This article appeared in a journal published by Elsevier The attached copy is furnished to the author for internal non commercial research and education use including for instruction at the authors institution and sharing with colleagues Other uses including reproduction and distribution or selling or licensing copies or posting to personal institutional or third party websites are prohibited In most cases authors are permitted to post their version of the article e g in Word or Tex form to their personal website or institutional repository Authors requiring further information regarding Elsevier s archiving and manuscript policies are encouraged to visit http www elsevier com authorsrights Author s personal copy Advanced Drug Delivery Reviews 69 70 2014 158 169 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage www elsevier com locate addr How multi organ microdevices can help foster drug development Mandy B Esch a Alec S T Smith b Jean Matthieu Prot a Carlota Oleaga b James J Hickman b Michael L Shuler a a b Department of Biomedical Engineering Cornell University 115 and 305 Weill Hall Ithaca NY 14853 USA NanoScience Technology Center University of Central Florida 12424 Research Parkway Suite 401 Orlando FL 32828 USA a r t i c l e i n f o Article history Accepted 10 December 2013 Available online 9 January 2014 Keywords Multi organ microdevices Body on a chip Microphysiological systems MPS Micro cell culture analogs of PBPKs CCAs a b s t r a c t Multi organ microdevices can mimic tissue tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro These systems are capable of simulating human metabolism including the conversion of a pro drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects Since tissue tissue interactions in the human body can play a signi cant role in determining the success of new pharmaceuticals the development and use of multi organ microdevices present an opportunity to improve the drug development process The devices have the potential to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate ef cacy and dose response Multi organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism as opposed to animal models Further when operated with human biopsy samples the devices could be a gateway for the development of individualized medicine Here we review studies in which multi organ microdevices have been developed and used in a ways that demonstrate how the devices capabilities can present unique opportunities for the study of drug action We will also discuss challenges that are inherent in the development of multiorgan microdevices Among these are how to design the devices and how to create devices that mimic the human metabolism with high authenticity Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi organ devices we will also mention single organ devices where appropriate in the discussion 2014 Elsevier B V All rights reserved Contents 1 2 3 Introduction 1 1 Limitations of the current drug development process 1 2 The concept of multi organ microdevices 1 3 Multi organ microdevices versus animal models 1 4 Single organ microdevices Examples of multi organ microdevices and ways in which they can contribute to the drug development process 2 1 Lowering the cost of drug discovery 2 1 1 Predicting drug ef cacy and toxic side effects for humans 2 1 2 Predicting the bioavailability of drugs 2 1 3 Testing combinations of drugs to elucidate synergistic drug action 2 2 Experimenting with non physiologic versions of the human body 2 3 Determining parameters for physiologically based pharmacokinetic models 2 4 Individualized medicine Challenges 3 1 Device development 3 1 1 Device design 3 1 2 The development of a common cell culture medium 3 1 3 Cell sources 3 1 4 Authenticity of cellular behavior This review is part of the Advanced Drug Delivery Reviews theme issue on Innovative tissue models for drug discovery and development Corresponding author Tel 1 607 255 7577 fax 1 607 255 1136 E mail address mls50 cornell edu M L Shuler 0169 409X see front matter 2014 Elsevier B V All rights reserved http dx doi org 10 1016 j addr 2013 12 003 159 159 159 161 161 161 161 161 162 163 163 163 163 164 164 164 164 165 165 Author s personal copy 159 M B Esch et al Advanced Drug Delivery Reviews 69 70 2014 158 169 3 2 Commercialization 3 2 1 Longevity 3 2 2 Validation and standardization 4 Conclusions Disclosure Acknowledgments References 1 Introduction 1 1 Limitations of the current drug development process Modern drug development requires implementation of extensive pre clinical testing and validation protocols before potential therapeutic compounds are approved to progress to clinical evaluation This process is costly and time consuming as well as inef cient as for every ten drugs entering clinical trials only one or two will typically be licensed for eventual use in humans 1 2 One of the major factors in uencing this poor success rate is the lack of preclinical model systems capable of providing accurate predictions of human responses to novel therapeutic drugs The current gold standard for laboratory based preclinical evaluation is a combination of in vitro cell culture assay and in vivo animal model experimentation and assessment Cell culture assays are advantageous since they provide controlled environments where cellular maturation and activity are easily observed and tested However cultures of single cell types or even co cultures of 2 or 3 complimentary cell types lack the complexity of living systems and are incapable of modeling situations where organ organ or tissue tissue communication is important This simplicity is a major drawback in drug development studies since it is dif cult to predict the oftentimes complex drug metabolism and the effect of metabolite activity on non target tissues Moreover cells maintained in standard in vitro culture conditions often suffer from incomplete maturation or are held in a con guration that prevents their full functional development making predictions of in vivo tissue function more dif cult to extrapolate Animal models maintain the intricacy
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