Final 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: Tuan, Rocky , Alexander, Peter
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 Amount: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

Project 1: Mammosphere Bioreactor For Life-Stage Specific Toxicology

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

Our goal is to develop robust in vitro three-dimensional (3D) organotypic culture models (OCMs) based on human mesenchymal stem cells (MSCs) to first examine critical phenomena of embryonic limb development that are prime targets of limb teratogenesis, and then examine their susceptibility to perturbation by known and candidate teratogens and environmental toxicants.

Project 3: Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks

The Objective of Project 3 is to develop and validate an instrumented fetal membrane on a chip (IFMOC) system in order to specifically identify toxicants which negatively impact the maintenance of pregnancy.

Project 4: Organotypic Liver Model for Predictive Human Toxicology and Metabolism

(1) Transfer current microfluidics-based, 4-cell type, 3D liver organoid into commercial device; (2) demonstrate normal and abnormal liver function, drug metabolism and toxicity responses for 50-60 ToxCast chemicals; (3) demonstrate IM-MS analysis of targeted secretome products including drug metabolites, cytokines, lipids, proteins; (4) implement realtime, fluorescence-based biosensors of key physiological functions for liver and other organoid culture models (OCMs); (5) provide liver+drug conditioned media to other OCMs; (6) validate iPSC hepatocytes for use in the device; (7) adapt University of Pittsburgh Microphysiology Database to manage, consolidate, visualize, QC and organize data for transfer to EPA.

 

Project 5: Systems Engineering & Analysis for Organotypic Culture Models

Summary/Accomplishments (Outputs/Outcomes):

Project 1: Mammosphere Bioreactor For Life-Stage Specific Toxicology

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

Using these cultures, timelines of chondrogenic and hypertrophic (1) gene expression, (2) matrix elaboration and (3) histochemical and immunohistochemical marker detection in both the chondrogenic and hypertrophic cultures were analyzed.  In collaboration with Project 5, a new mechanical stimulator for a joint segmentation model amenable to microscopy and microfluidics that maintains the region-of-interest in a focal plane was developed. These 10ul cultures were used to test the effects of 3 known teratogens (valproic acid, warfarin and thalidomide) on adult human MSC micromass culture chondrogenesis and hypertrophy. Using outcomes based on RT-PCR, immunohistochemistry and biochemistry, effective doses approximating reported maternal plasma levels were observed.  Initial tests for the effect of two candidate teratogens (bisphenol A and mifepristone) on adult human MSC chondrogenesis and hypertrophy were also been performed. To reduce cell numbers for each assay, Project 2 successfully developed planar micromass cultures comprising of only 40,000 cells on texturized, Col I coated polystyrene multiwell plates.  These cultures were further optimized by the addition of a gel overlay comprised of 5% w:v photocrosslinkable gelatin, PXL mGL, which increased the morphologic consistency between cultures and experiments significantly.  The increased utility of the gel overlay was evident in our work with the GFP collagen type 2 promoter.  In gel-overlay cultures, the number and intensity of GFP positive cells could be reliably counted.  We compared the fold change in Col2 gene expression assayed by RT-PCR with the corrected total cell fluorescence (CTCF) fold change and found excellent agreement.  Previous work showed the current model was insensitive to thalidomide treatment, a known and potent limb teratogen, at doses as high as 1mM thalidomide.  A putative mechanism of thalidomide action maybe by preventing angiogenesis during limb formation via disruption of normal cereblon-mediated protein turnover and concomitant changes in gene expression.  In light of this, the gel overlay was used to incorporate GFP-labeled HUVECs into our limb OCMs. OCMs that included MSCs overlaid with HUVECs showed a very significant decrease in chondrogenic gene expression in the presence of thalidomide. We have determined our cultures express cereblon and ikaros by Western blot analysis.  We hypothesize that thalidomide will decrease cereblon and ikaros in both MSC and HUVECs, angiogenesis will be completely inhibited, and MSC chondrogenesis will be decreased.  Work also continued on developing the OCM3 joint segmentation model. PXL mGL was used to encapsulate MSCs in the troughs of our concentric ring model which eliminated prior problems with leakage and non-uniform chondrogenesis.  Manual flexing of 1 hr a day for 7 days resulted in cultures with decreased matrix deposition and increased GDF5 expression at the site of flexion suggesting that interzone like changes are occurring in this OCM model. Our group utilized 3D printing to create prototypes of microfluidically enabled OCM 1 and 2 cultures which consisted of upper and lower chambers separated by polycarbonate membranes with low profiles for microscopy and small medium chambers useful in conservation of reagents and downstream ELISA assays.  Project 2 also verified the process of hypertrophy in the reduced cell number cultures. RT-PCR revealed T3 stimulation induced strong hypertrophic gene expression (COLX and MMP13).  Chondrogenic genes (COLII and AGG) were initially down-regulated with the addition of T3 (as expected), but increased again over the next 7 days. This “recovery” was not observed in the 10uL cultures.  That hMSCs in the micromass cultures co-express chondrogenic and hypertrophic genes during differentiation, lead us to hypothesize that perhaps induced pluripotent stem cells (iPSCs) might undergo sequential chondrogenesis and hypertrophy (as in the embryo) and more faithfully report the effect of environmental toxins on chondrogenesis and hypertrophy. Trends in iPSC differentiation appeared similar to that of bone marrow-derived MSCs (BM-MSCs), but gene expression values were much lower and cultures showed poor morphology.  Refinement of the dose responses of 2ul (40,000) chondrogenic and hypertrophic cultures to known and unknown teratogens was also studied. The initial dose responses to valproic acid (VPA), warfarin, thalidomide, mifepristone and bisphenol A (BPA) utilized drug concentrations over 5 orders of magnitude. Using VPA as a test, restricting the dose range to one or two orders of magnitude, we were able to separate effective concentration (defined by 50% reduction in the marker gene expression) and lethal concentration (defined by a 50% reduction in cell viability) for both chondrogenesis and hypertrophy. We also assessed the activity of a validated COL2 promoter reporter developed in VPA-exposed chondrogenic micromass cultures. This is essential for the future non-invasive analysis of both healthy and toxin-exposed micromass cultures. Project 2 worked closely with Project 5 to develop an automated joint segmentation reactor. MSCs-based constructs cultured in this bioreactor were viable after 2 weeks and showed robust Alcian blue staining, indicating that MSCs can reach chondrogenic differentiation in this bioreactor setup.  We also refined a design to our 3D printed low-profile microfluidically enabled bioreactor for OCM 1 and 2 cultures to enable uniform flow over the cultures with multiple configurations in one and two chamber form. 2 mL drops containing 40,000 MSCs was spotted on the polycarbonate membrane of the microfluidics enabled bioreactor. Cells were left to adhere for up to 60 minutes and the chamber filled with fresh chondrogenic medium, sealed with a glass coverslip and connected to the P5 microfluidic system. MSCs were viable in the bioreactor for 48 h after seeding. Imperfections in the printing requires us to adapt the reactor to PDMS manufacture in order to sustain a culture for 14 or 17 days.  Liver OCMs (Project 4) were challenged with 0 uM, 100uM, 1mM, 2mM VPA in chondrogenic media.  This conditioned media was then mixed 1:1 with fresh chondrogenic media.  Limb OCM micromass cultures grown in the liver conditioned media formed at all the VPA doses tested but all doses of VPA showed decreased Collagen II gene expression with the highest dose (2mM) showing the largest decrease.

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

  • Specific Aim 1: Define the temporal and concentration-dependent effects of TCDD on native fetal membrane immune responses to infection. Native fetal membranes from non-laboring women at delivery exhibit an enhanced responsiveness to an infection mimic (lipopolysaccharides (LPS, 10 ng/ml)) following pretreatments with TCDD (10 nM). These findings supported our central hypothesis that environmental toxicants prime the gravid uterus for exaggerated inflammatory responses. 
  • Specific Aim 2: Implement an in vitro, microscaled, living, instrumented fetal membrane on-a-chip (IFMOC) that recapitulates the physiological properties of the human tissue. The overarching goal of the current application is to determine the utility of the IFMOC compared to traditional cultures for screening of individual toxicants.
  •  Specific Aim 3:  Validate the IFMOC as a model of environmental toxicant immunomodulation compared with primary human fetal membranes. As noted above, using multiple organotypic (OoC) devices, we have exposed the primary cell types that comprise the endocrine/immune sensitive cells of the human maternal-fetal interface to a variety of toxicants and/or inflammatory agents.

Project 4: Organotypic Liver Model for Predictive Human Toxicology and Metabolism

Much of our final year 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 were addressed prior to the integration. Our initial approach to integration was using functional coupling (media is conditioned in the liver OCM, then used to perfuse another OCM [3]). In order to prepare conditioned media for functional coupling, we used allometric scaling to calculate the appropriate amount of liver conditioned media to provide to the other project teams. After the appropriate scaling was determined, we selected relevant test compounds for OCM treatment.  Drugs were chosen based upon availability of reference clinical data and distribution of liver activities (non-toxic, known toxic, metabolized).  Compounds with cLogP ≤ 3 were selected to minimize issues of drug binding to PDMS [7]. Treated and control liver conditioned media were prepared for 8 compounds and delivered to Projects 1,2,3, and 5 (Table 2). As preparation for physical integration, we trained the Vanderbilt project teams to recapitulate our liver OCM.  All protocols and SOPS for Liver OCM assembly and assays uploaded to the VPROMPT SharePoint site and the MPS database (https://mps.csb.pitt.edu/), were reviewed and approved.  All components are commercially available and detailed in the SOPs. We continued to validation iPSC hepatocytes from a collaborator.  

Project 5: Systems Engineering & Analysis for Organotypic Culture Models

Conclusions:

Project 1: Mammosphere Bioreactor For Life-Stage Specific Toxicology

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

Project 2 demonstrated successful chondrogenesis and hypertrophy of adult human MSCs in planar high-density culture comprised of 400,000 cells each in 10ul volume.

Project 3 : Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks

Using identical treatments with estradiol (1nM) and medroxyprogesterone acetate (500 nM) during the decidualization phase within our devices we have confirmed the cellular responses within the devices relative to the responses observed in the transwell system. Our studies reveal the utility of these devices to examine important physiological processes that can be disrupted by exposure to various toxicants.

Device Description Comment
IFMOC Multi-chamber device to mimic human fetal membrane This highly complex device will be useful for mechanistic studies but is not amenable for use as a screening tool.
MFI Two chamber device containing endometrial stromal cells and placental trophoblasts

Appropriate for both toxicant screening and mechanistic studies of secondary exposures.

Can additionally allow for the introduction of immune cells to study immune dysfunction.
LIver/MFI Connect the liver OoC to the MFI Although feasible in theory, timing constraints associated with acquisition of multiple human tissues limits the utility of this approach.
LIver CM/MFI Expose the MFI to liver conditioned media (CM). Liver CM, from the Liver OoC treated with toxicants, can readily be added to the MFI device to more effectively test the impact of liver metabolism of toxicants on the early pregnancy environment and common infections.
EndoChip Two chamber device of the human endometrium Appropriate response to steroids resulting in endometrial stromal cell decidualization is critical to establishment of pregnancy; thus, examining the impact of toxicants in a “non-pregnant” system is relevant.

Table 1. Organ-on-Chip Models Developed by Project 3

Project 4: Organotypic Liver Model for Predictive Human Toxicology and Metabolism

Matured iPSC-derived human hepatocytes were obtained from a collaborator in order to take advantage of his patented iPSC hepatocyte maturation methodology. The functionality of the iPSC hepatocytes was determined by testing a metabolism probe mixture for three specific isoforms of human Cytochrome P450 and two for glucuronidation. In that study, comparing iPSC derived human hepatocytes and a pool of 20 human donors of cryopreserved hepatocytes functional biomarkers such as albumin and urea secretion were comparable, and the oxidative metabolism activity found in iPSC cells for Cyp -1A2, -3A4 and -2C9 were 85 – 123% of donor pool levels. Finally, the results from a compound study are recently published in the 2020 Lab on a Chip. 

Project 5: Systems Engineering & Analysis for Organotypic Culture Models


Journal Articles: 50 Displayed | Download in RIS Format

Other center views: All 158 publications 49 publications in selected types All 49 journal articles
Type Citation Sub Project Document Sources
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 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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  • 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 R835736C001 (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 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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  • Journal Article 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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  • Journal Article 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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  • 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 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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  • 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. R835736C001 (2017)
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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 R835736C004 (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 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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  • Journal Article 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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  • 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 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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  • Journal Article 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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  • Journal Article 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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  • 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)
    R835736 (2016)
    R835736C004 (2015)
    R835736C004 (2016)
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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)
    R835736C004 (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)
    R835736 (2016)
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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)
    R835736 (2016)
    R835736 (2017)
    R835736C004 (2015)
    R835736C004 (2016)
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    R835736C004 (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 (14 pp.). R835736 (2017)
    R835736C004 (2018)
    R835738 (Final)
    R835738C002 (2017)
    R835738C005 (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)
    R835736 (2016)
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    R835736C004 (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)
    R835736 (2016)
    R835736C004 (2016)
    R835736C005 (2016)
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    R835738 (Final)
    R835738C003 (2017)
    R835738C005 (2017)
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  • Abstract: Nature-Abstract
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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.). R835736C004 (2017)
    R835738 (2017)
    R835738 (Final)
    R835738C002 (2016)
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  • Abstract: Scientific Reports-Abstract
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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)
    R835736 (2016)
    R835736C004 (2016)
    R835736C005 (2016)
    R835738 (2016)
    R835738 (Final)
    R835738C003 (2017)
    R835738C005 (2017)
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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)
    R835736C005 (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. R835736C005 (2017)
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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)
    R835736C005 (Final)
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  • Journal Article 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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  • 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. R835736C003 (2018)
    not available

    Supplemental Keywords:

    micromass culture, adult human mesenchymal stem cell chondrogenesis, hypertrophy, joint segmentation

    Relevant Websites:

    www.ccme.pitt.edu Exit ; www.vanderbilt.edu/vprompt Exit

    Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • 2018 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 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