Grantee Research Project Results

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: Mickey Leland National Urban Air Toxics Research Center (NUATRC)
Center Director: Beskid, Craig
Title: Systems Engineering & Analysis for Organotypic Culture Models
Investigators: Wikswo, John , Cliffel, David , McLean, John , Shotwell, Matt
Institution: Vanderbilt University
EPA Project Officer: Aja, Hayley
Project Period: December 1, 2014 through November 30, 2018 (Extended to November 30, 2019)
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability

Objective:

Project 5 is designed to ensure the 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 for each of the four VPROMPT OCMs. It will accomplish this by designing bioreactors that optimize commonality of design between different OCMs, developing readouts to quantify OCM response to toxins and elucidate Adverse Outcome Pathways (AOPs), determining the optimal means to couple a liver OCM to other OCMs, and identifying and circumventing bottlenecks and economic barriers to medium throughput screening (MTS) with OCMs.

Approach:

This project builds upon a microfluidic pump and valve technology already in an advanced state of development for DARPA, DTRA, and NIH microphysiological systems programs. Project 5 will be conducted in three phases, with the timing of each phase being determined by the state of development of each of the four OCMs: Phase 1 will deliver to Projects 1-4 standardized micropumps, V1.0 MicroClinical Analyzers (μCA), and other hardware based upon existing Vanderbilt technologies to both accelerate OCM development, enable initial toxin screening and OCM validation, and guide subsequent efforts in all projects. Phase 2 will deliver custom V1.0 IOM Perfusion Controllers (PC), standardized V2.0 IOM μCAs, and a V2.0 IOM MicroFormulator (μF) to enable Projects 1-4 to operate their OCMs in an unattended manner. Phase 3 will provide fully automated V2.0 IOM PCs that support multiple OCMs on the IOM, allow control of media flow from a liver OCM to another OCM, and serve as proof-of-concept devices for the transition to MTS. Phase 4 will evaluate the path to OCM MTS.

Expected Results:

Project 5 will improve toxic risk assessment by providing a high level of instrumentation and platform engineering for VPROMPT that will be of general utility to the OCM toxicology efforts worldwide. Successful completion of the project will lead to automated IOM hardware and procedures that reduce the costs of materials, supplies, cells, and personnel required for OCM toxicology tests; simplify the qualification of cell sources; minimize OCM variability and failure rate; and maximize the number of OCMs per module, their reliability, and the information obtained. Our approach of compact, independent, low-cost modules for OCM growth, maintenance, toxicant delivery, and response sensing is compatible with a transition to MTS, and will provide stakeholders worldwide with a new architecture for OCM toxicology.

Publications and Presentations:

Publications have been submitted on this subproject: View all 38 publications for this subproject | View all 169 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 8 journal articles for this subproject | View all 56 journal articles for this center

Supplemental Keywords:

microfabrication, systems engineering, organs-on-chips, control

Progress and Final Reports:

Main Center Abstract and Reports:

R835736 Mickey Leland National Urban Air Toxics Research Center (NUATRC)

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

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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.