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.
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.
|Chen, Huanhuan Joyce; Wei, Zhubo; Sun, Jian et al. (2016) A recellularized human colon model identifies cancer driver genes. Nat Biotechnol 34:845-51|
|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; 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|
|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|
|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|
|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|
|Thakore, Vaibhav; Hickman, James J (2015) Charge Relaxation Dynamics of an Electrolytic Nanocapacitor. J Phys Chem C Nanomater Interfaces 119:2121-2132|
|Stancescu, Maria; Molnar, Peter; McAleer, Christopher W et al. (2015) A phenotypic in vitro model for the main determinants of human whole heart function. Biomaterials 60:20-30|
|Berry, Bonnie J; Akanda, Nesar; Smith, Alec S T et al. (2015) Morphological and functional characterization of human induced pluripotent stem cell-derived neurons (iCell Neurons) in defined culture systems. Biotechnol Prog 31:1613-22|
|Sung, Jong Hwan; Srinivasan, Balaji; Esch, Mandy Brigitte et al. (2014) Using physiologically-based pharmacokinetic-guided "body-on-a-chip" systems to predict mammalian response to drug and chemical exposure. Exp Biol Med (Maywood) 239:1225-39|
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