Blood Cells Separation and Sorting Techniques of Passive Microfluidic Devices: From Fabrication to Applications

Abstract

Since the first microfluidic device was developed more than three decades ago, microfluidics is seen as a technology that exhibits unique features to provide a significant change in the way that modern biology is performed. Blood and blood cells are recognized as important biomarkers of many diseases. Taken advantage of microfluidics assets, changes on blood cell physicochemical properties can be used for fast and accurate clinical diagnosis. In this review, an overview of the microfabrication techniques is given, especially for biomedical applications, as well as a synopsis of some design considerations regarding microfluidic devices. The blood cells separation and sorting techniques were also reviewed, highlighting the main achievements and breakthroughs in the last decades.

Keywords: microfabrication; microfluidics; polymers; red blood cells (RBCs); separation and sorting techniques.

Figure 1

Timeline of the main microfluidics achievements from the first microfluidic device until the present.

Figure 2

Soft lithography technique introduced by Whitesides and co-workers in 1998. (a) Rapid prototyping using photolithography and (b) replica molding with poly(dimethylsiloxane) (PDMS). Reproduced with permission from [13].

Figure 3

Low-cost print-and-peel microfabrication techniques. (I) Xurography: (a) cutting plotter machine; (b) features being cut by the cutting plotter; (c) PDMS being added to a petri dish containing the vinyl mask; (d), (e) and (f) Cross sections of microchannels with 500, 300 and 200 m of width, respectively. (II) Micromilling; (a) milling machine; (b) operating milling tool and (c) microchannels. Reproduced with permission from [22]. (III) Direct laser plotting main steps. Reproduced with permission from [27].

Figure 4

Fabrication techniques from a time and cost perspective. Adapted from [14]. ^* Despite standard soft-lithography technique is considered expensive, new alternatives without the need of cleanroom facilities significantly drop the cost, being considered as low-cost, as the work published by Pinto et al., 2014 [21].

Figure 5

Classification of the main active and passive separation techniques used in microfluidic systems.

Figure 6

Hydrodynamic methods of separation: (a) the implied forces in a Poiseuille flow for cell separation. Reproduced with permission from [86] (b) the principle of hydrodynamic filtration in a microchannel with many outlets. Reproduced with permission from [81,84]. (c) trajectories analysis of rigid and deformable cells through a contraction for cell separation in two outlets. Reproduced with permission from [87]. (d) principle of deterministic lateral displacement. Reproduced with permission from [86]. (e) separation using inertial flow forces and at high flow rates creating vortices downstream a contraction. Reproduced with permission from [64,88]. (f) extensional forces for cell separation and mechanical analysis. Reproduced with permission from [89].

Figure 7

Blood separation microdevices based on hemodynamic flow separation techniques: (a) the Fåharaeus–Lindqvist effect in a microchannels with dimensions < 300 µm. Reproduced with permission from [23]. (b) cell-free layer as an advantage for cell and plasma separation and plasma skimming effect, WBCs margination. Adapted from [86,95,96]. (c) the Bifurcation law manipulated to remove cell-free plasma from blood and to mimic the microvasculature networks. Reproduced with permission from [86,97].

Figure 8

Schematic illustration for weir, pillar and cross-flow microfluidic filters. Images adapted from [81,84,109].