. 318, 625 (2004)CrossRefGoogle Scholar
  55. D.M. Nathan, N. Engl. J. Med. 328, 1676 (1993)CrossRefGoogle Scholar
  56. D.R. Nisbet, J.S. Forsythe, W. Shen, D.I. Finkelstein, M.K. Hotne, J. Biomater. Appl. 24, 7 (2009)CrossRefGoogle Scholar
  57. A. Nur-E-Kamal, I. Ahmed, J. Kamal, M. Schindler, S. Meiners, Stem Cells 24, 426 (2006)CrossRefGoogle Scholar
  58. H. Okubo, M. Matsushita, H. Kamachi, T. Kawai, M. Takahashi, T. Fujimoto, K. Nishikawa, S. Todo, Artif Organs 26, 497 (2002)CrossRefGoogle Scholar
  59. J. Park, C.H. Cho, N. Parashurama, Y. Li, F. Berthiaume, M. Toner, A.W. Tilles, M.L. Yarmush, Lab Chip 7, 1018 (2007)CrossRefGoogle Scholar
  60. E.A. Ryan, J.R.T. Lakey, R.V. Rajotte, G.S. Korbutt, T. Kin, S. Imes, A. Rabinovitch, J.F. Elliott, D. Bigam, N.M. Kneteman, G.L. Warnock, I. Larsen, A.M. Shapiro, Diabetes 50, 710 (2001)CrossRefGoogle Scholar
  61. E.A. Ryan, J.R.T. Lakey, B.W. Paty, S. Imes, G.S. Korbutt, N.M. Kneteman, D. Bigam, R.V. Rajotte, A.M. Shapiro, Diabetes 51, 2148 (2002)CrossRefGoogle Scholar
  62. M. Schindler, L. Ahmed, J. Kamal, A. Nur-E-Kamal, T.H. Grafe, H.Y. Chung, S.A. Meiners, Biomaterials 26, 5624 (2005)CrossRefGoogle Scholar
  63. A.M. Shapiro, J.R. Lakey, E.A. Ryan, G.S. Korbutt, E. Toth, G.L. Warnock, N.M. Kneteman, R.V. Rajotte, N. Engl. J. Med. 643, 230 (2000)CrossRefGoogle Scholar
  64. A.M. Shapiro, J.R. Lakey, B.W. Paty, P.A. Senior, D.L. Bigam, E.A. Ryan, Transplantation 79, 1304 (2005)CrossRefGoogle Scholar
  65. A. Shiroi, M. Yoshikawa, H. Yokota, H. Fukui, S. Ishizaka, K. Tatsumi, Y. Takahashi, Stem Cells 20, 284 (2002)CrossRefGoogle Scholar
  66. L.A. Smith, X. Liu, P.X. Ma, Soft Matter 4, 2144 (2008)CrossRefGoogle Scholar
  67. B. Soria, E. Roche, G. Berna, T. Leon-Quinto, J.A. Reig, F. Martin, Diabetes 49, 157 (2000)CrossRefGoogle Scholar
  68. J. Suzuki, Y. Murakami, K. Samejima, K.K. Ohtani, T. Oka, Endocr. Relat. Cancer 16, 649 (2009)CrossRefGoogle Scholar
  69. Y.C. Toh, S. Ng, Y.M. Khong, X. Zhang, Y. Zhu, P.C. Lin, C.M. Te, W. Sun, H. Yu, Nanotoday 1, 34 (2006)Google Scholar
  70. Y. Torisawa, B. Mosadegh, S.P. Cavnar, M. Ho, S. Takayama, Tissue Eng. C 17, 61 (2011)CrossRefGoogle Scholar
  71. C.C. Tsai, R.N. Huang, H.W. Sung, H.C. Liang, J. Biomed. Mater Res. 52, 58 (2000)CrossRefGoogle Scholar
  72. C. Wei, E. Geras-Raaka, B. Marcus-Samuels, Y. Oron, M.C. Gershengorn, J. Cell Physiol. 206, 322 (2006)CrossRefGoogle Scholar
  73. M.A. Woodruff, D.W. Hutmacher, Prog. Polym Sci. 35, 1217 (2010)CrossRefGoogle Scholar
  74. L. Yang, S. Li, H. Hatch, K. Ahrens, J.G. Cornelius, B.E. Petersen, A.B. Peck, Proc. Natl. Acad. Sci. USA 99, 8078 (2002)CrossRefGoogle Scholar
  75. T. Zhang, H. Wang, N.A. Saunee, M.B. Breslin, M.S. Lan, Endocrinology 151, 2030 (2010)CrossRefGoogle Scholar
  76. M. Zhao, C. Song, W. Zhang, Y. Hou, R. Huang, Y. Song, W. Xie, Y. Shi, C. Song, J. Biomed. Mater Res. A 94A, 667 (2010)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Daniel Gallego-Perez
    • 1
    • 2
  • Natalia Higuita-Castro
    • 1
  • Rashmeet K. Reen
    • 1
  • Marcela Palacio-Ochoa
    • 1
  • Sadhana Sharma
    • 3
  • L. James Lee
    • 2
    • 4
  • John J. Lannutti
    • 2
    • 5
  • Derek J. Hansford
    • 1
    • 2
  • Keith J. Gooch
    • 1
    • 6
    Email author
  1. 1.Department of Biomedical EngineeringThe Ohio State UniversityColumbusUSA
  2. 2.NSF Nanoscale Science and Engineering CenterThe Ohio State UniversityColumbusUSA
  3. 3.College of PharmacyThe Ohio State UniversityColumbusUSA
  4. 4.William G. Lowrie Department of Chemical and Biomolecular EngineeringThe Ohio State UniversityColumbusUSA
  5. 5.Department of Materials Science and EngineeringThe Ohio State UniversityColumbusUSA
  6. 6.Dorothy M. Davis Heart and Lung Research InstituteThe Ohio State UniversityColumbusUSA

Personalised recommendations