Microscopic Imaging Methods for Organ-on-a-Chip Platforms

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Abstract

Microscopic imaging is essential and the most popular method for in situ monitoring and evaluating the outcome of various organ-on-a-chip (OOC) platforms, including the number and morphology of mammalian cells, gene expression, protein secretions, etc. This review presents an overview of how various imaging methods can be used to image organ-on-a-chip platforms, including transillumination imaging (including brightfield, phase-contrast, and holographic optofluidic imaging), fluorescence imaging (including confocal fluorescence and light-sheet fluorescence imaging), and smartphone-based imaging (including microscope attachment-based, quantitative phase, and lens-free imaging). While various microscopic imaging methods have been demonstrated for conventional microfluidic devices, a relatively small number of microscopic imaging methods have been demonstrated for OOC platforms. Some methods have rarely been used to image OOCs. Specific requirements for imaging OOCs will be discussed in comparison to the conventional microfluidic devices and future directions will be introduced in this review.

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Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

Anna Herland, Andries D. van der Meer, Edward FitzGerald … (2016)

Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types.

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A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.

Dongeun Huh, Daniel C Leslie, Benjamin Matthews … (2012)

Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.

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Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment.

Kyung-Jin Jang, Ali Mehr, Geraldine A. Hamilton … (2013)

Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies.

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Author and article information

Contributors

Jeong-Yeol Yoon: (View ORCID Profile)

Journal

Title: Micromachines

Abbreviated Title: Micromachines

Publisher: MDPI AG

ISSN (Electronic): 2072-666X

Publication date Created: February 2022

Publication date (Electronic): February 19 2022

Volume: 13

Issue: 2

Page: 328

Article

DOI: 10.3390/mi13020328

PubMed ID: 35208453

SO-VID: 35f5a748-89de-4063-9d6d-a3689c3e56ab

License:

https://creativecommons.org/licenses/by/4.0/

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