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Review
. 2017 Mar;92(2):115-125.
doi: 10.1002/cyto.b.21388. Epub 2016 Jul 5.

Translating microfluidics: Cell separation technologies and their barriers to commercialization

C Wyatt Shields 4th  1   2 , Korine A Ohiri  1   3 , Luisa M Szott  1   2 , Gabriel P López  1   2   3   4
Affiliations
Review

Translating microfluidics: Cell separation technologies and their barriers to commercialization

C Wyatt Shields 4th et al. Cytometry B Clin Cytom. 2017 Mar.

Abstract

Advances in microfluidic cell sorting have revolutionized the ways in which cell-containing fluids are processed, now providing performances comparable to, or exceeding, traditional systems, but in a vastly miniaturized format. These technologies exploit a wide variety of physical phenomena to manipulate cells and fluid flow, such as magnetic traps, sound waves and flow-altering micropatterns, and they can evaluate single cells by immobilizing them onto surfaces for chemotherapeutic assessment, encapsulate cells into picoliter droplets for toxicity screenings and examine the interactions between pairs of cells in response to new, experimental drugs. However, despite the massive surge of innovation in these high-performance lab-on-a-chip devices, few have undergone successful commercialization, and no device has been translated to a widely distributed clinical commodity to date. Persistent challenges such as an increasingly saturated patent landscape as well as complex user interfaces are among several factors that may contribute to their slowed progress. In this article, we identify several of the leading microfluidic technologies for sorting cells that are poised for clinical translation; we examine the principal barriers preventing their routine clinical use; finally, we provide a prospectus to elucidate the key criteria that must be met to overcome those barriers. Once established, these tools may soon transform how clinical labs study various ailments and diseases by separating cells for downstream sequencing and enabling other forms of advanced cellular or sub-cellular analysis. © 2016 International Clinical Cytometry Society.

Keywords: cell sorting; commercial translation; flow cytometry; lab on a chip; microfluidic.

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Figures

Figure 1
Figure 1
Recent growth of microfluidic cell sorting technologies. (A) Number of publications versus publication year, organized by articles published in engineering, biology and medical journals and (B) total number of citations per year that resulted from the query “microfluidic cell sorting” on the Web of Science (Thomson Reuters, Co.).
Figure 2
Figure 2
Cell sorting by deterministic cell rolling. In this schematic, cells expressing a target ligand (purple) have specific, but transient, interactions with proteins immobilized on the floor of the channel, directing them across the channel and into the distal outlet. Cells that do not express the target ligand (blue) pass over the ridges and exit the proximal outlet. Reprinted with permission from Choi et al. (63). Copyright 2012 Royal Society of Chemistry.
Figure 3
Figure 3
Cell sorting device using SSAWs. Cells flow through the device from left to right. A stream of buffer fluid (central inlet) focuses cells (outer inlets) along the walls of the device whereupon acoustic fields generated by interdigitated transducers propel cells towards the pressure node at rates proportional to their size for sorting. Reprinted from permission by Shi et al. (86). Copyright 2009 Royal Society of Chemistry.
Figure 4
Figure 4
Integrated cell sorting devices. (A) Cell sorting by the “CTC-iChip”. Whole blood enters the device (the far end of the schematic) whereupon nucleated cells (i.e., white blood cells (WBCs) and CTCs) are separated from smaller, non-nucleated cells and plasma by deterministic lateral displacement. The nucleated cells then enter a serpentine channel where they focus into a single streamline by inertial forces. Finally, CTCs are separated from WBCs via magnetophoresis. Reprinted from permission by Karabacak et al. (23). Copyright 2014 Nature Publishing Group. (B) A hydrodynamic filtration system with an integrated magnetophoretic separation component. Cells enter the device (left), are pushed toward a series of drains by a co-flowing stream of buffer fluid and are separated by size. Once separated, cells are further fractionated by magnetic forces, which pull more strongly on cells with higher expressions of a target marker (i.e., due to their higher magnetic content). Reprinted with permission from Mizuno et al. (92). Copyright 2013 American Chemical Society.
Figure 5
Figure 5
Schematic of a representative microfluidic cell sorting setup. Top (from left to right): a computer control system to regulate the operating equipment, a microscope to observe the sorting junction and a power source to generate an external field (for active devices). Bottom (from left to right): vials to collect the sorted cell populations, the microfluidic chip and an automated syringe pump (note: objects are not to scale).
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