Screening applications in drug discovery based on microfluidic technology

Abstract

Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays.

FIG. 1.

Overview of drug discovery and development (a) steps from lab to market, (b) steps in preclinical phase: The stages of conventional path, C.II-III, can be replaced by microfluidic platforms, M1.

FIG. 2.

(a) Digital microfluidic device (DMF) containing hydrogel matrix. Reprinted with permission from Luk et al., Proteomics 12, 1310 (2012). Copyright 2012 John Wiley and Sons. (b) PMMA disc chip with a diameter of 120 mm containing eight identical structures. Reprinted with permission from Puckett et al., Anal. Chem. 76, 7263 (2004). Copyright 2004 American Chemical Society. (c) Serpentine-shaped concentration gradient generator. Reprinted with permission from Ye et al., Lab Chip 7, 1696 (2007). Copyright 2012 The Royal Society of Chemistry. (d) Droplet-based microfluidics for cell screening. Reprinted with permission from Brouzes et al., Proc. Natl. Acad. Sci. U.S.A. 106, 14195 (2009). Copyright 2009 National Academy of Sciences.

FIG. 3.

(a) Micro cell culture analog (μCCA) device containing fat, lung, liver, and other tissue chambers. Reprinted with permission from Viravaidya et al., Biotechnol. Prog. 20, 316 (2004). Copyright 2004 John Wiley and Sons. (b) Microfluidic chip for zebrafish embryo with a concentration gradient generator. Reprinted with permission from Biomicrofluidics 5, 1 (2011). Copyright 2011 AIP Publishing LLC. (c) 3D Hepatox chip design with a concentration gradient generator. Reprinted with permission from Toh et al., Lab Chip 9, 2026 (2009). Copyright 2009 The Royal Society of Chemistry.

FIG. 4.

(a) Microfluidic device for 3D-cell culture. Reprinted with permission from Kim et al., Biomed. Microdevices 9, 25 (2007). Copyright 2007 Springer. (b) Cell-embedded Matrigel (hydrogel) in a μCCA device. Reprinted with permission from Sung and Shuler, Lab Chip 9, 1385 (2009). Copyright 2009 The Royal Society of Chemistry. (c) 1 × 3 PIRE designed to uniformly pattern cells via DCP. Reprinted with permission from Hsiung et al., Lab Chip 11, 2333 (2011). Copyright 2011 The Royal Society of Chemistry. (d) HμREL biochip. Reprinted with permission from Chao et al., Biochem. Pharmacol. 78, 625 (2009). Copyright 2009 Elsevier.

FIG. 5.

(a) Microfluidic chip with cell sieves for cell trapping. Reprinted with permission from Wang et al., Lab Chip 7, 740 (2007). Copyright 2007 The Royal Society of Chemistry. (b) Microfluidic device for drug metabolism and cytotoxicity assay. Reprinted with permission from Mao et al., Lab Chip 12, 219 (2012). Copyright 2012 The Royal Society of Chemistry. (c) Microfluidic chip used for parallel microdroplets (PμD) technology. Reprinted with permission from Damean et al., Lab Chip 9, 1707 (2009). Copyright 2009 The Royal Society of Chemistry.