Rare Cell Capture in Microfluidic Devices

Abstract

This article reviews existing methods for the isolation, fractionation, or capture of rare cells in microfluidic devices. Rare cell capture devices face the challenge of maintaining the efficiency standard of traditional bulk separation methods such as flow cytometers and immunomagnetic separators while requiring very high purity of the target cell population, which is typically already at very low starting concentrations. Two major classifications of rare cell capture approaches are covered: (1) non-electrokinetic methods (e.g., immobilization via antibody or aptamer chemistry, size-based sorting, and sheath flow and streamline sorting) are discussed for applications using blood cells, cancer cells, and other mammalian cells, and (2) electrokinetic (primarily dielectrophoretic) methods using both electrode-based and insulative geometries are presented with a view towards pathogen detection, blood fractionation, and cancer cell isolation. The included methods were evaluated based on performance criteria including cell type modeled and used, number of steps/stages, cell viability, and enrichment, efficiency, and/or purity. Major areas for improvement are increasing viability and capture efficiency/purity of directly processed biological samples, as a majority of current studies only process spiked cell lines or pre-diluted/lysed samples. Despite these current challenges, multiple advances have been made in the development of devices for rare cell capture and the subsequent elucidation of new biological phenomena; this article serves to highlight this progress as well as the electrokinetic and non-electrokinetic methods that can potentially be combined to improve performance in future studies.

Figure 1

(A) Schematic of an micro-pillar device's architecture. Adapted from Gleghorn et al. (2010) (B) Schematic of a Weir microfilter's operation. Adapted from Ji et al. (2008) (C) Example of a Hele-Shaw flow cell where the dotted line is the region of linearly increasing shear (D) Schematic of a sheath-flow based separation system. Adapted from Wu et al. (2009)

Figure 2

(A) Interdigitated array (IDA) electrodes. (B) Electrosmear slide showing fractionation tumor cells and blood components. Reproduced from Cristofanilli et al. (2008). (C) Castellated IDA electrodes. (D) DEP field-flow fractionation operates by levitating cells against gravity to different heights in the channel via negative DEP, allowing separation to be achieved based on their differing flow velocities. (E) Configuration and forces in a twDEP electrode array. (F) Summation of forces near an angled electrode.

Figure 3

(A) Schematic of curved constriction in channel depth. Inset: top view of device fabricated in Zeonor 1020R polymer substrate. Reproduced from Hawkins et al. (2007). (B) Trapping of live (green) and dead (red) E. coli with separation of populations using insulative post array. Reproduced from Lapizco-Encinas et al. (2004a).