Our overall strategy is to utilize microphysiological systems in combination with functional readouts to establish systems capable of sophisticated analysis of drug candidates during pre-clinical testing. In the UH2 Phase, we will construct physiological systems that represent nervous, circulatory and gastrointestinal/liver. Hickman has published physiologically correct functional systems for cardiac, muscle, neuromuscular junction, myelination and neuronal networks. 3D liver models from RegeneMed and stem cell derived cardiomyocytes and hepatocytes from GE will be incorporated into these microphysiological systems. In the UH3 Phase our consortium will develop a low-cost in vitro predictive efficacy and toxicology system based on a novel """"""""pumpless"""""""" microphysiological platform described in Sung et al 2010. The platform will contain electronic functional readouts and microanalytical systems for rapid high throughput biomarker sensing. Shuler's group has demonstrated microphysiological systems with up to 5 chambers that are a direct analog to a physiologically-based pharmacokinetic (PBPK) model. This system has been used to evaluate combination therapy for colon cancer and secondary toxicity from liver metabolites, response to endocrine disruptions, drug efficacy in multidrug resistant cancer systems, and model transport across a barrier tissue (e.g. GI tract) with systemic response (e.g. liver). Dr. Michael Shuler at Cornell University has pioneered the micro cell culture analog (?CCA) or """"""""Body-on-a- Chip"""""""" system, a realistic system using cell cultures to predict human response to drugs and biologics and will create a next-generation device. Dr. James Hickman at the University of Central Florida will develop functional in vitro human physiological systems and integrate them onto the microphysiological platform. RegeneMed will supply liver and skin constructs for the next-generation Body-on-a-Chip device. GE Global Research will develop analytical capabilities for integration onto the device, provide human stem cell-derived cardiomyocytes and hepatocytes and develop new human stem cell-derived cellular models, and will adapt their pioneering in silico prediction models for drug efficacy and validation. The Sanford-Burnham Institute has expertise in drug discovery and development and will compare the data generated with the in vitro system to known preclinical and clinical results, and provide regulatory guidance during the development process. LTC. Thomas at Walter Reed Army Institute of Research will develop immune system models for evaluating infectious disease on the device. In total, our consortium contains all of the skill sets required to construct, evaluate and commercialize the integrated system and associated components to achieve the goals outlined in the microphysiometer RFA.

Public Health Relevance

We are developing microphsyiological modules to model the nervous system, circulatory system and gastrointestinal tract system utilizing our extensive experience in these areas in the UH2 Phase of this project. In the UH3 Phase, we will build a 10-organ system that will be low cost, yet highly functional for utilization in drug discovery, toxicity studies and eventually all aspects of pre clinical testing.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
3UH2TR000516-02S2
Application #
8899230
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tagle, Danilo A
Project Start
2012-07-24
Project End
2015-06-30
Budget Start
2014-09-13
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Chen, Huanhuan Joyce; Miller, Paula; Shuler, Michael L (2018) A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells. Lab Chip 18:2036-2046
Oleaga, Carlota; Riu, Anne; Rothemund, Sandra et al. (2018) Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system. Biomaterials 182:176-190
Wang, Ying I; Oleaga, Carlota; Long, Christopher J et al. (2017) Self-contained, low-cost Body-on-a-Chip systems for drug development. Exp Biol Med (Maywood) 242:1701-1713
Wang, Ying I; Abaci, Hasan Erbil; Shuler, Michael L (2017) Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng 114:184-194
Oleaga, Carlota; Bernabini, Catia; Smith, Alec S T et al. (2016) Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep 6:20030
Chen, Huanhuan Joyce; Wei, Zhubo; Sun, Jian et al. (2016) A recellularized human colon model identifies cancer driver genes. Nat Biotechnol 34:845-51
Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang et al. (2015) Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting. Nat Biotechnol 33:656-60
Abaci, Hasan Erbil; Shuler, Michael L (2015) Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr Biol (Camb) 7:383-91
Srinivasan, Balaji; Kolli, Aditya Reddy; Esch, Mandy Brigitte et al. (2015) TEER measurement techniques for in vitro barrier model systems. J Lab Autom 20:107-26
Esch, Mandy B; Prot, Jean-Matthieu; Wang, Ying I et al. (2015) Multi-cellular 3D human primary liver cell culture elevates metabolic activity under fluidic flow. Lab Chip 15:2269-77

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