Organs-on-chips: into the next decade

Low, Lucie A.; Mummery, Christine L.; Berridge, Brian R.; Austin, Christopher P.; Tagle, Danilo A.

doi:10.1038/s41573-020-0079-3

Cited by 576 publications

(556 citation statements)

References 168 publications

(161 reference statements)

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“…Another method that well-represents physiological metabolism is the recently developed organ-on-a-chip (OOAC) technique. OOAC refers to a physiological organ biomimetic system built on a microfluidic chip [128,129]. OOAC combines cell biology, bioengineering, and biomaterial technology allowing us to mimic a specific organ.…”

Section: Future Perspectivementioning

confidence: 99%

Application of In Vitro Metabolism Activation in High-Throughput Screening

Ooka

Lynch

Xia

2020

IJMS

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In vitro methods which incorporate metabolic capability into the assays allow us to assess the activity of metabolites from their parent compounds. These methods can be applied into high-throughput screening (HTS) platforms, thereby increasing the speed to identify compounds that become active via the metabolism process. HTS was originally used in the pharmaceutical industry and now is also used in academic settings to evaluate biological activity and/or toxicity of chemicals. Although most chemicals are metabolized in our body, many HTS assays lack the capability to determine compound activity via metabolism. To overcome this problem, several in vitro metabolic methods have been applied to an HTS format. In this review, we describe in vitro metabolism methods and their application in HTS assays, as well as discuss the future perspectives of HTS with metabolic activity. Each in vitro metabolism method has advantages and disadvantages. For instance, the S9 mix has a full set of liver metabolic enzymes, but it displays high cytotoxicity in cell-based assays. In vitro metabolism requires liver fractions or the use of other metabolically capable systems, including primary hepatocytes or recombinant enzymes. Several newly developed in vitro metabolic methods, including HepaRG cells, three-dimensional (3D) cell models, and organ-on-a-chip technology, will also be discussed. These newly developed in vitro metabolism approaches offer significant progress in dissecting biological processes, developing drugs, and making toxicology studies quicker and more efficient.

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Section: Future Perspectivementioning

confidence: 99%

Application of In Vitro Metabolism Activation in High-Throughput Screening

Ooka

Lynch

Xia

2020

IJMS

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“…We also tested the feasibility of screening for patient-specific drug resistance, and aim to extend this technique for high-throughput screening. In addition, other in vitro models are being developed to better mimic human physiology in the lab [18, 19]. Perfused organ-on-chips can be potentially coupled with RLM for high-resolution dynamic imaging and of PET tracer in vitro .…”

Section: Discussionmentioning

confidence: 99%

High-resolution radioluminescence microscopy of FDG uptake in an engineered 3D tumor-stoma model

Khan

Kim

Yang

et al. 2020

Preprint

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PURPOSEThe increased glucose metabolism of cancer cells is the basis for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, due to its coarse image resolution, PET is unable to resolve the metabolic role of cancer-associated stroma, which often influences the metabolic reprogramming of a tumor. This study investigates the feasibility of imaging engineered 3D tumor models with high resolution using FDG.METHODMulticellular tumor spheroids (A549 lung adenocarcinoma) were co-cultured with GFP-expressing human umbilical vein endothelial cells (HUVECs) within an artificial extracellular matrix to mimic a tumor and its surrounding stroma. The tumor model was constructed as a thin 3D layer over a transparent CdWO4 scintillator plate to allow high-resolution imaging of the cultured cells. The radioluminescence signal was collected by a highly sensitive microscope and camera. Fluorescence microscopy was performed in the same instrument to localize endothelial and tumor cells.RESULTSSimultaneous brightfield and fluorescence imaging, co-localized with radioluminescence signal, provided high-resolution information on FDG accumulation in the engineered tissue. The microvascular stromal compartment took up a large fraction of FDG, comparable to the tumor spheroids. In vitro gamma counting also revealed that both A549 and HUVEC cells were highly glycolytic and characterized by rapid FDG-uptake kinetics.CONCLUSIONOur study demonstrates the feasibility of imaging FDG distribution in tumor and stromal components separately with high spatial resolution in engineered in vitro tumor models. Our imaging method is safe, simple, rapid, and can be easily used for other in vitro cancer models, surgical tissue slices, and tumor biopsies to interrogate PET radiotracer uptake at high resolution.

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“…An OOC platform consists of an interconnected series of 3D channels and chambers filled with cells suspended in hydrogels. The geometry of these channels and chambers can be precisely selected to match a variety of tissue architectures and mechanical forces, has a scale of tens to hundreds of microns, and is carved into an optically clear polymer using microfabrication or 3D printing ( 24 , 102 ). Strengths of OOC systems include the ability to incorporate multiple human cell types at physiologically-relevant ratios; control hydrogel composition and spatial distribution; customize the physiochemical properties of the tissue microenvironment; and image tissues with high spatiotemporal resolution.…”

Section: Organ-on-a-chip Modelsmentioning

confidence: 99%

Advances in Modeling the Immune Microenvironment of Colorectal Cancer

et al. 2021

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Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment—including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature—are crucial for studies of immunity in the CRC TME and the utility of immunotherapies for CRC patients. We briefly review the discoveries, advantages, and disadvantages of current in vitro and in vivo model systems, including 2D cell culture models, 3D culture systems, murine models, and organ-on-a-chip technologies.

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Organs-on-chips: into the next decade

Cited by 576 publications

References 168 publications

Application of In Vitro Metabolism Activation in High-Throughput Screening

Application of In Vitro Metabolism Activation in High-Throughput Screening

High-resolution radioluminescence microscopy of FDG uptake in an engineered 3D tumor-stoma model

Advances in Modeling the Immune Microenvironment of Colorectal Cancer

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