2017 Progress Report: Systems Engineering & Analysis for Organotypic Culture Models

EPA Grant Number: R835736C005
Subproject: this is subproject number 005 , established and managed by the Center Director under grant R835736
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Vanderbilt Pittsburgh Resource for Organotypic Models for Predictive Toxicology
Center Director: Hutson, Michael Shane
Title: Systems Engineering & Analysis for Organotypic Culture Models
Investigators: Wikswo, John , Cliffel, David , McLean, John , Shotwell, Matt
Institution: Vanderbilt University
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, 2016 through November 30,2017
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health


Project 5 is designed to ensure physiologically realistic function of each of the mammary, limb, fetal membrane, and liver organotypic culture models (OCMs), operating separately and in combination, and will do so by coordinating the refinement of Integrated Organ Microfluidics (IOM) modules that will provide a common platform architecture.

Progress Summary:

Project 5 continues to deliver stand-alone pumps, Perfusion Controller (IOM-PC, v1.0), and MicroClinical Analyzer (µCA, v1.0) hardware integration modules as requested by organ developers. We have improved our designs, production capabilities, and quality control procedures for both standard and custom microfluidic pumps and valves, and have made substantial improvements to the hardware and computer software that controls them. We delivered limb segmentation (OCM 3.0) prototypes to Project 2 as described in Milestone P2.1. We continue to examine materials to replace polydimethylsiloxane (PDMS) in pump and valve fabrication.

Milestone 2.1 (carry-over): Develop offline metabolic secretion baselines for each OCM (IM-MS, μCA). We have received and analyzed effluent for metabolic baseline readouts via ion mobility-mass spectrometry (IM-MS) from Project 4 (liver). The liver team also has shipped samples for baseline analysis using the MicroClinical Analyzer (µCA), and we anticipate more samples in Year 4. We have not received samples from Projects 1, 3 for IM-MS or Projects 1, 2, 3 for µCA baseline analysis, but are ready to do so at any time. Project 2 elected not to conduct IM-MS analysis as it is not a milestone requirement for their OCM.

Milestone 2.4 (carry-over): Version 2.0 IOM-μCA integration. We currently provide and support µCA v2.0 modules with clamp and microfluidics, with a new, custom, screen-printed electrode (SPE) produced to our specifications by Pine Instruments that provides nine working electrodes, reference and counter electrodes. We have shown how this SPE can be used to measure media conductivity as needed to correct for evaporation, and developed and calibrated sensors for glucose, lactate, glutamate, ammonia, and cholesterol.

Extensive testing of pumps and valves produced with parametric variations of multi-device masters has allowed increase our production and quality control of both RPPM and RPV designs for the µCAs and organ-chip perfusion controllers. We now produce Rotary Planar Peristaltic Micropumps (RPPMs) that span a range of flow rate from 0.5 to 800 µL/min, and circular-segment 5-port and 24-port rotary planar valves (RPVs), as needed for IOM-μCA V2.0/3.0.

Milestone 2.5 (carry-over): Version 2.0 IOM-Microformulator integration (µF). Completed.

Milestone 3.1: Software will enable full automation of IOMs. Completed and in regular use.

Milestone 3.2: Integrate wireless capability to support many IOMs. With funding from NIH/NCATS and AstraZeneca, we are testing our first prototype Triple NEMA-8 Wireless SmartMotor Cartridge. Knowledge gained from this led to improvements in the NEMA-17 controllers and software that is benefiting all Projects 1-4 Perfusion Controllers, MicroClinical Analyzers, and MicroFormulators. Wireless control of both Triple NEMA-8 and NEMA-17 will be available in 2018 for upgrades of the delivered systems.

Milestone 3.3: Develop prediction models for organ health and chemical toxicity based on baseline metabolic secretions. We are modeling the chemical adsorption onto PDMS surfaces and the transport of potential toxicants in an organ-on-chip microsystem using computational fluid dynamics (CFD). Of several potentially toxic chemicals used, it was possible to establish quantitative relationships for chemical adsorption and extract time-dependent adsorption coefficients, saturation amount and forward and reverse rate constants.

Milestone 4.1: Increase the number of OCMs in each IOM to increase throughput towards MTS. We are developing new multichannel pumps and valves, particularly is support of Proj. 1.

Milestone 4.2: Maximize manufacturability and ease-of-use of IOM PC, µCA, and µF. Completed. Minimize physical size and cost to construct and operate IOM PC, µCA, and µF.

Future Activities:

Continued refinement of device integration and molding to reduce cost.

Journal Articles on this Report : 3 Displayed | Download in RIS Format

Other subproject views: All 32 publications 7 publications in selected types All 7 journal articles
Other center views: All 149 publications 39 publications in selected types All 39 journal articles
Type Citation Sub Project Document Sources
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)
R835736 (2018)
R835736C005 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: SAGE-Abstract
  • 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)
    R835736 (2018)
    R835736C005 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Sage Publishing-Abstract
  • 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)
    R835736C005 (2017)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Future Science-Full Text-HTML
  • Abstract: Future Science-Abstract
  • Other: Future Science-Full Text-PDF
  • Supplemental Keywords:

    Microfluidic pumps and valves, integrated organ microfluidics 

    Relevant Websites:

     www.vanderbilt.edu/viibre Exit ; www.vanderbilt.edu/vprompt Exit

    Progress and Final Reports:

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

  • Main Center Abstract and Reports:

    R835736    Vanderbilt Pittsburgh Resource for Organotypic Models for Predictive Toxicology

    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