Advertisement

Microfluidic self-assembly of tumor spheroids for anticancer drug discovery

Abstract

Creating multicellular tumor spheroids is critical for characterizing anticancer treatments since it may provide a better model than monolayer culture of in vivo tumors. Moreover, continuous dynamic perfusion allows the establishment of physiologically relevant drug profiles to exposed spheroids. Here we present a physiologically inspired design allowing microfluidic self-assembly of spheroids, formation of uniform spheroid arrays, and characterizations of spheroid dynamics all in one platform. Our microfluidic device is based on hydrodynamic trapping of cancer cells in controlled geometries and the formation of spheroids is enhanced by maintaining compact groups of the trapped cells due to continuous perfusion. It was found that spheroid formation speed (average of 7 h) and size uniformity increased with increased flow rate (up to 10 μl min−1). A large amount of tumor spheroids (7,500 spheroids per square centimeter) with a narrow size distribution (10 ± 1 cells per spheroid) can be formed in the device to provide a good platform for anticancer drug assays.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. H. Acker, J. Theor, Med. 1, 193–207 (1998)

  2. R.C. Bates, N.S. Edwards, J.D. Yates, Crit. Rev. Oncol. Hematol. 36, 61–74 (2000)

  3. V.I. Chin, P. Taupin, S. Sanga, J. Scheel, F.H. Gage, S.N. Bhatia1, Biotechnol. Bioeng. 88, 399–415 (2004)

  4. B. Desoize, Crit. Rev. Oncol. Hematol. 36, 59– 60 (2000)

  5. B. Desoize, D. Gimonet, J.C. Jardiller, Anticancer Res. 18, 4147–4158 (1998)

  6. M. Deutsch, A. Deutsch, O. Shirihai, I. Hurevich, E. Afrimzon, Y. Shafrana, N. Zurgil, Lab. Chip. 6, 995–1000 (2006)

  7. D. Di Carlo, N. Aghdam, L.P. Lee, Anal. Chem. 78, 4925–4930 (2006a)

  8. D. Di Carlo, L.Y. Wu, L.P. Lee, Lab. Chip. 6, 1445–1449 (2006b)

  9. M.A. Faute, L. Laurent, D. Ploton, M.F. Poupon, J.C. Jardillier, H. Bobichon, Clin. Exp. Metastasis. 19, 161–168 (2002)

  10. M. Haji-Karim, J. Carlsson, Cancer Res. 38, 1457–1464 (1978)

  11. P.J. Hung, P. Lee, L.P. Lee, Biotechnol. Bioeng. 89, 1–8 (2005a)

  12. P.J. Hung, P. Lee, P. Sabounchi, N. Aghdam, R. Lin, L.P. Lee, Lab. Chip. 5, 44–48 (2005b)

  13. G.M. Keller, Curr. Opin. Cell. Biol. 7, 862–869 (1995)

  14. J.M. Kelm, N.E. Timmins, C.J. Brown, M. Fussenegger, L.K. Nielsen, Biotechnol. Bioeng. 83, 173–180 (2003)

  15. L. Kim, M.D. Vahey, H. Lee, J. Voldman, Lab. Chip. 6, 394–406 (2006)

  16. R. Knuechel, R.M. Sutherland, Cancer J. 3, 234–243 (1990)

  17. L.A. Kunz-Schughart, M. Kreutz, R. Knuechel, Int. J. Exp. Pathol. 79, 1–23 (1998)

  18. W. Mueller-Klieser, Am. J. Physiol. 273, C1109–C1123 (1997)

  19. W. Mueller-Klieser, Crit. Rev. Oncol. Hematol. 36, 124–139 (2000)

  20. K.M. Nicholson, M.C. Bibby, R.M. Philips, Eur. J. Cancer 33, 1291–1298 (1997)

  21. P.L. Olive, R.E. Durand, Cancer Metastasis Rev. 13(2), 121–138 (1994)

  22. R.M. Sutherland, Science 240, 177–184 (1988)

  23. R.M. Sutherland, J.A. McCredie, W.R. Inch, J. Natl. Cancer Inst. 46, 113–120 (1971)

  24. D.M. Thompson, K.R. King, K.J. Wieder, M. Toner, M.L. Yarmush, A. Jayaraman, Anal. Chem. 76, 4098–4103 (2004)

  25. Y. Torisawa, A. Takagi, Y. Nashimoto, T. Yasukawa, H. Shiku, T. Matsue, Biomaterials 28, 559–566 (2006)

  26. A. Tourovskaia, X. Figueroa-Masot, A. Folch, Lab. Chip. 5, 14–19 (2005)

  27. J.M. Yuhas, A.P. Li, A.O. Martinez, A.J. Ladman, Cancer Res. 37, 3639–3643 (1977)

Download references

Acknowledgement

This research was supported by Intel Research Fund, GSK, Taiwan Merit Scholarship TMS-094-2-A-008 (L.W.) and a Whitaker Foundation graduate fellowship (D. D.). All master copies for PDMS molding were fabricated in the UC Berkeley microfabrication facility.

Author information

Correspondence to Luke P. Lee.

Additional information

Liz Y. Wu and Dino Di Carlo contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(AVI 2.72 mb)

(MPG 12.8 mb)

ESM 1

(AVI 2.72 mb)

ESM 2

(MPG 12.8 mb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wu, L.Y., Di Carlo, D. & Lee, L.P. Microfluidic self-assembly of tumor spheroids for anticancer drug discovery. Biomed Microdevices 10, 197–202 (2008). https://doi.org/10.1007/s10544-007-9125-8

Download citation

Keywords

  • Tumor spheroids
  • Drug assay
  • Cell culture
  • Microfluidic devices