2018 Progress Report: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology

EPA Grant Number: R835736
Center: Vanderbilt Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Center Director: Hutson, Michael Shane
Title: Vanderbilt - Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Investigators: Hutson, Michael Shane , Aronoff, David , Bruner-Tran, Kaylon L. , Cliffel, David , Davidson, Jeffrey M. , Gough, Albert , Markov, Dmitry , McCawley, Lisa J. , McLean, John , Osteen, Kevin G. , Shotwell, Matt , Taylor, D. Lansing , Tuan, Rocky , Vernetti, Lawrence , Wikswo, John
Institution: Vanderbilt University , University of Pittsburgh Main Campus
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
Project Period Covered by this Report: December 1, 2017 through November 30,2018
Project Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

Center-wide goals include: 1) Using OCMs as a bridging technology to identify the strongest confounding factors of in vitro to in vivo predictions, 2) Using OCMs as experimentally accessible systems to elucidate Adverse Outcome Pathways (AOPs), and 3) Solving engineering challenges that must be met before OCMs could be used for routine medium throughput toxicity screening.

Progress Summary:

For more detailed descriptions of the Center's progress, please refer to each subproject's site.

Project 1 - Mammosphere Bioreactor For Life-Stage Specific Toxicology

For the past year, we focused on validation of medium through put on-chip analysis using known toxicants of mammary development; the development of subchronic delivery of compounds and the development of connectivity strategies with common medias laying the foundations of integration with the Liver OCM .

Project 2 - Organotypic Culture Model to Analyze Developmental Limb Malformations Resulting from Toxicant/Teratogen Exposure

The Limb Development team is building and testing three distinct organotypic culture models for chondrogenesis (OCM1) , hypertrophy (OCM2) , and segmentation (OCM3) for each one of their milestones. Contrary to Project 1, the individual OCM versions are not designed to be used only during certain project development phases, but will be used throughout the project. In order to more exactly communicate progress regarding each of these OCMs, we decided to list their status of completion separately. Collaborators from the Vanderbilt Institute for Integrative Biosystems and Education (VIIBRE) are developing bioreactor device prototypes for OCM3 cultures.

Project 3 - Validating a fetal membrane on a chip model (IFMOC) for characterizing reproductive toxicant exposure risks

We have examined the potential influence of TCDD metabolism by the liver on altering the downstream tissue response. A major goal of the current application is to determine the utility of the IFMOC compared to traditional cultures for screening of individual toxicants. However, humans are not exposed to single toxicants, but rather combinations of agents. Therefore, in order to assess the impact of combinatorial exposures, we directly compared the two chamber organ-on-chip (OoC) model of the human fetal membrane containing human amnion epithelial cells and decidual cells to the transwell cultures of human fetal membranes. We have noted epigenetic modifications affecting progesterone receptor expression in the IFMOC, a toxicant mediated response that cannot be seen in the transwell cultures.

Project 4 - Liver

Much of our efforts were focused on coupling our Liver OCM to the OCMs from other projects. Multiple factors such as media, scaling, flow rate, hardware compatibility and other issues had to be addressed before this integration could take place. Our initial approach to integration was functional coupling (media is conditioned in the liver OCM, then used to perfuse another OCM). In order to prepare conditioned media for functional coupling, we have calculated by allometric scaling the appropriate amount of liver conditioned media to provide to the other project teams.

Project 5 - Systems Engineering & Analysis

Proj ect 5 continues to deliver standalone pumps, valves, IOM Perfusion Controllers (IOM-PCs, v2.0), and MicroClinical Analyzers (µCAs, v2.0) as requested by organ developers. A variety of Rotary Planar Peristaltic Micropumps (RPPMs) are in regular use by Projects 1 and 2, and we anticipate their use by Project 3 soon. Project 1 has evaluated the 5-port Rotary Planar Valves (RPVs). Project 5 has made significant progress in developing multi-port RPPMs and RPVs that will soon bring new capabilities to the pumps and valves used by all groups to perfuse OCMs and reduce the cost and increase the ease of use of the hardware.


Journal Articles: 43 Displayed | Download in RIS Format

Other center views: All 149 publications 39 publications in selected types All 39 journal articles
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Journal Article 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)
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  • Journal Article 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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  • Journal Article 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 R835736 (2018)
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  • Journal Article Auner AW, Kazi M. 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 R835736 (2018)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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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  • Journal Article 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. R835736 (2018)
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  • Journal Article 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)
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  • Journal Article 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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  • Journal Article 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)
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  • Journal Article 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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  • Journal Article 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 R835736 (2018)
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  • Journal Article 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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  • Journal Article 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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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article 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 (2018)
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  • Journal Article 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)
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  • Journal Article 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 (2018)
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  • Journal Article 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)
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  • Journal Article 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)
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  • Journal Article Wikswo JP. Looking to the future of organs-on-chips: interview with Professor John Wikswo. Future science OA 2017;3(2):FSO163. R835736 (2018)
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  • Journal Article Miller DR, McClain ES, Cliffel DE. Electrochemical Microphysiometry Detects Cellular Glutamate Up-take. Journal of The Electrochemical Society 2018;165(12):G3120-G3124. R835736C005 (2018)
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  • Journal Article 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. R835736 (2018)
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    Original Abstract
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  • 2017 Progress Report
  • 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 Developmental LimbMalformationsResulting 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