Blood-on-a-chip

Abstract

Accurate, fast, and affordable analysis of the cellular component of blood is of prime interest for medicine and research. Yet, most often sample preparation procedures for blood analysis involve handling steps prone to introducing artifacts, whereas analysis methods commonly require skilled technicians and well-equipped, expensive laboratories. Developing more gentle protocols and affordable instruments for specific blood analysis tasks is becoming possible through the recent progress in the area of microfluidics and lab-on-a-chip-type devices. Precise control over the cell microenvironment during separation procedures and the ability to scale down the analysis to very small volumes of blood are among the most attractive capabilities of the new approaches. Here we review some of the emerging principles for manipulating blood cells at microscale and promising high-throughput approaches to blood cell separation using microdevices. Examples of specific single-purpose devices are described together with integration strategies for blood cell separation and analysis modules.

Figure 1

Schematics of the main preparation steps for blood samples and potential impact of on-chip blood sample preparation in medicine and sciences.

Figure 2

Separation of cells using mechanical interactions. (A) Deterministic lateral displacement of fluorescent particles flown through an array of posts. Larger particles are deviated more from the axial flow stream (reprinted with permission from Reference ; Copyright 2004 AAAS). (B) Two-dimensional array of posts for the isolation of cells based on size characteristics. Posts are spaced from 5 to 20 µm and allow the passage of erythrocytes while capturing the larger cells (13; Copyright 2004 IEEE). (C) A small group of infected RBCs in the schizont malaria stage blocking the entrance to a 6 µm constricted capillary. A normal RBC (arrow) passes through the labyrinth of infected cells and flows easily through the channel constriction (18; Copyright 2003 National Academy of Sciences, U.S.A.).

Figure 3

Microfabricated DEP devices for the separation of cells. (A) Linear array of fluorescently tagged cells captured using DEP traps. (B, C) Pseudocolored scanning electron micrograph showing a single trap consisting of four electroplated gold electrodes arranged trapezoidally along with the substrate interconnects and an eight-trap array. Scale bars: (B) 20 µm, (C) 100 µm (reprinted with permission from Reference ; Copyright 2002 American Chemical Society). (D, E) Selective trapping of malaria-infected RBCs from a heterogeneous mixture using DEP (32; reproduced with permission from The Royal Society of Chemistry). (F) Hyperlayer separation through the differential sedimentation of cells in a dielectrophoretic field (43; Copyright 2004 Biophysical Society).

Figure 4

Microfluidic lysis device for selective lysis of RBCs in whole blood. (A) Device design and construction. (B) Snapshots illustrating lysis of erythrocytes in microfluidic channels. L denotes the distance traveled in the microchannels and % lysis denotes the percentage of lysed erythrocytes. Complete erythrocyte lysis is achieved in less than 30 s (reprinted with permission from Reference 55). (Copyright 2004 American Chemical Society.)

Figure 5

Leukocyte arrays on a PEG grid. (A) Scanning electron micrograph of the PEG grid and trapped lymphocytes (reprinted with permission from Reference ; Copyright 2003 American Chemical Society). (B) Composite image of differentially labeled T and B cells occupying the same PEG microwells array. T lymphocytes are fluorescently labeled green and Raji B lymphocytes are labeled orange (79; reproduced with permission of The Royal Society of Chemistry). (C) Biotinylated anti-CD5-Cy3 antibody bound to the bottom of avidin-modified PEG microwells for specific cell capture (79; reproduced with permission from The Royal Society of Chemistry). (D) Laser capture microdissection principle for retrieving cells from arrays (92).

Figure 6

Integrated devices for sample preparation and analysis. (A) Schematic of a plastic fluidic chip incorporating microfluidic networks, electrochemical and thermopneumatic pumps, valves, and a microarray chip (reproduced with permission from Reference ; Copyright 2004 American Chemical Society). (B) Scanning electron micrograph of a microfluidic device for single-cell handling, lysis, and quantitative analysis (108; Copyright 2004 American Chemical Society). (C) Assembled biochip with microfluidic control system, air-bursting detonators for fluid driving, and blood-gases analyzers (20; Copyright 2004 IEEE).