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WIREs Syst Biol Med
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Recent lab‐on‐chip developments for novel drug discovery

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Microelectromechanical systems (MEMS) and micro total analysis systems (μTAS) revolutionized the biochemical and electronic industries, and this miniaturization process became a key driver for many markets. Now, it is a driving force for innovations in life sciences, diagnostics, analytical sciences, and chemistry, which are called ‘lab‐on‐a‐chip, (LOC)’ devices. The use of these devices allows the development of fast, portable, and easy‐to‐use systems with a high level of functional integration for applications such as point‐of‐care diagnostics, forensics, the analysis of biomolecules, environmental or food analysis, and drug development. In this review, we report on the latest developments in fabrication methods and production methodologies to tailor LOC devices. A brief overview of scale‐up strategies is also presented together with their potential applications in drug delivery and discovery. The impact of LOC devices on drug development and discovery has been extensively reviewed in the past. The current research focuses on fast and accurate detection of genomics, cell mutations and analysis, drug delivery, and discovery. The current research also differentiates the LOC devices into new terminology of microengineering, like organ‐on‐a‐chip, stem cells‐on‐a‐chip, human‐on‐a‐chip, and body‐on‐a‐chip. Key challenges will be the transfer of fabricated LOC devices from lab‐scale to industrial large‐scale production. Moreover, extensive toxicological studies are needed to justify the use of microfabricated drug delivery vehicles in biological systems. It will also be challenging to transfer the in vitro findings to suitable and promising in vivo models. WIREs Syst Biol Med 2017, 9:e1381. doi: 10.1002/wsbm.1381

Concept and development of human‐on‐a‐chip models. (a) Typical human‐on‐a‐chip model for drug testing and development. Dynamic processes like absorption, metabolism, and excretion take place on a single integrated chip. (b) Micro cell culture analog (μCCA) on which various organs act as microreactor, absorber, or holder depending upon the functionality in the body. The compartments are connected by fluidic channels that carry and recirculate blood surrogate. μCCA chips are typically fabricated on silicon, polydimethylsiloxane (PDMS), or polystyrene using lithographic techniques. (c) μCCA chip in which multidrug resistance suppressors were analyzed using different cell lines. The μCCA chip shows liver, bone marrow, uterine cancer; slowly perfused and rapidly perfused compartments show an unexpected synergistic response to multidrug resistance suppressors that was not observable in traditional assay systems. (d) Schematic illustration of modeled microfluidic human‐on‐a‐chip containing 10 different organ chips integrated on a single platform linked with microfluidic circulatory system that might be a useful platform for screening drugs and discovery. (e) Formation of a microscale blood vessel module (μBVM) in a single microchannel device together with various steps of μBVM inside the microchannel. Firstly, the evaluated cells were injected, and later, the reservoirs were filled with culture medium; after 5 days of culturing, the cells transformed into blood vessel in mircochannels.
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Various models of organ‐on‐a‐chip evaluated for drug development and discovery. (a) Gut‐on‐a‐chip that mimics structural, mechanical, pathophysiological, transport, and absorptive functions. The chip also has properties to produce peristaltic motion and sustain bacterial flora. This chip in the future will develop various models for studying intestinal diseases and toxicology studies for new drugs. (b) Lung‐on‐a‐chip model used for studying physiology of lung. The mimic design is fabricated on a polydimethylsiloxane (PDMS) substrate. Various chambers are fabricated on a chip, and vacuum is created inside the chambers. The process mimics the reduction of intrapleural pressure in the lungs during breathing process. The process is highlighted in the bottom part of chip model. (c) Human kidney proximal tubule‐on‐a‐chip fabricated on a PDMS substrate. The device consists of a microfluidic channel, a porous membrane, and a PDMS reservoir. The device can be useful for evaluating renal toxicology and pathophysiology. Similarly, renal pharmacology, toxicology, and renal drug transport can be evaluated on this chip. (d) Blood vessel‐on‐a‐chip model used for studying various diseases involving blood vessel–whole blood interactions. The interactions can be observed through confocal micrography. The endothelial cell‐lined lumen within a device is shown in the bottom part. The nucleus is highlighted with blue, while cell membrane is highlighted with red color (Reprinted with permission from Ref . Copyright 2011 The American Society for Clinical Investigation). (e) Liver‐on‐a‐chip with four different cell types that self‐assembled into cords and generates various biochemical and metabolic information. Fluorescent biosensors indicate various cell functions like cell death and free radical formation on this chip. The image is obtained from National Center for Advancing Translational Sciences, USA (http://ncats.nih.gov/tissuechip/chip/liver).
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Drug delivery and screening using concentration gradient generators (CGGs). (a) Typical microfluidic CGG in which red and green dyes are used as model fluids. The incoming three channels are connected to syringes via tubing, and after combining into single streams, the gradient is created across the channel, perpendicular to the direction of flow (Reprinted with permission from Ref . Copyright © 2001, American Chemical Society). (b) Serpentine‐shaped CGG, here called multiple drug gradient generators, containing eight identical CGGs in which parallel cell culture chambers are located where processes of liquid diffusion and dilution, cell stimulation, culturing, and labeling are integrated into a single device. The above model can screen the anti‐cancer drug‐induced apoptosis in HepG2 cells. (c) A CGG microfluidic chip integrated with nano‐liquid chromatography (nano‐LC) in parallel with a mass spectrometer to analyze the blood coagulating enzymes Thrombin and factor Xa; this chip had three inlets connected to (1) nano‐LC, (2) enzyme inlet, (3) substrate, and (4) laser induced florescence (LIF) detector to detect the fluorescent products.
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Drug screening processing exploiting droplet microfluidics. (a) Droplet‐on‐demand platform for precise nanoliter assays for enzyme kinetics and inhibition. The samples are supplied using an oil‐filled carousel, and absorbance of each generated droplet is read by passaging between an LED source along with the photodetector (Reprinted with permission from Ref . Copyright 2013 American Chemical Society). (b) Droplet microfluidics in microreactor for evaluating protein–drug interactions. The magnetic beads bind the protein along with the drug (warfarin), and the measurement of bounded concentrations determines the association constant. (c) polydimethylsiloxane (PDMS)‐based droplet microfluidics for cytotoxicity assay. The integrated chip contains five modules that work in parallel to evaluate cell viability (Reprinted with permission from Ref . Copyright 2009 National Academy of Sciences). (d) Straight‐through microchannel emulsification (MCE) array plates used for producing monodisperse emulsion droplets. Asymmetric‐type array plate has ability to produce monodisperse droplets even with low viscous fluids. (e) Photograph of single silicon wafer (WMS 10–4) with four asymmetrical straight‐through MCs array, with each having an active cross‐sectional area of 10 mm2. The micrograph shows uniform droplet productivity from straight‐through microchannels.
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Fabrication methodologies of lab‐on‐a‐chip devices. (a) Rectangular channels fabricated photolithographically by replica molding from a master consisted of patterned negative photoresist on a silicon wafer. (b) 3D structure created by implanting a microfiber in a polydimethylsiloxane (PDMS) mold before curing. (c) Fabrication of microfluidic channels by hot embossing lithography in polymethylmethacrylate (PMMA). (d) Fabrication of channels by wet etching of photosensitive glass followed by UV exposure through chromium mask and heat treatment. (e) Cast molding technique for fabricating microfluidic channels coupled with wet chemical etch process for etching glass microfluidic chip.
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Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Analytical and Computational Methods > Analytical Methods

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Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

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