This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institutionand sharing with colleagues.Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third partywebsites are prohibited.In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further informationregarding Elsevier’s archiving and manuscript policies areencouraged to visit:http://www.elsevier.com/authorsrightsAuthor's personal copyHow multi-organ microdevices can help foster drug development☆Mandy B. Escha, Alec S.T. Smithb, Jean-Matthieu Prota, Carlota Oleagab,James J. Hickmanb, Michael L. Shulera,⁎aDepartment of Biomedical Engineering, Cornell University, 115 and 305 Weill Hall, Ithaca, NY 14853, USAbNanoScience Technology Center, University of Central Florida, 12424 Research Parkway Suite 401, Orlando, FL 32828, USAabstractarticle infoArticle history:Accepted 10 December 2013Available online 9 January 2014Keywords:Multi-organ microdevicesBody-on-a-chipMicrophysiological systemsMPSMicro-cell culture analogs of PBPKsμCCAsMulti-organ microdevices can mimic tissue–tissue interactions that occur as a result of metabolite travel fromone tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including theconversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic sideeffects. Since tissue–tissue interactions in the human body can play a significant role in determining the successof new pharmaceuticals, the development and use of multi-organ mic rodevices pr esent an op portunity toimprove the drug development process. The devices have the potential to predict potential toxic side effectswith higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacyand dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeu-tic strategies by providing a platform for testing in the context of human metabolism (as opposed to animalmodels). Further, when operated with human biopsy samples, the devices could be a gateway for the develop-ment of individualized medicine. Here we review studies in which multi-organ microdevices have beendeveloped and used in a ways that demonstrate how the devices' capabilities can present unique opportunitiesfor the study of drug action. We will also discuss challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic thehuman metabolism with high authenticity. Since single organ devices are testing platforms for tissues that canlater be combined with other tissues within multi-organ devices, we will also mention single organ deviceswhere appropriate in the discussion.© 2014 Elsevier B.V. All rights reserved.Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1591.1. Limitations of the current drug development process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1591.2. The concept of multi-organ microdevices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1591.3. Multi-organ microdevices versus animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611.4. Single organ microdevices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612. Examples of multi-organ microdevices and ways in which they can contribute to the drug development process . . . . . . . . . . . . . . . . 1612.1. Lowering the cost of drug discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612.1.1. Predicting drug efficacy and toxic side effects for humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612.1.2. Predicting the bioavailability of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1622.1.3. Testing combinations of drugs to elucidate synergistic drug action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1632.2. Experimenting with non-physiologic versions of the human body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1632.3. Determining parameters for physiologically based pharmacokinetic models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1632.4. Individualized medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1633. Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643.1. Device development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1643.1.1. Device design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . …
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