Label-free isolation of circulating tumor cells in microfluidic devices: Current research and perspectives

Abstract

This review will cover the recent advances in label-free approaches to isolate and manipulate circulating tumor cells (CTCs). In essence, label-free approaches do not rely on antibodies or biological markers for labeling the cells of interest, but enrich them using the differential physical properties intrinsic to cancer and blood cells. We will discuss technologies that isolate cells based on their biomechanical and electrical properties. Label-free approaches to analyze CTCs have been recently invoked as a valid alternative to "marker-based" techniques, because classical epithelial and tumor markers are lost on some CTC populations and there is no comprehensive phenotypic definition for CTCs. We will highlight the advantages and drawbacks of these technologies and the status on their implementation in the clinics.

Figures

Figure 1

Evolution of the CTC enrichment methods based on differences between cellular biomechanical properties: a) density gradient centrifugation in the presence of ficol, (b) CTC enrichment using microfluidic filter, (c) CTCs enrichment using Si membranes. We filtered 1 ml of whole blood from a colorectal cancer patient using the microsieve described in Lim et al. Stainings using cytokeratin (CK) and CD45 reveals CK positive, CD45 negative cellular clusters trapped on the microsieve. Scale bar = 10 μm d) device based on CTCs size and deformability proposed by Tan et al., (Reprinted with kind permission from G. E. Loeb, A. E. Walker, S. Uematsu, and B. W. Konigsmark, J. Biomed. Mater. Res. 11(2), 195-210 (1977). Copyright 1977 Springer Science and Business Media (e) CTCs enrichment using inertial migration (Reprinted with permission from S. C. Hur, A. J. Mach, and D. Di Carlo, Biomicrofluidics 5(2) (2011). Copyright 2011, American Institute of Physics) (f) Size separation of CTCs in spiral microfluidic channels (Reprinted with permission from J. Sun, M. Li, C. Liu, Y. Zhang, D. Liu, W. Liu, G. Hu, and X. Jiang, Lab Chip (2012).Copyright 2012 Royal Society of Chemistry).

Figure 2

(a) Working principle of dielectrophoretic separation under continuous flow: one cell population that exhibit negative DEP is trapped in the wells while the other one (that express positive DEP) is flushed to the outlet (Reprinted with permission from C. Iliescu, G. Tresset, and G. L. Xu, Appl. Phys. Lett. 90(23) (2007). Copyright 2007 American Institute of Physics). (b) Working principle of EIS: two electrodes are placed in a microfluidic channel (Reprinted from C. Iliescu, D. P. Poenar, M. Carp, and F. C. Loe, Sens. Actuators B 123(1), 168-176 (2007). Copyright 2007 with permission from Elsevier). (c) Magnetophoretic separation of RBCs under continuous flow as presented by Jung and Han (Reprinted with permission from J. Jung and K.-H. Han, Appl. Phys. Lett. 93(22), 223902-223902-223903 (2008).Copyright 2008 American Institute of Physics).