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Enrichment of prostate cancer cells from blood cells with a hybrid dielectrophoresis and immunocapture microfluidic system

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Abstract

The isolation of circulating tumor cells (CTCs) from cancer patient blood is a technical challenge that is often addressed by microfluidic approaches. Two of the most prominent techniques for rare cancer cell separation, immunocapture and dielectrophoresis (DEP), are currently limited by a performance tradeoff between high efficiency and high purity. The development of a platform capable of these two performance criteria can potentially be facilitated by incorporating both DEP and immunocapture. We present a hybrid DEP-immunocapture system to characterize how DEP controls the shear-dependent capture of a prostate cancer cell line, LNCaP, and the nonspecific adhesion of peripheral blood mononuclear cells (PBMCs). Characterization of cell adhesion with and without DEP effects was performed in a Hele-Shaw flow cell that was functionalized with the prostate-specific monoclonal antibody, J591. In this model system designed to make nonspecific PBMC adhesion readily apparent, we demonstrate LNCaP enrichment from PBMCs by precisely tuning the applied AC electric field frequency to enhance immunocapture of LNCaPs and reduce nonspecific adhesion of PBMCs with positive and negative DEP, respectively. Our work shows that DEP and immunocapture techniques can work synergistically to improve cancer cell capture performance, and it informs the design of future hybrid DEP-immunocapture systems with improved CTC capture performance to facilitate research on cancer metastasis and drug therapies.

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References

  • M. Alshareef, N. Metrakos, E. Juarez Perez, F. Azer, F. Yang, X. Yang, G. Wang, Separation of tumor cells with dielectrophoresis-based microfluidic chip. Biomicrofluidics 7(1), 011,803 (2013)

    Article  Google Scholar 

  • F.F. Becker, P.R. Gascoyne, X.B. Wang, Y. Huang, R. Pethig, J. Vykoukal, Separation of human breast cancer cells from blood by differential dielectric affinity. Proc. Natl. Acad. Sci. U.S.A. 92(3), 860–864 (1995)

    Article  Google Scholar 

  • E. Diamond, G.Y. Lee, N.H. Akhtar, B.J. Kirby, P. Giannakakou, S.T. Tagawa, D.M. Nanus, Isolation and characterization of circulating tumor cells in prostate cancer. Front. Oncol. 2, 131 (2012)

    Article  Google Scholar 

  • P.R.C. Gascoyne, J. Noshari, T.J. Anderson, F.F. Becker, Isolation of rare cells from cell mixtures by dielectrophoresis. Electrophor. 30(8), 1388–1398 (2009)

    Article  Google Scholar 

  • J.P. Gleghorn, E.D. Pratt, D. Denning, H. Liu, N.H. Bander, S.T. Tagawa, D.M. Nanus, P.A. Giannakakou, B.J. Kirby, Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. Lab Chip. 10(1), 27–29 (2010)

    Article  Google Scholar 

  • V. Gupta, I. Jafferji, M. Garza, V.O. Melnikova, D.K. Hasegawa, R. Pethig, D.W. Davis, ApoStream, a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. Biomicrofluidics 6(2), 024,133 (2012)

    Article  Google Scholar 

  • S.I. Han, Y.D. Joo, K.H. Han, An electrorotation technique for mea suring the dielectric properties of cells with simultaneous use of negative quadrupolar dielectrophoresis and electrorotation. The Anal. 138(5), 1529–1537 (2013)

    Article  Google Scholar 

  • B.G. Hawkins, A.E. Smith, Y.A. Syed, B.J. Kirby, Continuous-flow particle separation by 3D insulative dielectrophoresis using coherently shaped, dc-biased, ac electric fields. Anal. Chem. 79(19), 7291–7300 (2007)

    Article  Google Scholar 

  • B.G. Hawkins, J.P. Gleghorn, B.J. Kirby, in Dielectrophoresis for Particle and Cell Manipulations, ed. by J.D. Zahn. Methods in Bioengineering: Biomicrofabrication and Biomicrofluidics, chap. 6 (Artech House, Boston, 2009), pp. 133–181

  • B.G. Hawkins, C. Huang, S. Arasanipalai, B.J. Kirby, Automated dielectrophoretic characterization of Mycobacterium smegmatis. Anal. Chem. 83(9), 3507–3515 (2011)

    Article  Google Scholar 

  • E.A. Henslee, M.B. Sano, A.D. Rojas, E.M. Schmelz, R.V. Davalos, Selective concentration of human cancer cells using contactless dielectrophoresis. Electrophoresis 32(18), 2523–2529 (2011)

    Article  Google Scholar 

  • C. Huang, S.M. Santana, H. Liu, N.H. Bander, B.G. Hawkins B.J. Kirby, Characterization of a hybrid dielectrophoresis and immunocapture microfluidic system for cancer cell capture. submitted (2013)

  • K.A. Hyun, H.I. Jung, Microfluidic devices for the isolation of circulating rare cells: a focus on affinity-based, dielectrophoresis, and hydrophoresis. Electrophoresis. 34(7), 1028–1041 (2013)

    Article  Google Scholar 

  • C.P. Jen, H.H. Chang, C.T. Huang, K.H. Chen, A microfabricated module for isolating cervical carcinoma cells from peripheral blood utilizing dielectrophoresis in stepping electric fields. Microsyst. Technol. 18(11), 1887–1896 (2012)

    Article  Google Scholar 

  • B.J. Kirby, Micro- and Nanoscale Fluid Mechanics: Transport in Microfluidic Devices (Cambridge University Press, New York, 2010)

  • B.J. Kirby, M. Jodari, M.S. Loftus, G. Gakhar, E.D. Pratt, C. Chanel-Vos, J.P. Gleghorn, S.M. Santana, H. Liu, J.P. Smith, V.N. Navarro, S.T. Tagawa, N.H. Bander, D.M. Nanus, P. Giannakakou, Functional characterization of circulating tumor cells with a prostate cancer-specific microfluidic device. PLOS ONE. 7(4), e35,976 (2012)

    Article  Google Scholar 

  • R.T. Krivacic, A. Ladanyi, D.N. Curry, H.B. Hsieh, P. Kuhn, D.E. Bergsrud, J.F. Kepros, T. Barbera, M.Y. Ho, L.B. Chen, R.A. Lerner, R.H. Bruce, A rare-cell detector for cancer. Proc. Natl. Acad. Sci. U.S.A. 101(29), 10,501–10,504 (2004)

    Article  Google Scholar 

  • M.A. Leversha, J. Han, Z. Asgari, D.C. Danila, O. Lin, R. Gonzalez Espinoza, A. Anand, H. Lilja, G. Heller, M. Fleisher, H.I. Scher, Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin. Cancer Res. 15(6), 2091–2097 (2009)

    Article  Google Scholar 

  • H. Liu, P. Moy, S. Kim, Y. Xia, A. Rajasekaran, V. Navarro, B. Knudsen, N.H. Bander, Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res. 57(17), 3629–3634 (1997)

    Google Scholar 

  • H. Morgan, N. Green, AC Electrokinetics: Colloids and Nanoparticles (Research Studies Press, Ltd., Baldock, 2002)

  • S.K. Murthy, A. Sin, R.G. Tompkins, M. Toner, Effect of flow and surface conditions on human lymphocyte isolation using microfluidic chambers. Langmuir. 20(26), 11,649–11,655 (2004)

    Article  Google Scholar 

  • S. Nagrath, L.V. Sequist, S. Maheswaran, D.W. Bell, D. Irimia, L. Ulkus, M.R. Smith, E.L. Kwak, S. Digumarthy, A. Muzikansky, P. Ryan, U.J. Balis, R.G. Tompkins, D.A. Haber, M. Toner, Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173), 1235–1239 (2007)

    Article  Google Scholar 

  • E.D. Pratt, C. Huang, B.G. Hawkins, J.P. Gleghorn, B.J. Kirby, Rare cell capture in microfluidic devices. Chem. Eng. Sci. 66(7), 1508–1522 (2011)

    Article  Google Scholar 

  • E. Racila, D. Euhus, A.J. Weiss, C. Rao, J. McConnell, L.W.M.M. Terstappen, J.W. Uhr, Detection and characterization of carcinoma cells in the blood. Proc. Natl. Acad. Sci. U.S.A. 95(8), 4589–94 (1998)

    Article  Google Scholar 

  • A.D. Rhim, E.T. Mirek, N.M. Aiello, A. Maitra, J.M. Bailey, F. McAllister, M. Reichert, G.L. Beatty, A.K. Rustgi, R.H. Vonderheide, S.D. Leach, B.Z. Stanger, EMT and dissemina tion precede pancreatic tumor formation. Cell 148(1–2), 349–361 (2012)

    Article  Google Scholar 

  • A. Salmanzadeh, L. Romero, H. Shafiee, R.C. Gallo-Villanueva, M.A. Stremler, S.D. Cramer, R.V. Davalos, Isolation of prostate tumor initiating cells (TICs) through their dielectrophoretic signature. Lab Chip. 12(1), 182–189 (2012)

    Article  Google Scholar 

  • A. Salmanzadeh, M.B. Sano, R.C. Gallo-Villanueva, P.C. Roberts, E.M. Schmelz, R.V. Davalos, Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells. Biomicrofluidics 7(1), 011,809 (2013)

    Article  Google Scholar 

  • M.B. Sano, J.L. Caldwell, R.V. Davalos, Modeling and development of a low frequency contactless dielectrophoresis (cDEP) platform to sort cancer cells from dilute whole blood samples. Biosens. Bioelectron. 30(1), 13–20 (2011a)

    Article  Google Scholar 

  • M.B. Sano, E.A. Henslee, E. Schmelz, R.V. Davalos, Contactless dielectrophoretic spectroscopy: examination of the dielectric properties of cells found in blood. Electrophoresis 32(22), 3164–3171 (2011b)

    Article  Google Scholar 

  • S.M. Santana, H. Liu, N.H. Bander, J.P. Gleghorn, B.J. Kirby, Immunocapture of prostate cancer cells by use of anti-PSMA anti-bodies in microdevices. Biomed. Microdevices. 14(2), 401–407 (2012)

    Article  Google Scholar 

  • S. Shim, K. Stemke-Hale, J. Noshari, F.F. Becker, P.R.C. Gascoyne, Dielectrophoresis has broad applicability to marker-free isolation of tumor cells from blood by microfluidic systems. Biomicrofluidics 7(1), 011,808 (2013a)

    Article  Google Scholar 

  • S. Shim, K. Stemke-Hale, A.M. Tsimberidou, J. Noshari, T.E. Anderson, P.R.C. Gascoyne, Antibody-independent isolation of circulating tumor cells by continuous-flow dielectrophoresis. Biomicrofluidics 7(1), 011,807 (2013b)

    Article  Google Scholar 

  • J.P. Smith, A.C. Barbati, S.M. Santana, J.P. Gleghorn, B.J. Kirby, Microfluidic transport in microdevices for rare cell capture. Electrophoresis 33(21), 3133–3142 (2012)

    Article  Google Scholar 

  • S.L. Stott, C.H. Hsu, D.I. Tsukrov, M. Yu, D.T. Miyamoto, B.A. Waltman, S.M. Rothenberg, A.M. Shah, M.E. Smas, G.K. Korir, F.P. Floyd, A.J. Gilman, J.B. Lord, D. Winokur, S. Springer, D. Irimia, S. Nagrath, L.V. Sequist, R.J. Lee, K.J. Isselbacher, S. Maheswaran, D.A. Haber, M. Toner, Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc. Natl. Acad. Sci. U.S.A. 107(43), 18,392–18,397 (2010a)

    Article  Google Scholar 

  • S.L. Stott, R.J. Lee, S. Nagrath, M. Yu, D.T. Miyamoto, L. Ulkus, E.J. Inserra, M. Ulman, S. Springer, Z. Nakamura, A.L. Moore, D.I. Tsukrov, M.E. Kempner, D.M. Dahl, C.L. Wu, A.J. Iafrate, M.R. Smith, R.G. Tompkins, L.V. Sequist, M. Toner, D.A. Haber, S. Maheswaran, Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci. Transl. Med. 2(25), 25ra23 (2010b)

    Article  Google Scholar 

  • S. Usami, H.H. Chen, Y. Zhao, S. Chien, R. Skalak, Design and construction of a linear shear stress flow chamber. Ann. Biomed. Eng. 21(1), 77–83 (1993)

    Article  Google Scholar 

  • J. Voldman, Electrical forces for microscale cell manipulation. Annu. Rev. Biomed. Eng. 8, 425–54 (2006)

    Article  Google Scholar 

  • S. Wang, K. Liu, J. Liu, Z.T.F. Yu, X. Xu, L. Zhao, T. Lee, E.K. Lee, J. Reiss, Y.K. Lee, L.W.K. Chung, J. Huang, M. Rettig, D. Seligson, K.N. Duraiswamy, C.K.F. Shen, H.R. Tseng, Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. Angew. Chem. Int. Ed. 50(13), 3084–3088 (2011)

    Article  Google Scholar 

  • M. Yu, D.T. Ting, S.L. Stott, B.S. Wittner, F. Ozsolak, S. Paul, J.C. Ciciliano, M.E. Smas, D. Winokur, A.J. Gilman, M.J. Ulman, K. Xega, G. Contino, B. Alagesan, B.W. Brannigan, P.M. Milos, D.P. Ryan, L.V. Sequist, N. Bardeesy, S. Ramaswamy, M. Toner, S. Maheswaran, D.A. Haber, RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 487(7408), 510–513 (2012)

    Article  Google Scholar 

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Acknowledgments

This work was supported by the Center on the Microenvironment and Metastasis at Cornell (Award Number U54CA-143876) from the National Cancer Institute Physical Sciences Oncology Center (NCI PS-OC). CH was supported by a National Science Foundation (NSF) Graduate Research Fellowship. Device fabrication was performed in part at the Cornell NanoScale Science and Technology Facility (CNF), a member of the National Nanotechnology Infrastructure Network, which is supported by the NSF (Grant ECS-0335765).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA

    Chao Huang

  2. Department of Urology, Weill Medical College of Cornell University, New York, NY, 10065, USA

    He Liu & Neil H. Bander

  3. Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, 14853, USA

    Brian J. Kirby

  4. Division of Hematology and Medical Oncology, Departmentof Medicine, Weill Medical College of Cornell University, New York, NY, 10065, USA

    Brian J. Kirby

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  1. Chao Huang
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Correspondence to Brian J. Kirby.

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Huang, C., Liu, H., Bander, N.H. et al. Enrichment of prostate cancer cells from blood cells with a hybrid dielectrophoresis and immunocapture microfluidic system. Biomed Microdevices 15, 941–948 (2013). https://doi.org/10.1007/s10544-013-9784-6

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