title: Design and demonstration of a pumpless 14 compartment microphysiological system.
abstract: We describe a human "Body-on-a-chip" device (or microphysiological system) that could be used to emulate drug distribution, metabolism, and action in the body. It is based upon a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model, where multiple chambers representing different organs are connected with fluidic channels to mimic multi-organ interactions within the body. Here we describe a pumpless 14 chamber (13 organs) microfluidic cell culture device that provides a separation between barrier and nonbarrier types of cell cultures. Our barrier chamber layer (skin, GI tract, and lung) allows for direct access and/or exposures to chemical or biological reagents forcing these reagents to pass through a barrier of cells established on a microfabricated membrane before exposing the nonbarrier tissue chambers (fat, kidney, heart, adrenal glands, liver, spleen, pancreas, bone marrow, brain, muscle) or entering the microfluidic circulation within the device. Our nonbarrier tissue chambers were created as three-dimensional configurations by resuspending cells in hydrogel (PGMatrix). We used cell lines to represent five of these organs (barrier lines-A549 [lung] and Caco2 [GI]) (nonbarrier lines-HepG2 C3A [liver], Meg01 [bone marrow], and HK2 [kidney]). The dimensions of our straight duct-like channels to each organ chamber were designed to provide the appropriate flow of a culture medium. The organ volumes and organ flow rates that have been reported for an average human male were used to estimate the desired fluid retention times in each organ chamber. The flow through the channels was induced by gravity on a custom programmed rocker platform which enabled pumpless operation and minimized bubble entrapment. The purpose of this paper is to describe the design and operation of a 14 chamber multi-organ system representing 13 tissues/organs with both barrier and nonbarrier tissue chambers and to study the interactive responses among the various cell lines. We demonstrate that five different cell lines survived with high viability (above 85%) for 7 days. We compared the individual observed flow rates to the compartments to the desired or estimated flow rates. This work demonstrates the feasibility of constructing, operating and maintaining a simple, gravity-driven, multi-organ microphysiological system with the capability of measuring cellular functions such as CYP1A1 and CYP3A4 activities, albumin release, urea, maintenance of tight junctions, and presence of surfactant for a sustained period. Biotechnol. Bioeng. 2016;113: 2213-2227. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biomedical Engineering, Cornell University, 113 Weill Hall, Ithaca, 14853, New York.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Miller
authors.affiliation: Department of Biomedical Engineering, Cornell University, 113 Weill Hall, Ithaca, 14853, New York. mls50@cornell.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shuler
mesh_terms: D040761:Biomimetic Materials; D002478:Cells, Cultured; D004867:Equipment Design; D019544:Equipment Failure Analysis; D006801:Humans; D056656:Lab-On-A-Chip Devices; D008953:Models, Anatomic; D014781:Viscera / Q000502:physiology*
keywords: PBPK model; drug evaluation; human surrogates; microfabrication; microphysiological systems; tissue engineered models