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Review
. 2021 Jan 28;12(2):139.
doi: 10.3390/mi12020139.

Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing

Leslie Donoghue  1   2 , Khanh T Nguyen  1   2 , Caleb Graham  1   2 , Palaniappan Sethu  1   2
Affiliations
Review

Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing

Leslie Donoghue et al. Micromachines (Basel). .

Abstract

Tissue chips (TCs) and microphysiological systems (MPSs) that incorporate human cells are novel platforms to model disease and screen drugs and provide an alternative to traditional animal studies. This review highlights the basic definitions of TCs and MPSs, examines four major organs/tissues, identifies critical parameters for organization and function (tissue organization, blood flow, and physical stresses), reviews current microfluidic approaches to recreate tissues, and discusses current shortcomings and future directions for the development and application of these technologies. The organs emphasized are those involved in the metabolism or excretion of drugs (hepatic and renal systems) and organs sensitive to drug toxicity (cardiovascular system). This article examines the microfluidic/microfabrication approaches for each organ individually and identifies specific examples of TCs. This review will provide an excellent starting point for understanding, designing, and constructing novel TCs for possible integration within MPS.

Keywords: body-on-a-chip; microfluidics; microphysiological systems; organ-on-a-chip; tissue chips; tissue-on-a-chip.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic of modular microphysiological system. (a) Three-dimensional heart chip with cardiomyocytes (CMs) and stromal cells suspended in hydrogel between posts. The chip mimics the pressure-volume changes seen in the left ventricle. The “diastolic filling pressure,” which is directly proportional to the fluid reservoir’s height, pushes the flexible polydimethylsiloxane (PDMS) membrane downward, stretching the cardiac fiber. A pneumatic pump then generates “systolic pressure” in the lower air-filled chamber, returning the membrane and cardiac fiber to the baseline stretch. (b) Perfusable 3D vessel chip with microvessels composed of endothelial cells (ECs) and smooth muscle cells (SMCs) surrounded by an extracellular matrix (ECM), with key tunable parameters indicated. (c) Three-dimensional kidney chip mimicking the proximal tubule and adjacent peritubular capillary. To mimic the proximal tubule, renal proximal tubule epithelial cells (RPTEpCs) are cultured upon a bed of ECM. RPTEpCs have a prominent brush border, as they would in vivo. The underlying porous membrane recapitulates the selective barrier function of the tubule wall. In addition to the upstream drug infusion port, there is a valve allowing for media to bypass the kidney chip, as well as a valve splitting the kidney chip media inflow. One inflow branch passes through a “glomerular” filter and enters the proximal tubule chamber as “urine.” The remaining unfiltered media flows into the bottom vascular chamber, the superior aspect of which is lined with ECs. Other applications of this chip include modeling transport phenomena related to drugs or other key molecules. (d) Liver chip with liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) lining the “sinusoid,” a porous membrane mimicking the perisinusoidal space, and hepatocytes (HCs) and hepatic stellate cells (HSCs) cultured below the membrane. HCs have microvilli projecting towards the “perisinusoidal space,” as they would in vivo.
Figure 2
Figure 2
(a) Microfluidic Cardiac Cell Culture Model developed by Giridharan et al., along with a schematic diagram, images of an assembled device, pulsatile collapsible valve, and the complete working setup. Reproduced with permission from the American Chemical Society [32]. (b) Biomimetic Cardiac Tissue Model (BCTM), developed by Rogers et al., depicting the cardiac cell culture chamber and schematic diagrams representing how the BCTM reproduces the cardiac cycle. Arrows represent the direction of fluid flow and membrane stretch. Reproduced with permission from the American Chemical Society [34].
Figure 3
Figure 3
(a) Endothelial Cell Culture Model (ECCM), developed by Estrada et al., replicating physiological pressure, stretch, flow, and shear stress. The schematic diagram and system set up includes: a. peristaltic pump, b. pulmonary compliance, c. pulmonary resistance, d. collapsible chamber, e. one-way valve, f. inline flow sensor, g. cell culture chamber, h. aortic/systemic compliance, i. inline pressure sensor, j. aortic/systemic resistance, and k. medium reservoir. The schematic diagrams of the vascular chip within the ECCM show the cell culture chamber (bottom-left) and a cross-section view of the cell culture chamber showing the thin membrane on which cells are cultured (bottom-right). Reproduced with permission from the American Chemical Society [82]. (b) Modified ECCM setup replicating both normal pulsatile flow and continuous flow, as seen in CVAD usage. Reproduced with permission from [83,84].
Figure 4
Figure 4
(a) Boos et al.’s microfluidic liver hanging-drop platform patterned on the surface of a PDMS substrate, bonded to a microscopy slide, and a lid is inserted into a groove structure to cover the open system. Scale bar: 5 mm. Reproduced with permission from [111]. This work was published under a CC BY license (Creative Commons Attribution 4.0 International License; https://creativecommons.org/licenses/by/4.0/); (b) Design of microfluidically-perfused liver biochip with a vascular layer composed of ECs and tissue macrophages, and a hepatic layer comprising HSCs co-cultured with HCs (i). Biochip device denoting inlet and outlet ports (ii). Reproduced with permission from Elsevier [112]; (c) Assembled two-chambered microfluidic device separated by a porous membrane (i), and a side-view schematic of the device with the four cell types: primary human HCs, EA.hy926 (human umbilical vein ECs), LX-2 (human HSCs), and U937 cells (human macrophage cell line) (ii). Reproduced with permission from John Wiley and Sons [113]; (d) Schematic representation of the micropillar and microwell chip platform with 3D-cultured Hep3B cells encapsulated in PuraMatrix™ for compound hepatotoxicity assessment. Reproduced with permission from Elsevier [114].
Figure 5
Figure 5
(a) Schematics of isolated human kidney tissue (i–ii) seeded into Nortis Inc.’s single-channel 3D MPS platform (iii) with phase contrast and live/dead images of primary RPTEpCs at day 28 (iv). Reproduced with permission from Elsevier [136]. (b) Convoluted proximal tubule schematic and images of Homan et al.’s 3D bioprinting fabrication steps (i–iv) and confocal 3D renderings of their RPTEpCs organized into a tubule with an open lumen: actin (red), nuclei (blue), and tubulin (orange). Reproduced with permission from [137]. The work was published under a CC BY license (Creative Commons Attribution 4.0 International License; https://creativecommons.org/licenses/by/4.0/).
Figure 6
Figure 6
(a) The first example of a multi-organ tissue chip designed by Viravaidya et al. to recreate interactions between the liver, adipose tissue, and the lung to probe naphthalene toxicity. Reproduced with permission from John Wiley and Sons [148]; (b) A complex four-organ tissue chip developed by Maschmeyer et al. where interactions between the intestine (1), liver (2), skin (3), and kidney (4) were recreated, and circulatory and excretory circuits established. Reproduced with permission from the Royal Chemical Society [154].
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References

    1. DiMasi J.A., Grabowski H.G., Hansen R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ. 2016;47:20–33. doi: 10.1016/j.jhealeco.2016.01.012. - DOI - PubMed
    1. Dickson M., Gagnon J.P. Key factors in the rising cost of new drug discovery and development. Nat. Rev. Drug Discov. 2004;3:417–429. doi: 10.1038/nrd1382. - DOI - PubMed
    1. DiMasi J.A., Hansen R.W., Grabowski H.G. The price of innovation: New estimates of drug development costs. J. Health Econ. 2003;22:151–185. doi: 10.1016/S0167-6296(02)00126-1. - DOI - PubMed
    1. Tagle D. National Center for Advancing Translational Sciences: About Tissue Chip. [(accessed on 28 November 2020)]; Available online: https://ncats.nih.gov/tissuechip/about.
    1. Tagle D. National Center for Advancing Translational Sciences: Tissue Chip Initiatives & Projects. [(accessed on 28 November 2020)]; Available online: https://ncats.nih.gov/tissuechip/projects.

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