Abstract
Microphysiological systems (MPS) or tissue chips/organs-on-chips are novel in vitro models that emulate human physiology at the most basic functional level. In this review, we discuss various hurdles to widespread adoption of MPS technology focusing on issues from multiple stakeholder sectors, e.g., academic MPS developers, commercial suppliers of platforms, the pharmaceutical and biotechnology industries, and regulatory organizations. Broad adoption of MPS technology has thus far been limited by a gap in translation between platform developers, end-users, regulatory agencies, and the pharmaceutical industry. In this brief review, we offer a perspective on the existing barriers and how end-users may help surmount these obstacles to achieve broader adoption of MPS technology.
References
1.
Ahn
SI
, Sei
YJ
, Park
HJ
, Kim
J
, Ryu
Y
, Choi
JJ
, Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms
. Nat Commun
. 2020
;11
(1
):175
. .2.
Ainslie
GR
, Davis
M
, Ewart
L
, Lieberman
LA
, Rowlands
DJ
, Thorley
AJ
, Microphysiological lung models to evaluate the safety of new pharmaceutical modalities: a biopharmaceutical perspective
. Lab Chip
. 2019
;19
(19
):3152
–61
. .3.
Alex
A
, Harris
J
, Smith
DA
. Introduction. In: Attrition in the Pharmaceutical Industry: Reasons, Implications, and Pathways Forward
. John Wiley & Sons
; 2016
. p. 1
–4
.4.
Apati
A
, Varga
N
, Berecz
T
, Erdei
Z
, Homolya
L
, Sarkadi
B
. Application of human pluripotent stem cells and pluripotent stem cell-derived cellular models for assessing drug toxicity
. Expert Opin Drug Metab Toxicol
. 2019
;15
(1
):61
–75
.5.
Arrowsmith
J
. Trial watch: Phase II failures: 2008-2010
. Nat Rev Drug Discov
. 2011
;10
(5
):328
–9
. .6.
Arrowsmith
J
. Trial watch: phase III and submission failures: 2007-2010
. Nat Rev Drug Discov
. 2011
;10
(2
):87
. .7.
Arrowsmith
J
, Miller
P
. Trial watch: phase II and phase III attrition rates 2011-2012
. Nat Rev Drug Discov
. 2013
;12
(8
):569
. .8.
Atchison
L
, Zhang
H
, Cao
K
, Truskey
GA
. A tissue engineered blood vessel model of Hutchinson-Gilford progeria syndrome using human iPSC-derived smooth muscle cells
. Sci Rep
. 2017
;7
(1
):8168
. .9.
Bale
SS
, Manoppo
A
, Thompson
R
, Markoski
A
, Coppeta
J
, Cain
B
, A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions
. Biotechnol Bioeng
. 2019
;116
(12
):3409
–20
. .10.
Barrile
R
, van der Meer
AD
, Park
H
, Fraser
JP
, Simic
D
, Teng
F
, Organ-on-chip recapitulates thrombosis induced by an anti-CD154 monoclonal antibody: translational potential of advanced microengineered systems
. Clin Pharmacol Ther
. 2018
;104
(6
):1240
–8
. .11.
Baudy
AR
, Otieno
MA
, Hewitt
P
, Gan
J
, Roth
A
, Keller
D
, Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry
. Lab Chip
. 2020
;20
(2
):215
–25
. .12.
Blumenrath
SH
, Lee
BY
, Low
L
, Prithviraj
R
, Tagle
D
. Tackling rare diseases: Clinical trials on chips
. Exp Biol Med (Maywood)
. 2020
;245
(13
):1155
–62
. .13.
Brown
JA
, Faley
SL
, Shi
Y
, Hillgren
KM
, Sawada
GA
, Baker
TK
, Advances in blood-brain barrier modeling in microphysiological systems highlight critical differences in opioid transport due to cortisol exposure
. Fluids Barriers CNS
. 2020
;17
(1
):38
. .14.
Caliari
SR
, Burdick
JA
. A practical guide to hydrogels for cell culture
. Nat Methods
. 2016
;13
(5
):405
–14
. .15.
Chang
SY
, Weber
EJ
, Sidorenko
VS
, Chapron
A
, Yeung
CK
, Gao
C
, Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity
. JCI Insight
. 2017
;2
(22
). .16.
Chapron
A
, Chapron
BD
, Hailey
DW
, Chang
SY
, Imaoka
T
, Thummel
KE
, An improved vascularized, dual-channel microphysiological system facilitates modeling of proximal tubular solute secretion
. ACS Pharmacol Transl Sci
. 2020
;3
(3
):496
–508
. .17.
Chramiec
A
, Teles
D
, Yeager
K
, Marturano-Kruik
A
, Pak
J
, Chen
T
, Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety
. Lab Chip
. 2020
.18.
Crapo
PM
, Tottey
S
, Slivka
PF
, Badylak
SF
. Effects of biologic scaffolds on human stem cells and implications for CNS tissue engineering
. Tissue Eng Part A
. 2014 Jan
;20
(1–2
):313
–23
.19.
Curzer
HJ
, Perry
G
, Wallace
MC
, Perry
D
. The three Rs of animal research: what they mean for the institutional animal care and use committee and why
. Sci Eng Ethics
. 2016
;22
(2
):549
–65
. .20.
Davis
BN
, Yen
R
, Prasad
V
, Truskey
GA
. Oxygen consumption in human, tissue-engineered myobundles during basal and electrical stimulation conditions
. APL Bioeng
. 2019
;3
(2
):026103
. .21.
DiMasi
JA
, Grabowski
HG
, Hansen
RW
. Innovation in the pharmaceutical industry: New estimates of R&D costs
. J Health Econ
. 2016
;47
:20
–33
.22.
Duffy
DC
, McDonald
JC
, Schueller
OJ
, Whitesides
GM
. Rapid prototyping of microfluidic systems in poly(dimethylsiloxane)
. Anal Chem
. 1998
;70
(23
):4974
–84
. .23.
Edington
CD
, Chen
WLK
, Geishecker
E
, Kassis
T
, Soenksen
LR
, Bhushan
BM
, Interconnected microphysiological systems for quantitative biology and pharmacology studies
. Sci Rep
. 2018
;8
(1
):4530
. .24.
Ekert
JE
, Deakyne
J
, Pribul-Allen
P
, Terry
R
, Schofield
C
, Jeong
CG
, Recommended Guidelines for Developing, Qualifying, and Implementing Complex In Vitro Models (CIVMs) for Drug Discovery
. SLAS Discov
. 2020
;25
:1174
. .25.
Ewart
L
, Roth
A
. Opportunities and challenges with microphysiological systems: a pharma end-user perspective
. Nat Rev Drug Discov
. 2020
.26.
Ewart
L
, Fabre
K
, Chakilam
A
, Dragan
Y
, Duignan
DB
, Eswaraka
J
, Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective
. Exp Biol Med (Maywood)
. 2017
;242
(16
):1579
–85
. .27.
Ewart
L
, Dehne
EM
, Fabre
K
, Gibbs
S
, Hickman
J
, Hornberg
E
, Application of microphysiological systems to enhance safety assessment in drug discovery
. Annu Rev Pharmacol Toxicol
. 2018
;58
:65
–82
. .28.
Fabre
KM
, Delsing
L
, Hicks
R
, Colclough
N
, Crowther
DC
, Ewart
L
. Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting
. Adv Drug Deliv Rev
. 2019
;140
:129
–35
. .29.
Fabre
K
, Berridge
B
, Proctor
WR
, Ralston
S
, Will
Y
, Baran
SW
, Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications
. Lab Chip
. 2020
;20
(6
):1049
–57
. .30.
FDA-NIH Biomarker Working Group
. BEST (Biomarkers, EndpointS, and other Tools) Resource
. Silver Spring (MD); Bethesda (MD)
: Food and Drug Administration (US); National Institutes of Health (US)
; 2016
.31.
Fowler
S
, Chen
WLK
, Duignan
DB
, Gupta
A
, Hariparsad
N
, Kenny
JR
, Microphysiological systems for ADME-related applications: current status and recommendations for system development and characterization
. Lab Chip
. 2020
;20
(3
):446
–67
. .32.
Franzen
N
, van Harten
WH
, Retèl
VP
, Loskill
P
, van den Eijnden-van Raaij
J
, IJzerman
M
. Impact of organ-on-a-chip technology on pharmaceutical R&D costs
. Drug Discov Today
. 2019
;24
(9
):1720
–4
. .33.
Friese
MA
, Montalban
X
, Willcox
N
, Bell
JI
, Martin
R
, Fugger
L
. The value of animal models for drug development in multiple sclerosis
. Brain
. 2006
;129
(Pt 8
):1940
–52
. .34.
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
. Appl In Vitro Toxicol
. 2016
;2
(2
):103
–17
. .35.
Gribkoff
VK
, Kaczmarek
LK
. The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes
. Neuropharmacology
. 2017
;120
:11
–9
. .36.
Hardwick
RN
, Betts
CJ
, Whritenour
J
, Sura
R
, Thamsen
M
, Kaufman
EH
, Drug-induced skin toxicity: gaps in preclinical testing cascade as opportunities for complex in vitro models and assays
. Lab Chip
. 2020
;20
(2
):199
–214
. .37.
Hawkins
KG
, Casolaro
C
, Brown
JA
, Edwards
DA
, Wikswo
JP
. 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
. Clin Pharmacol Ther
. 2020
.38.
Heringa
MB
, Park
M
, Kienhuis
AS
, Vandebriel
RJ
. The value of organs-on-chip for regulatory safety assessment
. ALTEX
. 2020
;37
(2
):208
–22
. .39.
Herland
A
, Maoz
BM
, Das
D
, Somayaji
MR
, Prantil-Baun
R
, Novak
R
, Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips
. Nat Biomed Eng
. 2020
;4
(4
):421
–36
. .40.
Herron
LA
, Hansen
CS
, Abaci
HE
. Engineering tissue-specific blood vessels
. Bioeng Transl Med
. 2019
;4
(3
):e10139
. .41.
Ingber
DE
. Is it time for reviewer 3 to request human organ chip experiments instead of animal validation studies?
Adv Sci (Weinh)
. 2020
;7
(22
):2002030
. .42.
Jang
KJ
, Mehr
AP
, Hamilton
GA
, McPartlin
LA
, Chung
S
, Suh
KY
, Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment
. Integr Biol (Camb)
. 2013
;5
(9
):1119
–29
. .43.
Jang
KJ
, Otieno
MA
, Ronxhi
J
, Lim
HK
, Ewart
L
, Kodella
KR
, Reproducing human and cross-species drug toxicities using a Liver-Chip
. Sci Transl Med
. 2019
;11
(517
). .44.
Jardim
DL
, Groves
ES
, Breitfeld
PP
, Kurzrock
R
. Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review
. Cancer Treat Rev
. 2017
;52
:12
–21
. .45.
Kim
K
, Doi
A
, Wen
B
, Ng
K
, Zhao
R
, Cahan
P
, Epigenetic memory in induced pluripotent stem cells
. Nature
. 2010
;467
(7313
):285
–90
. .46.
Kim
HJ
, Li
H
, Collins
JJ
, Ingber
DE
. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip
. Proc Natl Acad Sci U S A
. 2016
;113
(1
):E7
–15
. .47.
Kim
K
, Jeon
HM
, Choi
KC
, Sung
GY
. Testing the effectiveness of Curcuma longa leaf extract on a skin equivalent using a pumpless skin-on-a-chip model
. Int J Mol Sci
. 2020
;21
(11
). .48.
Kloks
C
, Berger
C
, Cortez
P
, Dean
Y
, Heinrich
J
, Bjerring Jensen
L
, A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective
. J Immunol Methods
. 2015
;417
:1
–9
. .49.
Kwak
BS
, Jin
SP
, Kim
SJ
, Kim
EJ
, Chung
JH
, Sung
JH
. Microfluidic skin chip with vasculature for recapitulating the immune response of the skin tissue
. Biotechnol Bioeng
. 2020
;117
(6
):1853
–63
. .50.
Lee
CS
, Leong
KW
. Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery
. Curr Opin Biotechnol
. 2020
;66
:78
–87
. .51.
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 Chip
. 2018
;18
(17
):2614
–31
. .52.
Lind
JU
, Busbee
TA
, Valentine
AD
, Pasqualini
FS
, Yuan
H
, Yadid
M
, Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing
. Nat Mater
. 2017
;16
(3
):303
–8
. .53.
Lind
JU
, Yadid
M
, Perkins
I
, O'Connor
BB
, Eweje
F
, Chantre
CO
, Cardiac microphysiological devices with flexible thin-film sensors for higher-throughput drug screening
. Lab Chip
. 2017
;17
(21
):3692
–703
. .54.
Liu
L
, Koo
Y
, Akwitti
C
, Russell
T
, Gay
E
, Laskowitz
DT
, Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening
. PLoS One
. 2019
;14
(11
):e0224657
. .55.
Liu
Y
, Sakolish
C
, Chen
Z
, Phan
DTT
, Bender
RHF
, Hughes
CCW
, Human in vitro vascularized micro-organ and micro-tumor models are reproducible organ-on-a-chip platforms for studies of anticancer drugs
. Toxicology
. 2020
;445
:152601
. .56.
Low
LA
, Tagle
DA
. Tissue Chips to aid drug development and modeling for rare diseases
. Expert Opin Orphan Drugs
. 2016
;4
(11
):1113
–21
. .57.
Low
LA
, Tagle
DA
. Organs-on-chips: Progress, challenges, and future directions
. Exp Biol Med (Maywood)
. 2017
;242
(16
):1573
–8
. .58.
Low
LA
, Tagle
DA
. Tissue chips – innovative tools for drug development and disease modeling
. Lab Chip
. 2017
;17
(18
):3026
–36
. .59.
Low
LA
, Mummery
C
, Berridge
BR
, Austin
CP
, Tagle
DA
. Organs-on-chips: into the next decade
. Nat Rev Drug Discov
. 2020
.60.
Low
LA
, Sutherland
M
, Lumelsky
N
, Selimovic
S
, Lundberg
MS
, Tagle
DA
. Organs-on-a-Chip
. Adv Exp Med Biol
. 2020
;1230
:27
–42
. .61.
Maass
C
, Sorensen
NB
, Himmelfarb
J
, Kelly
EJ
, Stokes
CL
, Cirit
M
. Translational assessment of drug-induced proximal tubule injury using a kidney microphysiological system
. CPT Pharmacometrics Syst Pharmacol
. 2019
;8
(5
):316
–25
. .62.
Marx
U
, Akabane
T
, Andersson
TB
, Baker
E
, Beilmann
M
, Beken
S
, Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development
. ALTEX
. 2020
;37
(3
):364
–94
. .63.
Nicholas
CR
, Chen
J
, Tang
Y
, Southwell
DG
, Chalmers
N
, Vogt
D
, Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development
. Cell Stem Cell
. 2013
;12
(5
):573
–86
. .64.
Nishizawa
M
, Chonabayashi
K
, Nomura
M
, Tanaka
A
, Nakamura
M
, Inagaki
A
, Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity
. Cell Stem Cell
. 2016
;19
(3
):341
–54
. .65.
Novak
R
, Ingram
M
, Marquez
S
, Das
D
, Delahanty
A
, Herland
A
, Robotic fluidic coupling and interrogation of multiple vascularized organ chips
. Nat Biomed Eng
. 2020
;4
(4
):407
–20
. .66.
Osaki
T
, Uzel
SGM
, Kamm
RD
. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons
. Sci Adv
. 2018
;4
(10
):eaat5847
. .67.
Paek
J
, Park
SE
, Lu
Q
, Park
KT
, Cho
M
, Oh
JM
, Microphysiological engineering of self-assembled and perfusable microvascular beds for the production of vascularized three-dimensional human microtissues
. ACS Nano
. 2019
;13
(7
):7627
–43
. .68.
Pamies
D
, Barreras
P
, Block
K
, Makri
G
, Kumar
A
, Wiersma
D
, A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity
. ALTEX
. 2017
;34
(3
):362
–76
. .69.
Parasrampuria
DA
, Benet
LZ
, Sharma
A
. Why drugs fail in late stages of development: case study analyses from the last decade and recommendations
. AAPS J
. 2018
;20
(3
):46
. .70.
Peters
MF
, Choy
AL
, Pin
C
, Leishman
DJ
, Moisan
A
, Ewart
L
, Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems
. Lab Chip
. 2020
;20
(7
):1177
–90
. .71.
Peterson
NC
, Mahalingaiah
PK
, Fullerton
A
, Di Piazza
M
. Application of microphysiological systems in biopharmaceutical research and development
. Lab Chip
. 2020
;20
(4
):697
–708
. .72.
Phillips
JA
, Grandhi
TSP
, Davis
M
, Gautier
JC
, Hariparsad
N
, Keller
D
, A pharmaceutical industry perspective on microphysiological kidney systems for evaluation of safety for new therapies
. Lab Chip
. 2020
;20
(3
):468
–76
. .73.
Rajamohan
D
, Matsa
E
, Kalra
S
, Crutchley
J
, Patel
A
, George
V
, Current status of drug screening and disease modelling in human pluripotent stem cells
. Bioessays
. 2013
;35
(3
):281
–98
. .74.
Ribas
J
, Zhang
YS
, Pitrez
PR
, Leijten
J
, Miscuglio
M
, Rouwkema
J
, Biomechanical strain exacerbates inflammation on a progeria-on-a-chip model
. Small
. 2017
;13
(15
). .75.
Ribeiro
AJS
, Yang
X
, Patel
V
, Madabushi
R
, Strauss
DG
. Liver microphysiological systems for predicting and evaluating drug effects
. Clin Pharmacol Ther
. 2019
;106
(1
):139
–47
. .76.
Romero-Lopez
M
, Li
Z
, Rhee
C
, Maruyama
M
, Pajarinen
J
, O'Donnell
B
, Macrophage effects on mesenchymal stem cell osteogenesis in a three-dimensional in vitro bone model
. Tissue Eng Part A
. 2020
.77.
Ronaldson-Bouchard
K
, Vunjak-Novakovic
G
. Organs-on-a-chip: a fast track for engineered human tissues in drug development
. Cell Stem Cell
. 2018
;22
(3
):310
–24
. .78.
Rudmann
DG
. The emergence of microphysiological systems (organs-on-chips) as paradigm-changing tools for toxicologic pathology
. Toxicol Pathol
. 2019
;47
(1
):4
–10
. .79.
Sakolish
C
, Weber
EJ
, Kelly
EJ
, Himmelfarb
J
, Mouneimne
R
, Grimm
FA
, Technology transfer of the microphysiological systems: a case study of the human proximal tubule tissue chip
. Sci Rep
. 2018
;8
(1
):14882
. .80.
Safaee
H
, Bakooshli
MA
, Davoudi
S
, Cheng
RY
, Martowirogo
AJ
, Li
EW
, Tethered jagged-1 synergizes with culture substrate stiffness to modulate notch-induced myogenic progenitor differentiation
. Cell Mol Bioeng
. 2017 Aug
;10
(5
):501
–13
.81.
Sakolish
C
, Chen
Z
, Dalaijamts
C
, Mitra
K
, Liu
Y
, Fulton
T
, Predicting tubular reabsorption with a human kidney proximal tubule tissue-on-a-chip and physiologically-based modeling
. Toxicol In Vitro
. 2020
;63
:104752
. .82.
Sano
E
, Mori
C
, Matsuoka
N
, Ozaki
Y
, Yagi
K
, Wada
A
, Tetrafluoroethylene-propylene elastomer for fabrication of microfluidic organs-on-chips resistant to drug absorption
. Micromachines (Basel)
. 2019
;10
(11
). .83.
Schurdak
M
, Vernetti
L
, Bergenthal
L
, Wolter
QK
, Shun
TY
, Karcher
S
, Applications of the microphysiology systems database for experimental ADME-Tox and disease models
. Lab Chip
. 2020
;20
(8
):1472
–92
. .84.
Shirure
VS
, George
SC
. Design considerations to minimize the impact of drug absorption in polymer-based organ-on-a-chip platforms
. Lab Chip
. 2017
;17
(4
):681
–90
. .85.
Sontheimer-Phelps
A
, Chou
DB
, Tovaglieri
A
, Ferrante
TC
, Duckworth
T
, Fadel
C
, Human colon-on-a-chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology
. Cell Mol Gastroenterol Hepatol
. 2020
;9
(3
):507
–26
.86.
Stein
JM
, Mummery
CL
, Bellin
M
. Engineered models of the human heart: directions and challenges
. Stem Cell Reports
. 2020
.87.
Tagle
DA
. The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development
. Curr Opin Pharmacol
. 2019
;48
:146
–54
. .88.
Takahashi
K
, Yamanaka
S
. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
. Cell
. 2006
;126
(4
):663
–76
. .89.
Takahashi
K
, Okita
K
, Nakagawa
M
, Yamanaka
S
. Induction of pluripotent stem cells from fibroblast cultures
. Nat Protoc
. 2007
;2
(12
):3081
–9
. .90.
Takahashi
K
, Tanabe
K
, Ohnuki
M
, Narita
M
, Ichisaka
T
, Tomoda
K
, Induction of pluripotent stem cells from adult human fibroblasts by defined factors
. Cell
. 2007
;131
(5
):861
–72
. .91.
Tang
H
, Abouleila
Y
, Si
L
, Ortega-Prieto
AM
, Mummery
CL
, Ingber
DE
, Human organs-on-chips for virology
. Trends Microbiol
. 2020
.92.
Terrell
JA
, Jones
CG
, Kabandana
GKM
, Chen
C
. From cells-on-a-chip to organs-on-a-chip: scaffolding materials for 3D cell culture in microfluidics
. J Mater Chem B
. 2020
;8
(31
):6667
–85
. .93.
Trappmann
B
, Baker
BM
, Polacheck
WJ
, Choi
CK
, Burdick
JA
, Chen
CS
. Matrix degradability controls multicellularity of 3D cell migration
. Nat Commun
. 2017
;8
:371
.94.
Truskey
GA
. Development and application of human skeletal muscle microphysiological systems
. Lab Chip
. 2018
a;18
(20
):3061
–73
. .95.
Truskey
GA
. Human microphysiological systems and organoids as in vitro models for toxicological studies
. Front Public Health
. 2018
b;6
:185
. .96.
Urquhart
L
. Top companies and drugs by sales in 2019
. Nat Rev Drug Discov
. 2020
;19
(4
):228
. .97.
van den Berg
A
, Mummery
CL
, Passier
R
, van der Meer
AD
. Personalised organs-on-chips: functional testing for precision medicine
. Lab Chip
. 2019
;19
(2
):198
–205
. .98.
van Meer
BJ
, de Vries
H
, Firth
KSA
, van Weerd
J
, Tertoolen
LGJ
, Karperien
HBJ
, Small molecule absorption by PDMS in the context of drug response bioassays
. Biochem Biophys Res Commun
. 2017
;482
(2
):323
–8
. .99.
Verhulsel
M
, Vignes
M
, Descroix
S
, Malaquin
L
, Vignjevic
DM
, Viovy
JL
. A review of microfabrication and hydrogel engineering for micro-organs on chips
. Biomaterials
. 2014
;35
(6
):1816
–32
. .100.
Vernetti
L
, Gough
A
, Baetz
N
, Blutt
S
, Broughman
JR
, Brown
JA
, Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle
. Sci Rep
. 2017
;7
:42296
. 101.
Wagner
J
, Dahlem
AM
, Hudson
LD
, Terry
SF
, Altman
RB
, Gilliland
CT
, A dynamic map for learning, communicating, navigating and improving therapeutic development
. Nat Rev Drug Discov
. 2018
;17
(2
):150
. .102.
Wagner
JA
, Dahlem
AM
, Hudson
LD
, Terry
SF
, Altman
RB
, Gilliland
CT
, Application of a dynamic map for learning, communicating, navigating, and improving therapeutic development
. Clin Transl Sci
. 2018
;11
(2
):166
–74
. .103.
Wang
G
, McCain
ML
, Yang
L
, He
A
, Pasqualini
FS
, Agarwal
A
, Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies
. Nat Med
. 2014
;20
(6
):616
–23
. .104.
Waring
MJ
, Arrowsmith
J
, Leach
AR
, Leeson
PD
, Mandrell
S
, Owen
RM
, An analysis of the attrition of drug candidates from four major pharmaceutical companies
. Nat Rev Drug Discov
. 2015
;14
(7
):475
–86
. .105.
Watanabe
T
, Furukawa
T
, Sharyo
S
, Ohashi
Y
, Yasuda
M
, Takaoka
M
, Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism
. J Toxicol Sci
. 2000
;25
(5
):423
–31
. .106.
Wikswo
JP
, Curtis
EL
, Eagleton
ZE
, Evans
BC
, Kole
A
, Hofmeister
LH
, Scaling and systems biology for integrating multiple organs-on-a-chip
. Lab Chip
. 2013
;13
(18
):3496
–511
. .107.
Xiao
S
, Coppeta
JR
, Rogers
HB
, Isenberg
BC
, Zhu
J
, Olalekan
SA
, A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle
. Nat Commun
. 2017
;8
:14584
. .108.
Yeung
CK
, Koenig
P
, Countryman
S
, Thummel
KE
, Himmelfarb
J
, Kelly
EJ
. Tissue chips in space – challenges and opportunities
. Clin Transl Sci
. 2020
;13
(1
):8
–10
. .109.
Zhang
B
, Radisic
M
. Organ-on-a-chip devices advance to market
. Lab Chip
. 2017
;17
(14
):2395
–420
. .110.
Zhang
X
, Hong
S
, Yen
R
, Kondash
M
, Fernandez
CE
, Truskey
GA
. A system to monitor statin-induced myopathy in individual engineered skeletal muscle myobundles
. Lab Chip
. 2018
;18
(18
):2787
–96
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