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Review Article

Organ-on-Chip Devices Toward Applications in Drug Development and Screening

[+] Author and Article Information
Christopher Uhl, Wentao Shi

Department of Bioengineering,
Lehigh University,
Bethlehem, PA 18015

Yaling Liu

Department of Bioengineering,
Lehigh University,
Bethlehem, PA 18015;
Department of Mechanical Engineering
and Mechanics,
Lehigh University,
Bethlehem, PA 18015
e-mail: yal310@lehigh.edu

1Corresponding author.

Manuscript received February 12, 2018; final manuscript received May 2, 2018; published online September 21, 2018. Assoc. Editor: Xiaoming He.

J. Med. Devices 12(4), 040801 (Sep 21, 2018) (14 pages) Paper No: MED-18-1028; doi: 10.1115/1.4040272 History: Received February 12, 2018; Revised May 02, 2018

As a necessary pathway to man-made organs, organ-on-chips (OOC), which simulate the activities, mechanics, and physiological responses of real organs, have attracted plenty of attention over the past decade. As the maturity of three-dimensional (3D) cell-culture models and microfluidics advances, the study of OOCs has made significant progress. This review article provides a comprehensive overview and classification of OOC microfluidics. Specifically, the review focuses on OOC systems capable of being used in preclinical drug screening and development. Additionally, the review highlights the strengths and weaknesses of each OOC system toward the goal of improved drug development and screening. The various OOC systems investigated throughout the review include, blood vessel, lung, liver, and tumor systems and the potential benefits, which each provides to the growing challenge of high-throughput drug screening. Published OOC systems have been reviewed over the past decade (2007–2018) with focus given mainly to more recent advances and improvements within each organ system. Each OOC system has been reviewed on how closely and realistically it is able to mimic its physiological counterpart, the degree of information provided by the system toward the ultimate goal of drug development and screening, how easily each system would be able to transition to large scale high-throughput drug screening, and what further improvements to each system would help to improve the functionality, realistic nature of the platform, and throughput capacity. Finally, a summary is provided of where the broad field of OOCs appears to be headed in the near future along with suggestions on where future efforts should be focused for optimized performance of OOC systems in general.

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Figures

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Fig. 1

Photolithography technology approach to produce microfluidic devices for cell culture and therapeutic testing. Spin coating of silicon wafer with thin layer of photoresist. A photomask is positions and an exposure set is carried out with UV light. A final development of the cured photoresist is required before PDMS can be cast from the wafer. PDMS pieces are bonded to glass sides to produce devices, which can then be used for testing after appropriate sterilization.

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Fig. 2

Microvascular scaffold fabrication and mixing experiment. (a) Robotic deposition of fugitive organic ink through a cylindrical nozzle onto a moving xy stage. (b) Schematic representations of microfluidic device mixing experiment, where two fluids are mixed at Re = 30.6 to produce the output. The arrows indicate the flowdirection. The two fluids meet at a Y-junction where theyenter a 17 mm straight microchannel. (c) Fluorescent microscope image of microfluidic device mixing experiment in Y-junction. Scale bare = 0.5 mm. Reproduced from Ref. [19] with permission.

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Fig. 3

Schematic representation of bioprinting of agarose template fibers and subsequent formation of microchannels via template micromolding. (a) A bioprinter equipped with a piston fitted inside a glass capillary aspirates the agarose (inset). After gelation in 4 °C, agarose fibers are bioprinted at predefined locations. (b) A hydrogel precursor is casted over the bioprinted mold and photocrosslinked. (c) The template is removed from the surrounding photocrosslinked gel. (d) Fully perfusable microchannels are formed. Reproduced from Ref. [62] with permission.

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Fig. 4

(a) A nonplanar microfluidic encapsulation device is used for encapsulating cancer cells in core–shell microcapsules, and the cells are cultured in the microcapsules for 10 days to form microtumors (μtumors, < ∼200 μm in radius). Mineral oil infused with calcium chloride, aqueous sodium alginate solution (to form the microcapsule shell), aqueous collagen solution (with or without cells) to form the microcapsule core, and aqueous extraction solution are pumped into the device via inlets I1, I2, I3, and I4, respectively. The aqueous phase (containing core–shell microcapsules) and oil exit the device from outlets O1 and O2, respectively. (b) A microfluidic perfusion device is used to assemble the μ tumors and stromal cells including endothelial cells for perfusion culture to form 3D vascularized tumor. The μtumors in core–shell microcapsules are assembled together with human umbilical vein endothelial cells and human adipose-derived stem cells in collagen hydrogel in the microfluidic perfusion device. The alginate shell of the microcapsules is dissolved to allow cell–cell interactions and the formation of 3D vascularized tumor in the microfluidic perfusion device under perfusion driven by hydrostatic pressure. Units for the dimensions of micropillars and sample chamber: mm; P: pressure; ρ: density; g: gravitational acceleration; and h: height of medium column linked to the reservoirs. Reprinted with permission from Agarwal et al. [59]. Copyright (2018) American Chemical Society.

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Fig. 5

SyM-BBB model. Concept showing the apical and basolateral sides separated by 3 mm gaps formed by microfabricated pillars. Apical side contains endothelial cells while basolateral side contains astrocytes conditioned media. The design is based on the idealized concept of the microvasculature comprising of diverging and converging bifurcations. (Reproduced with permission from Prabhakarpandian et al. [31]. Copyright 2013 by Royal Society of Chemistry.)

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Fig. 6

Three-dimensional hydrogel-based vascular structures with multilevel fluidic channels fabricated by extrusion-based 3D bioprinting. (a) Printing a layer of smooth muscle cell-laden structure over a rod (inset on the right: cross section of the selected area) and seeding endothelial cells into the inner wall of the structure. (b) Longitudinal section of the double-layer structure under different magnification. (c) Printed vessel-like structure containing three kinds of vascular cells: L929, MOVAS, and HUVEC. (Reproduced with permission from Gao et al. [24]. Copyright 2017 by ACS Publications.)

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Fig. 7

Coupling of the cell array with a microfluidic platform. (a) Schematic representation of the microfluidic platform containing eight microfluidic channels for media perfusion and containing a membrane-vacuum system, acting as a suction pad for reversible sealing and which delimits the culture chamber. Cell array is represented in background. (b) Images of the assembled microfluidic platform under fluorescent light on the microscope stage. Two channels deliver a fluorescein solution. ((c) and (d)) Validation of the coupled system using a nuclear dye (HOECHST). Phase contrast (c) and fluorescence image (d) of the entire cell array show how the HOECHST signal could be detected only on the area selectively exposed to the fluid stream containing the nuclear dye (arrows). ((e)–(h)) Validation of the coupled system using adenoviral vectors for EGFP delivery. (e) Phase contrast of the entire cell array and ((f)–(h)) fluorescence images of the temporal sequence showing an increased EFGP expression at 16 h (f), 22 h (g), 26 h (h) postinfection. The viral transduction is clearly compartmentalized on the area selectively exposed to the fluid stream containing the viral particles. (Reproduced with permission from Serena et al. [75]. Copyright 2012 by PLoS One.)

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Fig. 8

Biologically inspired design of a human breathing lung-on-a-chip microdevice. (a) The microfabricated lung mimic device uses compartmentalized PDMS microchannels to form an alveolar-capillary barrier on a thin, porous, flexible PDMS membrane coated with ECM. The device recreates physiological breathing movements by applying vacuum to the side chambers and causing mechanical stretching of the PDMS membrane forming the alveolar-capillary barrier. (b) During inhalation in the living lung, contraction of the diaphragm causes a reduction in intrapleural pressure (Pip), leading to distension of the alveoli and physical stretching of the alveolar-capillary interface. (Reproduced with permission from Huh et al. [8]. Copyright 2010 by Science.)

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Fig. 9

(a) Schematic of the microfluidic airway model. (b) Schematic of components of the experimental setup. (c) The process of liquid plug generation from air and liquid streams. (Reproduced with permission from Tavana et al. [43]. Copyright 2011 by Springer.)

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Fig. 10

Soft lithographic process to fabricate microscale liver hepatocyte cultures in a multiwell format. (a) Schematic of the process flow aside photomicrographs taken at each step. A reusable PDMS stencil is seen consisting of membranes with through-holes at the bottom of each well in a 24-well mold. To micropattern all wells simultaneously, one seals the device under dry conditions to a culture substrate. A photograph of a device (scale bar represents 2 cm) sealed to a polystyrene omni-tray is seen along with an electron micrograph of a thin stencil membrane. Each well is incubated with a solution of extracellular matrix protein (ECM) to allow protein to adsorb to the substrate via the through-holes. The stencil is then peeled off leaving micropatterned ECM protein on the substrate (fluorescently labeled collagen pattern). A 24-well PDMS “blank” lacking membranes is then sealed to the plate before cell seeding (not shown here). Primary hepatocytes selectively adhere to matrix-coated domains, allowing supportive stromal cells to be seeded into the remaining bare areas (scale bar is 500 mm). (b) Photograph of a 24-well device with repeating hepatic microstructures (37 colonies of 500 mm diameter in each well), stained by methylthiazol tetrazolium (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide). Scale bars, 2 cm and 1 cm for enlargement. (c) Phase-contrast micrographs of micropatterned cocultures. Primary human hepatocytes are spatially arranged in B500-mm collagen coated islands with B1, 200 mm center-to-center spacing, surrounded by 3T3-J2 fibroblasts. Images depict pattern fidelity over several weeks of culture. Scale bars, 500 mm. (Reproduced with permission from Khetani and Bhatia [9]. Copyright 2008 by Nature.)

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Fig. 11

Magnified view of a single cell culture channel of the multiplexed cell culture chip. An array of 30–50 mm micropillars separated the channel into three compartments: a central cell culture compartment and two side media perfusion compartments. (Reproduced with permission from Toh et al. [12]. Copyright 2009 by Royal Society of Chemistry.)

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Fig. 12

Schematic illustration and photograph of the PDMS biochip. (a) Cross-sectional view of one chamber with the integrated polycarbonate (10 mm thick) and PDMS membranes (250 mm thick). The dimensions of the microchamber are Ø 4 mm × 2 mm high. (b) Animated illustration of how liquid flows through the biochip. A substrate is added at the inlet and converted into metabolites by the liver slice, which are then transported to the outlet by the flow. (c) Photograph of the PDMS biochip containing six microchambers in the polycarbonate holder. The dimensions of one chip are 30 mm × 20 mm × 12 mm (L × W × H). (Reproduced with permission from van Midwoud et al. [10]. Copyright 2010 by Royal Society of Chemistry.)

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Fig. 13

Schematic drawings of tumor microenvironment and 3D microfluidic cell array (μFCA). (a) Tumor microenvironment including cancer cells, surrounding stromal cells, venules, and arterioles; (b) nutrient and gas transport between microvessels and tumor cells; (c) engineering 3D microenvironment by a layered structure; (d) schematics of each layer of 3D μFCA; and (e) cross section view of 3D μFCA. The bottom layer has microchambers with cancer cells embedded in hydrogel. The middle layer is a permeable membrane with clustered pores. The upper layer has microchannels with seeded endothelial cells to simulate blood microvessels. (Reproduced with permission from Dereli-Korkut et al. [34]. Copyright 2014 by Nature.)

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Fig. 14

Schematic of the bMTM (a) with magnified view of the vascular compartment, vascular-tumor compartment interface and the tumor compartment (b). Optical image of the bMTM (c) with HBTAEC cultured in the vascular compartment (d) and MDA-MB-231 cultured in the tumor compartment (e). HBTAEC cultured under flow in the vascular compartment of bMTM form a complete lumen as shown with 3D reconstruction of confocal images of HBTAEC cultured in bMTM stained with f-actin and Draq5 after 4 days in culture maintained under flow of 0.05 μL/min ((f)–(i)); images are shown with a Y-axis rotation of 0, 60, 180, and 240 deg in ((f), (g), (h), and (i)), respectively. (Reproduced with permission from Tang et al. [34]. Copyright 2017 by Nature.)

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