Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs

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Abstract

We report on a functional human model to evaluate multi-organ toxicity in a 4-organ system under continuous flow conditions in a serum-free defined medium utilizing a pumpless platform for 14 days. Computer simulations of the platform established flow rates and resultant shear stress within accepted ranges. Viability of the system was demonstrated for 14 days as well as functional activity of cardiac, muscle, neuronal and liver modules. The pharmacological relevance of the integrated modules were evaluated for their response at 7 days to 5 drugs with known side effects after a 48 hour drug treatment regime. The results of all drug treatments were in general agreement with published toxicity results from human and animal data. The presented phenotypic culture model exhibits a multi-organ toxicity response, representing the next generation of in vitro systems, and constitutes a step towards an in vitro “human-on-a-chip” assay for systemic toxicity screening.

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Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods.

J. van der Valk, D. Brunner, K De Smet … (2010)

Quality assurance is becoming increasingly important. Good laboratory practice (GLP) and good manufacturing practice (GMP) are now established standards. The biomedical field aims at an increasing reliance on the use of in vitro methods. Cell and tissue culture methods are generally fast, cheap, reproducible and reduce the use of experimental animals. Good cell culture practice (GCCP) is an attempt to develop a common standard for in vitro methods. The implementation of the use of chemically defined media is part of the GCCP. This will decrease the dependence on animal serum, a supplement with an undefined and variable composition. Defined media supplements are commercially available for some cell types. However, information on the formulation by the companies is often limited and such supplements can therefore not be regarded as completely defined. The development of defined media is difficult and often takes place in isolation. A workshop was organised in 2009 in Copenhagen to discuss strategies to improve the development and use of serum-free defined media. In this report, the results from the meeting are discussed and the formulation of a basic serum-free medium is suggested. Furthermore, recommendations are provided to improve information exchange on newly developed serum-free media. Copyright 2010 Elsevier Ltd. All rights reserved.

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Microengineered physiological biomimicry: organs-on-chips.

Dongeun Huh, Yu-suke Torisawa, Geraldine A. Hamilton … (2012)

Microscale engineering technologies provide unprecedented opportunities to create cell culture microenvironments that go beyond current three-dimensional in vitro models by recapitulating the critical tissue-tissue interfaces, spatiotemporal chemical gradients, and dynamic mechanical microenvironments of living organs. Here we review recent advances in this field made over the past two years that are focused on the development of 'Organs-on-Chips' in which living cells are cultured within microfluidic devices that have been microengineered to reconstitute tissue arrangements observed in living organs in order to study physiology in an organ-specific context and to develop specialized in vitro disease models. We discuss the potential of organs-on-chips as alternatives to conventional cell culture models and animal testing for pharmaceutical and toxicology applications. We also explore challenges that lie ahead if this field is to fulfil its promise to transform the future of drug development and chemical safety testing.

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Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions.

Diane K Wysowski, L. Swartz (2005)

The Adverse Event Reporting System is the primary surveillance database used by the Food and Drug Administration for identifying postmarketing drug safety problems. We analyzed all reports of suspected adverse drug reactions submitted to the Food and Drug Administration from the inception of the Adverse Event Reporting System database in 1969 through December 2002. We documented drug withdrawals and restricted distribution programs based on safety concerns. During the 33-year period from 1969 when adverse drug event reporting was initiated through 2002, about 2.3 million case reports of adverse events for the cumulative number of approximately 6000 marketed drugs were entered in the database. Most reports were for female patients. During this period, numerous drug reactions have been identified and added to the product labeling as boxed warnings, warnings, precautions, contraindications, and adverse reactions. More than 75 drugs/drug products have been removed from the market due to safety problems. In addition, 11 drugs have special requirements for prescriptions or have restricted distribution programs. Drugs withdrawn or restricted represent a small proportion (about 1%) of marketed drugs. The Food and Drug Administration's Adverse Event Reporting System is the primary surveillance database used for the identification of safety problems of marketed drugs. Despite the limitations of underreporting, differential reporting, and uneven quality, submitted reports often allow the identification of serious adverse events that are added to the product labeling information. In rare instances, additional regulations, up to and including market removal, have been required. We encourage physicians, pharmacists, other health care professionals, and patients to continue to report serious suspected and known adverse drug reactions to manufacturers and the Food and Drug Administration.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 03 February 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 20030

Affiliations

[1 ]NanoScience Technology Center, University of Central Florida, 12424 Research Parkway Suite 400 , Orlando, FL 32828

[2 ]Department of Biomedical Engineering, Cornell University, 115 and 305 Weill Hall , Ithaca, NY 14853

[3 ]L’Oreal Research and Innovation, Clark, NJ, 07666/ Aulnay sous Bois , France, 93600

[4 ]L’Oreal Research and Innovation, Aulnay sous Bois , France

Author notes

[a ] jhickman@ 123456mail.ucf.edu

[*]

These authors contributed equally to this work.

Article

Publisher Item ID: srep20030

DOI: 10.1038/srep20030

PMC ID: 4738272

PubMed ID: 26837601

SO-VID: 2de64da1-1032-41b8-85e6-96d5e3166dda

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 26 August 2015

Date accepted : 18 December 2015

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Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs

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Most cited references 48

Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods.

Microengineered physiological biomimicry: organs-on-chips.

Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions.

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