SCIENTIfIC REPORTS | (2018) 8:4530 | DOI:10.1038/s41598-018-22749-0
Systems for Quantitative Biology
and Pharmacology Studies
Collin D. Edington
, Wen Li Kelly Chen
, Emily Geishecker
, Timothy Kassis
, Luis R.
, Brij M. Bhushan
, Duncan Freake
, Jared Kirschner
, Christian Maass
, Jorge Valdez
, Christi D. Cook
, Tom Parent
, Stephen Snyder
, Emily Suter
, Michael Shockley
, Jason Velazquez
, Jeremy J. Velazquez
, Julia P. Papps
, Iris Lee
, Nicholas Vann
, Mario Gamboa
, Matthew E. LaBarge
, Xin Wang
, Laurie A. Boyer
, Douglas A. Lauenburger
, Rebecca L. Carrier
, Steven R. Tannenbaum
, Cynthia L. Stokes
, David J. Hughes
, David L. Trumper
, Murat Cirit
& Linda G. Grith
Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function
through use of specialized culture microenvironments, including 3D matrices and microperfusion.
Here, we report an approach to co-culture multiple dierent MPSs linked together physiologically on
re-useable, open-system microuidic platforms that are compatible with the quantitative study of
a range of compounds, including lipophilic drugs. We describe three dierent platform designs – “4-
way”, “7-way”, and “10-way” – each accommodating a mixing chamber and up to 4, 7, or 10 MPSs.
Platforms accommodate multiple dierent MPS ow congurations, each with internal re-circulation to
enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently
programmable ow rates to provide precise control over both intra- and inter-MPS ow partitioning
and drug distribution. We rst developed a 4-MPS system, showing accurate prediction of secreted
liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS
and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic
function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of
diclofenac metabolism. This study illustrates several generalizable design and operational principles for
implementing multi-MPS “physiome-on-a-chip” approaches in drug discovery.
e failure of pre-clinical cell culture and animal models to predict drug safety and ecacy in humans results in
billions of wasted dollars each year and slows development of treatments for needy patients
. ese gaps have
driven an explosion of approaches to capture complex human physiology in vitro, merging several parallel threads
of science and technology, including pluripotent stem cell (PSC) and organoid biology; design principles and
tools for 3D tissue and organ culture; microuidic and mesouidic approaches to controlling perfusion ow; and
quantitative systems pharmacology models
. ese eorts are driving development of tools oen referred to as
“microphysiological systems” (MPSs) or “organs-on-chips” (OOCs), which encompass the subset of approaches
employing (i) perfusion ow to improve physiology or workow even for monolayer cultures of a single cell
type, and (ii) 3D cultures comprising multiple dierent cell types, representing a desirable subset of organ or
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Center for Gynepathology
Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Research Laboratory of Electronics,
Massachusetts Institute of Technology, Cambridge, MA, USA.
Continuum LLC, Boston, MA, USA.
of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Chemical Engineering,
Northeastern University, Boston, MA, USA.
Center for Environmental Health Sciences, Massachusetts Institute of
Technology, Cambridge, MA, USA.
Stokes Consulting, Redwood City, CA, USA.
CnBio Innovations, Hertfordshire,
United Kingdom. Collin D. Edington and Wen Li Kelly Chen contributed equally to this work. Correspondence and
requests for materials should be addressed to D.L.T. (email: email@example.com) or M.C. (email: firstname.lastname@example.org) or
L.G.G. (email: email@example.com)
Received: 9 November 2017
Accepted: 28 February 2018
Published: xx xx xxxx