Grantee Research Project Results
2017 Progress Report: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology
EPA Grant Number: R835736Center: Mickey Leland National Urban Air Toxics Research Center (NUATRC)
Center Director: Beskid, Craig
Title: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Investigators: Hutson, Michael Shane , Osteen, Kevin G. , McCawley, Lisa J. , Bruner-Tran, Kaylon L. , Taylor, D. Lansing , Davidson, Jeffrey M. , Gough, Albert , Cliffel, David , Aronoff, David , Markov, Dmitry , Wikswo, John , McLean, John , Vernetti, Lawrence , Shotwell, Matt , Tuan, Rocky
Current Investigators: Tuan, Rocky , Alexander, Peter
Institution: Vanderbilt University , University of Pittsburgh
Current Institution: University of Pittsburgh , Vanderbilt University
EPA Project Officer: Callan, Richard
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2016 through November 30,2017
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Objective:
This center is advancing predictive toxicology by developing four organotypic culture models (OCMs): liver, mammary gland, limb/joint development, and fetal membrane. These 3D cultures of heterotypic cells will better approximate the in vivo cellular microenvironment and are amenable and affordable for medium to high-throughput screening. Screening of these OCMs against 30-50 chemicals from the ToxCast inventory will demonstrate whether OCM toxicity is predictable from ToxCast in vitro assays and whether OCM toxicity is predictive of previous animal studies and/or human epidemiology.
Progress Summary:
In year 3 the VPROMPT Center has:
a. Successfully integrated the mammary OCM with Project 5 perfusion pumps and control software, a commercial 7-port selector valve and has made great progress in describing chemical surface interactions with PDMS as part of our careful quality assurance strategy. Further, fluorescent proteolytic and lentiviral biosensors were incorporated into the 3D hydrogel mammosphere OCMs.
b. Increased morphological consistency in chondrogenic and hypertrophic limb development cultures via hydrogel overlays. Chondrogenic micromasses were demonstrated to be sensitive to thalidomide. Perhaps most notably, we successfully finalizing the design of a joint segmentation device in collaboration with Professor Wikswo's lab from Project 5. Further, we verified chondrogenesis and hypertrophy of adult human MSC micromass cultures under fluid flow.
c. Established an actively perfused fetal membrane OCM (IFMOC 3.0) and successfully conducted dose-response studies for selected toxicants. In this device, we are able to decidualize human endometrial stromal cells with associated cellular morphology changes, inhibit decidualization via TCDD exposure, and we demonstrate prolactin production in the IFMOC.
d. Successfully validated iPSC-derived human hepatocytes in the liver bioreactor; developed two additional (to the five already developed) real-time, fluorescence-based biosensors available to VPROMPT Center collaborators; and demonstrated successful integrated liver OCM culture integrated with the Vanderbilt platform developed under Project 5. In addition, we have defined media mixtures suitable for integration with the mammary gland and limb development OCMs.
e. Integrated organ module (IOM) control software is capable of full automation of Project 5 hardware and we are close to incorporating wireless capabilities into the modules. Production of microfluidic pump and valve inserts was streamlined to maximize manufacturability and have made advances in minimizing the cost and physical size of Project 5 hardware. In addition, metabolic baselines were established for the mammary gland and electrochemical sensor capabilities were extended to include glutamate and choline, while progress was also made for cholesterol and ammonium sensors. Finally, we started to establish computational fluid dynamics models for PDMS adsorption and transport of toxicants.
For more information, please see the individual Project reports.
Journal Articles: 58 Displayed | Download in RIS Format
| Other center views: | All 169 publications | 57 publications in selected types | All 56 journal articles |
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Alexander PG, Clark KL, Tuan RS. Prenatal exposure to environmental factors and congenital limb defects. Birth Defects Research, Part C, Embryo Today: Reviews 2016;108(3):243-273. |
R835736 (2015) R835736 (2016) R835736 (2017) R835736C002 (2016) |
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Anders AP, Gaddy JA, Doster RS, Aronoff DM. Current concepts in maternal-fetal immunology: recognition and response to microbial pathogens by decidual stromal cells. American Journal of Reproductive Immunology 2017;77(3):e12623 (14 pp.). |
R835736 (2016) |
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Argemie J, Latasa M, Atkinson S, Blokhin I, Massey V, Gue J, Cabezas J, Lozano J, Booven D, Bell A, Cao S, Vernetti L, Arab J. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nature Communications 2019;10(1):3126. |
R835736 (2018) |
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Auner AW, Tasneem KM, Markov DA, McCawley LJ, Hutson MS. Chemical-PDMS Binding Kinetics and Implications for Bioavailability in microfluidic Devices. Lab on a Chip 2019;19(5):864-874 |
R835736C001 (2018) R835736C001 (Final) R835736C005 (2018) |
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Bruner-Tran KL, Duleba AJ, Taylor HS, Osteen KG. Developmental toxicant exposure is associated with transgenerational adenomyosis in a murine model. Biology of Reproduction 2016;95(4):73 (10 pp.). |
R835736 (2015) R835736 (2016) R835736C003 (2018) |
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Bruner-Tran KL, Gnecco J, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: translating lessons from murine models. Reproductive Toxicology 2017;68:59-71. |
R835736 (2015) R835736 (2016) R835736 (2017) R835736C003 (2016) R835736C003 (2017) R835736C003 (2018) R826300 (Final) |
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Bruner-Tran KL, Mokshagundam S, Herington JL, Osteen KG. Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets. Current Women's Health Reviews 2018;14(2):173–188 |
R835736C003 (2018) |
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Cyr KJ, Avaldi OM, Wikswo JP. Circadian hormone control in a human-on-a-chip:in vitro biology’s ignored component? Experimental Biology and Medicine 2017;242(17):1714-1731. |
R835736 (2017) R835736C005 (2017) |
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Ding T, Lambert LA, Aronoff DM, Osteen KG, Bruner-Tran KL. Sex-dependent influence of developmental toxicant exposure on group B Streptococcus -mediated preterm birth in a murine model. Reproductive Sciences 2018;25(5):662-673. |
R835736 (2017) R835736C003 (2017) R835736C003 (2018) |
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Dodds JN, May JC, McLean JA. Investigation of the complete suite of the leucine and isoleucine isomers: toward prediction of ion mobility separation capabilities. Analytical Chemistry 2017;89(1):952-959. |
R835736 (2015) R835736 (2016) R835736 (2017) |
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Ellis B, Fischer C, Martin L, Bachmann B, McLean J. Spatiochemically Profiling Microbial Interactions with Membrane Scaffolded Desorption Electrospray Ionization-Ion Mobility-Imaging Mass Spectrometry and Unsupervised Segmentation. Analytical Chemistry 2019;91(21):13703-13711. |
R835736 (2018) |
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Ellis B, Babele P, May J, Johnson C, Pfleger B, Young J, McLean J. Accelerating strain phenotyping with desorption electrospray ionization-imaging mass spectrometry and untargeted analysis of intact microbial colonies. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022;118(49):e2109633118. |
R835736 (Final) |
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Ellis B, Babele P, May J, Johnson C, Pfleger B, Young J, McLean J. Molecular Gatekeeper Discovery:Workflow for Linking Multiple Exposure Biomarkers to Metabolomics br. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022;56(10):6162-6171. |
R835736 (Final) |
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Gnecco JS, Anders AP, Cliffel D, Pensabene V, Rogers LM, Osteen K, Aronoff DM. Instrumenting a fetal membrane on a chip as emerging technology for preterm birth research. Current Pharmaceutical Design 2017;23(40):6115-6124. |
R835736 (2016) R835736 (2017) R835736C003 (2016) R835736C003 (2017) R835736C003 (2018) |
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Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Annals of Biomedical Engineering 2017;45(7):1758-1769. |
R835736 (2017) R835736C003 (2016) |
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Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Annals of Biomedical Engineering 2017;45(7):1758-1769. |
R835736 (2015) R835736 (2016) R835736C003 (2017) R835736C003 (2018) |
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Gnecco JS, Ding T, Smith C, Lu J, Bruner-Tran KL, Osteen KG. Hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin in a microfluidic model of the human endometrium. Human Reproduction 2019;43(4):702-714 |
R835736C003 (2018) R839501 (2022) |
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Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. |
R835736 (2015) R835736 (2016) R835736C004 (2017) |
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Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. |
R835736 (2017) |
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Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The MicroPhysiology Systems Database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. |
R835736 (2015) R835736 (2016) R835736C004 (2017) |
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Hawkins K, Casolaro C, Brown JA, Edwards D, WIksow J. The Microbiome and the Gut-Liver-Brain Axis for Central Nervous System Clinical Pharmacology:Challenges in Specifying and Integrating In Vitro and In Silico Models. Clinical Pharmacology & Theraputics 2020 |
R835736 (2018) |
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Hutson MS, Alexander PG, Allwardt V, Aronoff DM, Bruner-Tran KL, Cliffel DE, Davidson JM, Gough A, Markov DA, McCawley LJ, McKenzie JR, McLean JA, Osteen KG, Pensabene V, Samson PC, Senutovitch NK, Sherrod SD, Shotwell MS, Taylor DL, Tetz LM, Tuan RS, Vernetti LA, Wikswo JP. Organs-on-chips as bridges for predictive toxicology. Applied In Vitro Toxicology 2016;2(2):97-102. |
R835736 (2015) R835736 (2016) R835736 (2017) R835736C001 (2018) R835736C003 (2016) R835736C003 (2017) R835736C003 (2018) |
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Hutson MS, Leung MCK, Baker NC, Spencer RM, Knudsen TB. Computational model of secondary palate fusion and disruption. Chemical Research in Toxicology 2017;30(4):965-979. |
R835736 (2015) R835736 (2016) R835736 (2017) |
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Iannetti L, D'Urso G, Conoscenti G, Cutri E, Tuan RS, Raimondi MT, Gottardi R, Zunino P. Distributed and Lumped Parameter Models for the Characterization of High Throughput Bioreactors. PLoS One 2016;11(9):e0162774 (25 pp.). |
R835736 (2016) |
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Karolak A, Markov DA, McCawley LJ, Rejniak KA. Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues. Journal of the Royal Society Interface 2018;15(138):20170703. |
R835736C001 (2017) |
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Kimmel DW, Rogers LM, Aronoff DM, Cliffel DE. Prostaglandin E2 regulation of macrophage innate immunity. Chemical Research in Toxicology 2016;29(1):19-25. |
R835736 (2016) R835738 (2017) |
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Lee-Montiel FT, George SM, Gough AH, Sharma AD, Wu J, DeBiasio R, Vernetti LA, Taylor DL. “Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems. Exp Biol Med 2017;242(16):1617-1632. |
R835736C004 (2018) |
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Leung MC, Hutson MS, Seifert AW, Spencer RM, Knudsen TB. Computational modeling and simulation of genital tubercle development. Reproductive Toxicology 2016;64:151-161. |
R835736 (2015) R835736 (2016) R835736C005 (2016) |
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Leung MCK, Hutson MS, Seifert AW, Spencer RM, Knudsen TB. Computational modeling and simulation of genital tubercle development. Reproductive Toxicology 2016;64:151-161. |
R835736 (2017) |
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Li X, George SM, Vernetti L, Gough AH, Taylor DL. A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab on a Chip 2018;21;18(17):2614-2631 |
R835736C004 (2018) |
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May JC, Morris CB, McLean JA. Ion mobility collision cross section compendium. Analytical Chemistry 2017;89(2):1032-1044. |
R835736 (2016) |
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May J, Jurneczko E, Stow A, Kratochvil I, Kalhof S, McLean J. Conformational landscapes of ubiquitin, cytochrome c, and myoglobin: Uniform field ion mobility measurements in helium and nitrogen drift gas. INTERNATIONAL JOURNAL OF MASS SPECTROMETRY 2018;427:79-90 |
R835736 (Final) |
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Melow S, Miller D, Gizzie E, Cliffel D. A low-interference, high-resolution multianalyte electrochemical biosensor. Analytical Methods 2020;12(31):3873-3882. |
R835736 (Final) |
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MHarris R, May J, Stinson C, Xia Y, McLean J. Determining Double Bond Position in Lipids Using Online Ozonolysis Coupled to Liquid Chromatography and Ion Mobility-Mass Spectrometry. ANALYTICAL CHEMISTRY 2018;90(3):1959-1924 |
R835736 (Final) |
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Morris C, May J, Leaptrot K, McLean J. Evaluating Separation Selectivity and Collision Cross Section Measurement Reproducibility in Helium, Nitrogen, Argon, and Carbon Dioxide Drift Gases for Drift Tube Ion Mobility-Mass Spectrometry. JOURNAL OF THE AMERICAN SOCIETY FO MASS SPECTROMETRY 2019;30(6):1059-1068 |
R835736 (Final) |
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Nichols C, May J, Sherrod S, McLead J. Automated flow injection method for the high precision determination of drift tube ion mobility collision cross sections. ANALYST 2018;143(7):1556-1559 |
R835736 (Final) |
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Nichols C, Dodds J, Rose B, Piache J, Morris C, Codreau S, May J, Sherrod S, McLean J. Untargeted Molecular Discovery in Primary Metabolism: Collision Cross Section as a Molecular Descriptor in Ion Mobility-Mass Spectrometry. ANALYTICAL CHEMISTRY 2018;90(24):14484-14492 |
R835736 (Final) |
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Richardson L, Gnecco J, Ding T, Osteen K, Rogers L, Arnoff DM, Menon R. Fetal Membrane Organ-On-Chip:An Innovative Approach to Study Cellular Interactions. Reproductive Sciences 2020;. |
R835736 (2018) |
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Rogers JM, Anders AP, Doster RS, Gill EA, Gnecco JS, Holley JM, Randis TM, Ratner AJ, Gaddy JA, Osteen K, Arnoff DM. Decidual stromal cell-derived PGE(2) regulates macrophage responses to microbial threat. American Journal of Reproductive Immunology 2018;80(4). |
R835736C003 (2018) |
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Sakolish C, Luo Y, Valdiviezo A, Vernetti L, Rusyn I, Chiu W. Prediction of hepatic drug clearance with a human microfluidic four-cell liver acinus microphysiology system. Toxicology 2021;463. |
R835736 (Final) |
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Sakolish C, Reese CE, Luo YS, Valdiviezo A, Schurdak ME, Gough A, Taylor DL, Chiu WA, Venetti LA, Rusyn I. Analysis of reproducibility and robustness of a human microfluidic four-cell liver acinus microphysiology system (LAMPS). Toxicology 2021;448. |
R835736 (Final) RD840032 (2021) |
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Schurdak M, Vernetti L, Bergenthal L, Wolter Q, Shun T, Karcher S, Taylor D, Gough A. Applications of the microphysiology systems database for experimental ADME-Tox and disease models. LAB ON A CHIP 2020;20(8):1472-1492. |
R835736 (2018) |
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Senutovitch N, Vernetti L, Boltz R, DeBiasio R, Gough A, Taylor DL. Fluorescent protein biosensors applied to microphysiological systems. Experimental Biology and Medicine 2015;240(6):795-808. |
R835736 (2015) R835736 (2016) R835736C004 (2015) R835736C004 (2016) |
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Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Experimental Biology and Medicine 2017;242(16):1605-1616. |
R835736 (2017) R835736C004 (2017) |
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Stocks MM, Crispens MA, Ding T, Mokshagundam S, Bruner-Tran KL, Osteen KG. Therapeutically targeting the inflammasome product in a chimeric model of endometriosis-related surgical adhesions. Reproductive Sciences 2017;24(8):1121-1128. |
R835736 (2015) R835736 (2016) |
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Stow S, Onifer T, Forsythe J, Jefzger H, Keiecien N, May J, McLean J, Hercules D. Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility-Mass Spectrometry and Tandem Mass Spectrometry. 4. 3-Ring and 4-Ring Isomers. ANALYTICAL CHEMISTRY 2015;87(12):6288-6296 |
R835736 (Final) |
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Stow S, Causon T, Zheng X, Krulugama R, Meringer T, May J, Rennie E, Baker E, Smith R, McLean J, Hann S, Fjeldsted J. An Interlaboratory Evaluation of Drift Tube Ion Mobility-Mass Spectrometry Collision Cross Section Measurements. ANALYTICAL CHEMISTRY 2017;89(17):9048-9055 |
R835736 (Final) |
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Vernetti LA, Senutovitch N, Boltz R, DeBiasio R, Shun TY, Gough A, Taylor DL. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Experimental Biology and Medicine 2016;241(1):101-114. |
R835736 (2015) R835736 (2016) R835736 (2017) R835736C004 (2015) R835736C004 (2016) R835736C004 (2017) R835736C004 (2018) |
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Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). |
R835736 (2017) R835736C004 (2018) R835738C002 (2017) R835738C005 (2017) |
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Vernetti LA, Vogt A, Gough A, Taylor DL. Evolution of experimental models of the liver to predict human drug hepatotoxicity and efficacy. Clinics in Liver Disease 2017;21(1):197-214. |
R835736 (2015) R835736 (2016) R835736 (2017) R835736C004 (2017) R835736C004 (2018) |
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Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). |
R835736 (2015) R835736 (2016) R835736C004 (2016) R835736C005 (2016) R835738 (2016) R835738C003 (2017) R835738C005 (2017) |
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Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (14 pp.). |
R835736C004 (2017) R835738 (2017) R835738C002 (2016) |
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Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). |
R835736 (2015) R835736 (2016) R835736C004 (2016) R835736C005 (2016) R835738 (2016) R835738C003 (2017) R835738C005 (2017) |
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Watson DE, Hunziker R, Wikswo JP. Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Experimental Biology and Medicine 2017;242(16):1559-1572. |
R835736 (2017) R835736C005 (2017) |
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Wikswo JP. Looking to the future of organs-on-chips: interview with Professor John Wikswo. Future science OA 2017;3(2):FSO163. |
R835736C005 (2017) |
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Miller DR, McClain ES, Cliffel DE. Electrochemical Microphysiometry Detects Cellular Glutamate Up-take. Journal of The Electrochemical Society 2018;165(12):G3120-G3124. |
R835736 (Final) R835736C005 (2018) R835736C005 (Final) |
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Rogers M, Sobolik T, Schaffer DK, Samson PC, Johnson AC, Owens P, Codreanu SG, Sherrod SD, McLean JA, Wikswo JP, Richmond A. Engineered microfluidic bioreactor for examining the three-dimensional breast tumor microenvironment Biomicrofluidics 2018;12(3):034102. |
R835736C005 (Final) |
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Ding T et al, 2018. Reproductive Sciences 25(5):662-673 Bruner-Tran KL et al, 2018. Current Women’s Health Rev Jun;14(2):173-188 Rogers et al, 2018. American Journal of Reproductive Immunology Oct;80(4):e13032. |
R835736C003 (2018) |
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Supplemental Keywords:
Predictive toxicology, new alternative methods, NAMs, mammary development, mammary toxicology, organs on chip, mammary on chip, PDMS bioreactors, thick tissue bioreactor, PDMS interactions, organotypic cell culture.Relevant Websites:
Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT) Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R835736C001 Mammosphere Bioreactor For Life-Stage Specific Toxicology
R835736C002 Organotypic Culture Model to Analyze DevelopmentalLimbMalformationsResulting from Toxicant/Teratogen Exposure
R835736C003 Validating a fetal membrane on a chip model for characterizing
reproductive toxicant exposure risks
R835736C004 Organotypic Liver Model for Predictive Human Toxicology and Metabolism
R835736C005 Systems Engineering & Analysis for Organotypic Culture Models
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.