Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools.
DiMasiJAGrabowskiHGHansenRW.Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ2016;
47:20–33
2.
WagnerJDahlemAMHudsonLDTerrySFAltmanRBGillilandCTDeFeoCAustinCP.A dynamic map for learning, communicating, navigating and improving therapeutic development. Nat Rev Drug Discov2018;
17:150
3.
WagnerJADahlemAMHudsonLDTerrySFAltmanRBGillilandCTDeFeoCAustinCP.Application of a dynamic map for learning, communicating, navigating, and improving therapeutic development. Clin Transl Sci2018;
11:166–74
4.
ArrowsmithJ.Trial watch: phase II failures: 2008-2010. Nat Rev Drug Discov2011;
10:328–9
5.
ArrowsmithJ.Trial watch: phase III and submission failures: 2007-2010. Nat Rev Drug Discov2011;
10:87
6.
LowLATagleDA.Tissue chips to aid drug development and modeling for rare diseases. Expert Opin Orphan Drugs2016;
4:1113–21
7.
BlumenrathSHLeeBYLowLPrithvirajRTagleD.Tackling rare diseases: clinical trials on chips. Exp Biol Med (Maywood)2020;
245:1155–62
8.
LowLASutherlandMLumelskyNSelimovicSLundbergMSTagleDA.Organs-on-a-chip. Adv Exp Med Biol2020;
1230:27–42
9.
BreslinSO'DriscollL.Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today2013;
18:240–9
10.
WatsonDEHunzikerRWikswoJP.Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Exp Biol Med (Maywood)2017;
242:1559–72
11.
ZuberiALutzC.Mouse models for drug discovery. Can new tools and technology improve translational power?ILAR J2016;
57:178–85
12.
TagleDA.The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development. Curr Opin Pharmacol2019;
48:146–54
13.
IngberDE.Is it time for reviewer 3 to request human organ chip experiments instead of animal validation studies?Adv Sci (Weinh)2020;
7:2002030
14.
AhadianSCivitareseRBannermanDMohammadiMHLuRWangEDavenport-HuyerLLaiBZhangBZhaoYMandlaSKoroljARadisicM.Organ-on-a-chip platforms: a convergence of advanced materials, cells, and microscale technologies. Adv Healthc Mater2018;
7:1700506
15.
ZhangYSArneriABersiniSShinSRZhuKGoli-MalekabadiZAlemanJColosiCBusignaniFDell'ErbaVBishopCShupeTDemarchiDMorettiMRasponiMDokmeciMRAtalaAKhademhosseiniA.Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials2016;
110:45–59
16.
LiXGeorgeSMVernettiLGoughAHTaylorDL.A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab Chip2018;
18:2614–31
PoliniAProdanovLBhiseNSManoharanVDokmeciMRKhademhosseiniA.Organs-on-a-chip: a new tool for drug discovery. Expert Opin Drug Discov2014;
9:335–52
19.
TanataweethumNZelayaAYangFCohenRNBreyEMBhushanA.Establishment and characterization of a primary murine adipose tissue-chip. Biotechnol Bioeng2018;
115:1979–87
20.
Ronaldson-BouchardKVunjak-NovakovicG.Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell2018;
22:310–24
21.
KratzSRAHollGSchullerPErtlPRothbauerM.Latest trends in biosensing for microphysiological organs-on-a-chip and body-on-a-chip systems. Biosensors (Basel)2019;
9:110
22.
PeelSCorriganAMEhrhardtBJangKJCaetano-PintoPBoeckelerMRubinsJEKodellaKPetropolisDBRonxhiJKulkarniGFosterAJWilliamsDHamiltonGAEwartL.Introducing an automated high content confocal imaging approach for organs-on-chips. Lab Chip2019;
19:410–21
23.
KimJHParkJYJinSYoonSKwakJYJeongYH.A microfluidic chip embracing a nanofiber scaffold for 3D cell culture and real-time monitoring. Nanomaterials (Basel)2019;
9:588
24.
CurzerHJPerryGWallaceMCPerryD.The three Rs of animal research: what they mean for the Institutional Animal Care and Use Committee and why. Sci Eng Ethics2016;
22:549–65
25.
EkertJEDeakyneJPribul-AllenPTerryRSchofieldCJeongCGStoreyJMohametLFrancisJNaidooAAmadorAKleinJLRowanW.Recommended guidelines for developing, qualifying, and implementing complex in vitro models (CIVMs) for drug discovery. SLAS Discov2020;
25:1174–90
26.
LowLAMummeryCBerridgeBRAustinCPTagleDA.Organs-on-chips: into the next decade. Nat Rev Drug Discov2020. doi: 10.1038/s41573-020-0079-3.
27.
ApatiAVargaNBereczTErdeiZHomolyaLSarkadiB.Application of human pluripotent stem cells and pluripotent stem cell-derived cellular models for assessing drug toxicity. Expert Opin Drug Metab Toxicol2019;
15:61–75
28.
RudmannDG.The emergence of microphysiological systems (organs-on-chips) as paradigm-changing tools for toxicologic pathology. Toxicol Pathol2019;
47:4–10
29.
HeringaMBParkMKienhuisASVandebrielRJ.The value of organs-on-chip for regulatory safety assessment. ALTEX2020;
37:208–22
30.
AtchisonLZhangHCaoKTruskeyGA.A tissue engineered blood vessel model of Hutchinson-Gilford progeria syndrome using human iPSC-derived smooth muscle cells. Sci Rep2017;
7:8168
31.
RibasJZhangYSPitrezPRLeijtenJMiscuglioMRouwkemaJDokmeciMRNissanXFerreiraLKhademhosseiniA.Biomechanical strain exacerbates inflammation on a progeria-on-a-chip model. Small2017;
13. doi: 10.1002/smll.201603737
32.
WangGMcCainMLYangLHeAPasqualiniFSAgarwalAYuanHJiangDZhangDZangiLGevaJRobertsAEMaQDingJChenJWangDZLiKWangJWandersRJKulikWVazFMLaflammeMAMurryCEChienKRKelleyRIChurchGMParkerKKPuWT.Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med2014;
20:616–23
33.
van der MeerADOrlovaVVten DijkePvan den BergAMummeryCL.Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. Lab Chip2013;
13:3562–8
34.
van den BergAMummeryCLPassierRvan der MeerAD.Personalised organs-on-chips: functional testing for precision medicine. Lab Chip2019;
19:198–205
35.
ChangSYWeberEJSidorenkoVSChapronAYeungCKGaoCMaoQShenDWangJRosenquistTADickmanKGNeumannTGrollmanAPKellyEJHimmelfarbJEatonDL.Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight2017;
2:e95978
36.
TruskeyGA.Human microphysiological systems and organoids as in vitro models for toxicological studies. Front Public Health2018;
6:185
37.
LiuLKooYAkwittiCRussellTGayELaskowitzDTYunY.Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening. PLoS One2019;
14:e0224657
38.
YangJWShenYCLinKCChengSJChenSLChenCYKumarPVLinSFLuHEChenGY.Organ-on-a-chip: opportunities for assessing the toxicity of particulate matter. Front Bioeng Biotechnol2020;
8:519
39.
TangHAbouleilaYSiLOrtega-PrietoAMMummeryCLIngberDEMashaghiA.Human organs-on-chips for virology. Trends Microbiol2020;
28:934–46
40.
HawkinsKGCasolaroCBrownJAEdwardsDAWikswoJP.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 Ther2020;
108:929–48
41.
RibeiroAJSYangXPatelVMadabushiRStraussDG.Liver microphysiological systems for predicting and evaluating drug effects. Clin Pharmacol Ther2019;
106:139–47
42.
PaekJParkSELuQParkKTChoMOhJMKwonKWYiYSSongJWEdelsteinHIIshibashiJYangWMyersonJWKiselevaRYAprelevPHoodEDStambolianDSealePMuzykantovVRHuhD.Microphysiological engineering of self-assembled and perfusable microvascular beds for the production of vascularized three-dimensional human microtissues. ACS Nano2019;
13:7627–43
BrownJAFaleySLShiYHillgrenKMSawadaGABakerTKWikswoJPLippmannES.Advances in blood-brain barrier modeling in microphysiological systems highlight critical differences in opioid transport due to cortisol exposure. Fluids Barriers CNS2020;
17:38
45.
LeeCSLeongKW.Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery. Curr Opin Biotechnol2020;
66:78–87
46.
AhnSISeiYJParkHJKimJRyuYChoiJJSungHJMacDonaldTJLeveyAIKimY.Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms. Nat Commun2020;
11:175
47.
DavisBNYenRPrasadVTruskeyGA.Oxygen consumption in human, tissue-engineered myobundles during basal and electrical stimulation conditions. APL Bioeng2019;
3:026103
48.
TruskeyGA.Development and application of human skeletal muscle microphysiological systems. Lab Chip2018;
18:3061–73
49.
ZhangXHongSYenRKondashMFernandezCETruskeyGA.A system to monitor statin-induced myopathy in individual engineered skeletal muscle myobundles. Lab Chip2018;
18:2787–96
LindJUYadidMPerkinsIO'ConnorBBEwejeFChantreCOHemphillMAYuanHCampbellPHVlassakJJParkerKK.Cardiac microphysiological devices with flexible thin-film sensors for higher-throughput drug screening. Lab Chip2017;
17:3692–703
52.
SidorovVYSamsonPCSidorovaTNDavidsonJMLimCCWikswoJP.I-Wire heart-on-a-chip I: three-dimensional cardiac tissue constructs for physiology and pharmacology. Acta Biomater2017;
48:68–78
53.
ZhaoYRafatianNFericNTCoxBJAschar-SobbiRWangEYAggarwalPZhangBConantGRonaldson-BouchardKPahnkeAProtzeSLeeJHDavenport HuyerLJekicDWickelerANaguibHEKellerGMVunjak-NovakovicGBroeckelUBackxPHRadisicM.A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell2019;
176:913–27
54.
ConantGLaiBFLLuRXZKoroljAWangEYRadisicM.High-content assessment of cardiac function using heart-on-a-chip devices as drug screening model. Stem Cell Rev Rep2017;
13:335–46
55.
HuebschNLoskillPDeveshwarNSpencerCIJudgeLMMandegarMAFoxCBMohamedTMMaZMathurASheehanAMTruongASaxtonMYooJSrivastavaDDesaiTASoPLHealyKEConklinBR.Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci Rep2016;
6:24726
56.
MathurALoskillPShaoKHuebschNHongSMarcusSGMarksNMandegarMConklinBRLeeLPHealyKE.Human iPSC-based cardiac microphysiological system for drug screening applications. Sci Rep2015;
5:8883
57.
SchroerAPardonGCastilloEBlairCPruittB.Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment. Prog Biophys Mol Biol2019;
144:3–15
58.
MaassCSorensenNBHimmelfarbJKellyEJStokesCLCiritM.Translational assessment of drug-induced proximal tubule injury using a kidney microphysiological system. CPT Pharmacometrics Syst Pharmacol2019;
8:316–25
59.
SakolishCChenZDalaijamtsCMitraKLiuYFultonTWadeTLKellyEJRusynIChiuWA.Predicting tubular reabsorption with a human kidney proximal tubule tissue-on-a-chip and physiologically-based modeling. Toxicol in Vitro2020;
63:104752
60.
ChapronAChapronBDHaileyDWChangSYImaokaTThummelKEKellyEHimmelfarbJShenDYeungCK.An improved vascularized, dual-channel microphysiological system facilitates modeling of proximal tubular solute secretion. ACS Pharmacol Transl Sci2020;
3:496–508
61.
PhillipsJAGrandhiTSPDavisMGautierJCHariparsadNKellerDSuraRVan VleetTR.A pharmaceutical industry perspective on microphysiological kidney systems for evaluation of safety for new therapies. Lab Chip2020;
20:468–76
62.
XiaoSCoppetaJRRogersHBIsenbergBCZhuJOlalekanSAMcKinnonKEDokicDRashediASHaisenlederDJMalpaniSSArnold-MurrayCAChenKJiangMBaiLNguyenCTZhangJLarondaMMHopeTJManiarKPPavoneMEAvramMJSeftonECGetsiosSBurdetteJEKimJJBorensteinJTWoodruffTK.A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat Commun2017;
8:14584
63.
KomeyaMKimuraHNakamuraHYokonishiTSatoTKojimaKHayashiKKatagiriKYamanakaHSanjoHYaoMKamimuraSInoueKOgonukiNOguraAFujiiTOgawaT.Long-term ex vivo maintenance of testis tissues producing fertile sperm in a microfluidic device. Sci Rep2016;
6:21472
64.
PamiesDBarrerasPBlockKMakriGKumarAWiersmaDSmirnovaLZangCBresslerJChristianKMHarrisGMingGLBerlinickeCJKyroKSongHPardoCAHartungTHogbergHT.A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity. ALTEX2017;
34:362–76
65.
KwakBSJinSPKimSJKimEJChungJHSungJH.Microfluidic skin chip with vasculature for recapitulating the immune response of the skin tissue. Biotechnol Bioeng2020;
117:1853–63
66.
HardwickRNBettsCJWhritenourJSuraRThamsenMKaufmanEHFabreK.Drug-induced skin toxicity: gaps in preclinical testing Cascade as opportunities for complex in vitro models and assays. Lab Chip2020;
20:199–214
67.
KimKJeonHMChoiKCSungGY.Testing the effectiveness of curcuma longa leaf extract on a skin equivalent using a pumpless skin-on-a-chip model. Int J Mol Sci2020;
21:3898
68.
Romero-LopezMLiZRheeCMaruyamaMPajarinenJO'DonnellBLinTHLoCWHanlonJDubowitzRYaoZBunnell Ba LinHTuanRSGoodmanSB.Macrophage effects on mesenchymal stem cell osteogenesis in a three-dimensional in vitro bone model. Tissue Eng Part A2020. doi: 10.1089/ten.TEA.2020.0041
69.
AchbergerKProbstCHaderspeckJBolzSRogalJChuchuyJNikolovaMCoraVAntkowiakLHaqWShenNSchenke-LaylandKUeffingMLiebauSLoskillP.Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform. Elife2019;
8:e46188
70.
WrightCBBeckerSMLowLATagleDASievingPA.Improved ocular tissue models and eye-on-a-chip technologies will facilitate ophthalmic drug development. J Ocul Pharmacol Ther2020;
36:25–9
71.
VernettiLGoughABaetzNBluttSBroughmanJRBrownJAFoulke-AbelJHasanNInJKellyEKovbasnjukORepperJSenutovitchNStabbJYeungCZachosNCDonowitzMEstesMHimmelfarbJTruskeyGWikswoJPTaylorDL.Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci Rep2017;
7:42296
72.
NovakRIngramMMarquezSDasDDelahantyAHerlandAMaozBMJeantySSFSomayajiMRBurtMCalamariEChalkiadakiAChoAChoeYChouDBCronceMDauthSDivicTFernandez-AlconJFerranteTFerrierJFitzGeraldEAFlemingRJalili-FiroozinezhadSGrevesseTGossJAHamkins-IndikTHenryOHinojosaCHuffstaterTJangKJKujalaVLengLMannixRMiltonYNawrothJNestorBANgCFO'ConnorBParkTESanchezHSlizJSontheimer-PhelpsASwenorBThompsonG, 2nd Touloumes GJ, Tranchemontagne Z, Wen N, Yadid M, Bahinski A, Hamilton GA, Levner D, Levy O, Przekwas A, Prantil-Baun R, Parker KK, Ingber DE.
Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nat Biomed Eng2020;
4:407–20
73.
EdingtonCDChenWLKGeisheckerEKassisTSoenksenLRBhushanBMFreakeDKirschnerJMaassCTsamandourasNValdezJCookCDParentTSnyderSYuJSuterEShockleyMVelazquezJVelazquezJJStockdaleLPappsJPLeeIVannNGamboaMLaBargeMEZhongZWangXBoyerLALauffenburgerDACarrierRLCommunalCTannenbaumSRStokesCLHughesDJRohatgiGTrumperDLCiritMGriffithLG.Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci Rep2018;
8:4530
74.
MiyoshiTHiratsukaKSaizEGMorizaneR.Kidney organoids in translational medicine: disease modeling and regenerative medicine. Dev Dyn2020;
249:34–45
75.
WengKCKurokawaYKHajekBSPaladinJAShirureVSGeorgeSC.Human induced pluripotent stem-cardiac-endothelial-tumor-on-a-chip to assess anticancer efficacy and cardiotoxicity. Tissue Eng Part C Methods2020;
26:44–55
76.
LinZLiZLiENLiXDelDCShenHHaoTO'DonnellBBunnellBAGoodmanSBAlexanderPGTuanRS.LinH.Osteochondral tissue chip derived from iPSCs: modeling OA pathologies and testing drugs. Front Bioeng Biotechnol2019;
7:411
77.
SharmaASancesSWorkmanMJSvendsenCN.Multi-lineage human iPSC-derived platforms for disease modeling and drug discovery. Cell Stem Cell2020;
26:309–29
78.
ZhangQZhangXTruskeyGA.Vascular microphysiological systems to model diseases. Cell Gene Ther Insights2020;
6:93–102
79.
ChramiecATelesDYeagerKMarturano-KruikAPakJChenTHaoLWangMLockRTavakolDNLeeMBKimJRonaldson-BouchardKVunjak-NovakovicG.Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety. Lab Chip2020. doi: 10.1039/d0lc00424c
80.
SakolishCWeberEJKellyEJHimmelfarbJMouneimneRGrimmFAHouseJSWadeTHanAChiuWARusynI.Technology transfer of the microphysiological systems: a case study of the human proximal tubule tissue chip. Sci Rep2018;
8:14882
81.
LiuYSakolishCChenZPhanDTTBenderRHFHughesCCWRusynI.Human in vitro vascularized micro-organ and micro-tumor models are reproducible organ-on-a-chip platforms for studies of anticancer drugs. Toxicology2020;
445:152601
82.
SakolishCHouseJSChramiecALiuYChenZHalliganSPVunjak-NovakovicGRusynI.Tissue-engineered bone tumor as a reproducible human in vitro model for studies of anticancer drugs. Toxicol Sci2020;
173:65–76
83.
GoughAVernettiLBergenthalLShunTYTaylorDL.The microphysiology systems database for analyzing and modeling compound interactions with human and animal organ models. Appl in Vitro Toxicol2016;
2:103–17
84.
SchurdakMVernettiLBergenthalLWolterQKShunTYKarcherSTaylorDLGoughA.Applications of the microphysiology systems database for experimental ADME-Tox and disease models. Lab Chip2020;
20:1472–92
85.
VernettiLGoughABaetzNBluttSBroughmanJRBrownJAFoulke-AbelJHasanNInJKellyEKovbasnjukORepperJSenutovitchNStabbJYeungCZachosNCDonowitzMEstesMHimmelfarbJTruskeyGWikswoJPTaylorDL.Corrigendum: functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci Rep2017;
7:44517
86.
AlexanderPGClarkKLTuanRS.Prenatal exposure to environmental factors and congenital limb defects. Birth Defects Res C Embryo Today2016;
108:243–73
87.
LowLATagleDA.Organs-on-chips: progress, challenges, and future directions. Exp Biol Med (Maywood)2017;
242:1573–8
88.
EwartLFabreKChakilamADraganYDuignanDBEswarakaJGanJGuzzie-PeckPOtienoMJeongCGKellerDAde MoraisSMPhillipsJAProctorWSuraRVan VleetTWatsonDWillYTagleDBerridgeB.Navigating tissue chips from development to dissemination: a pharmaceutical industry perspective. Exp Biol Med (Maywood)2017;
242:1579–85
89.
JangKJOtienoMARonxhiJLimHKEwartLKodellaKRPetropolisDBKulkarniGRubinsJEConeglianoDNawrothJSimicDLamWSingerMBaraleESinghBSoneeMStreeterAJMantheyCJonesBSrivastavaAAnderssonLCWilliamsDParkHBarrileRSlizJHerlandAHaneySKaralisKIngberDEHamiltonGA.Reproducing human and cross-species drug toxicities using a liver-chip. Sci Transl Med2019;
11:eeax516
90.
FowlerSChenWLKDuignanDBGuptaAHariparsadNKennyJRLaiWGLirasJPhillipsJAGanJ.Microphysiological systems for ADME-related applications: current status and recommendations for system development and characterization. Lab Chip2020;
20:446–67
91.
FabreKBerridgeBProctorWRRalstonSWillYBaranSWYoderGVan VleetTR.Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications. Lab Chip2020;
20:1049–57
92.
FabreKMDelsingLHicksRColcloughNCrowtherDCEwartL.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 Rev2019;
140:129–35
93.
AinslieGRDavisMEwartLLiebermanLARowlandsDJThorleyAJYoderGRyanAM.Microphysiological lung models to evaluate the safety of new pharmaceutical modalities: a biopharmaceutical perspective. Lab Chip2019;
19:3152–61
94.
BaudyAROtienoMAHewittPGanJRothAKellerDSuraRVan VleetTRProctorWR.Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry. Lab Chip2020;
20:215–25
95.
PetersonNCMahalingaiahPKFullertonADi PiazzaM.Application of microphysiological systems in biopharmaceutical research and development. Lab Chip2020;
20:697–708
96.
PetersMFChoyALPinCLeishmanDJMoisanAEwartLGuzzie-PeckPJSuraRKellerDAScottCWKolajaKL.Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems. Lab Chip2020;
20:1177–90
97.
EckstrumKStrizAFergusonMZhaoYWelchBSolomotisNOlejnikNSprandoR.Utilization of a model hepatotoxic compound, diglycolic acid, to evaluate liver organ-chip performance and in vitro to in vivo concordance. Food Chem Toxicol2020;
146:111850
98.
MarxUAkabaneTAnderssonTBBakerEBeilmannMBekenSBrendler-SchwaabSCiritMDavidRDehneEMDurieuxIEwartLFitzpatrickSCFreyOFuchsFGriffithLGHamiltonGAHartungTHoengJHogbergHHughesDJIngberDEIskandarAKanamoriTKojimaHKuehnlJLeistMLiBLoskillPMendrickDLNeumannTPalloccaGRusynISmirnovaLSteger-HartmannTTagleDATonevitskyATsybSTrapecarMVan de WaterBVan den Eijnden-van RaaijJVultoPWatanabeKWolfAZhouXRothA.Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. ALTEX2020;
37:364–94
99.
TakahashiKYamanakaS.Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell2006;
126:663–76
100.
KwistKBridgesWCBurgKJ.The effect of cell passage number on osteogenic and adipogenic characteristics of D1 cells. Cytotechnology2016;
68:1661–7
101.
Briske-AndersonMJFinleyJWNewmanSM.The influence of culture time and passage number on the morphological and physiological development of Caco-2 cells. Proc Soc Exp Biol Med1997;
214:248–57
102.
EsquenetMSwinnenJVHeynsWVerhoevenG.LNCaP prostatic adenocarcinoma cells derived from low and high passage numbers display divergent responses not only to androgens but also to retinoids. J Steroid Biochem Mol Biol1997;
62:391–9
103.
YuHCookTJSinkoPJ.Evidence for diminished functional expression of intestinal transporters in Caco-2 cell monolayers at high passages. Pharm Res1997;
14:757–62
104.
TakahashiKOkitaKNakagawaMYamanakaS.Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc2007;
2:3081–9
105.
TakahashiKTanabeKOhnukiMNaritaMIchisakaTTomodaKYamanakaS.Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell2007;
131:861–72
106.
LiangPSallamKWuHLiYItzhakiIGargPZhangYVermglinchanVLanFGuMGongTZhugeYHeCEbertADSanchez-FreireVChurkoJHuSSharmaALamCKScheinmanMMBersDMWuJC.Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome. J Am Coll Cardiol2016;
68:2086–96
107.
BurridgePWLiYFMatsaEWuHOngSGSharmaAHolmstromAChangACCoronadoMJEbertADKnowlesJWTelliMLWittelesRMBlauHMBernsteinDAltmanRBWuJC.Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med2016;
22:547–56
108.
NishizawaMChonabayashiKNomuraMTanakaANakamuraMInagakiANishikawaMTakeiIOishiATanabeKOhnukiMYokotaHKoyanagi-AoiMOkitaKWatanabeATakaori-KondoAYamanakaSYoshidaY.Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell2016;
19:341–54
109.
KimKDoiAWenBNgKZhaoRCahanPKimJAryeeMJJiHEhrlichLIYabuuchiATakeuchiACunniffKCHongguangHMcKinney-FreemanSNaveirasOYoonTJIrizarryRAJungNSeitaJHannaJMurakamiPJaenischRWeisslederROrkinSHWeissmanILFeinbergAPDaleyGQ.Epigenetic memory in induced pluripotent stem cells. Nature2010;
467:285–90
110.
RajamohanDMatsaEKalraSCrutchleyJPatelAGeorgeVDenningC.Current status of drug screening and disease modelling in human pluripotent stem cells. Bioessays2013;
35:281–98
111.
DossMXSachinidisA.Current challenges of iPSC-based disease modeling and therapeutic implications. Cells2019;
8:403
112.
ChristofferssonJMandeniusCF.Fabrication of a microfluidic cell culture device using photolithographic and soft lithographic techniques. Methods Mol Biol2019;
1994:227–33
113.
DuffyDCMcDonaldJCSchuellerOJWhitesidesGM.Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal Chem1998;
70:4974–84
114.
BhattacharjeeNUrriosAKangSFolchA.The upcoming 3D-printing revolution in microfluidics. Lab Chip2016;
16:1720–42
115.
ZhangYSYueKAlemanJMoghaddamKMBakhtSMYangJJiaWDell'ErbaVAssawesPShinSRDokmeciMROkluRKhademhosseiniA.3D bioprinting for tissue and organ fabrication. Ann Biomed Eng2017;
45:148–63
116.
Quiros-SolanoWFGaioNStassenOArikYBSilvestriCVan EngelandNCAVan der MeerAPassierRSahlgrenCMBoutenCVCvan den BergADekkerRSarroPM.Microfabricated tuneable and transferable porous PDMS membranes for organs-on-chips. Sci Rep2018;
8:13524
117.
van MeerBJde VriesHFirthKSAvan WeerdJTertoolenLGJKarperienHBJJonkheijmPDenningCIjzermanAPMummeryCL.Small molecule absorption by PDMS in the context of drug response bioassays. Biochem Biophys Res Commun2017;
482:323–8
118.
ShirureVSGeorgeSC.Design considerations to minimize the impact of drug absorption in polymer-based organ-on-a-chip platforms. Lab Chip2017;
17:681–90
119.
SanoEMoriCMatsuokaNOzakiYYagiKWadaATashimaKYamasakiSTanabeKYanoKTorisawaYS.Tetrafluoroethylene-propylene elastomer for fabrication of microfluidic organs-on-chips resistant to drug absorption. Micromachines (Basel)2019;
10:793
120.
DomanskyKLeslieDCMcKinneyJFraserJPSlizJDHamkins-IndikTHamiltonGABahinskiAIngberDE.Clear castable polyurethane elastomer for fabrication of microfluidic devices. Lab Chip2013;
13:3956–64
121.
RogersHBZhouLTKusuharaAZanikerEShafaieSOwenBCDuncanFEWoodruffTK.Dental resins used in 3D printing technologies release ovo-toxic leachates. Chemosphere2020;
270:129003
122.
LiYYangYXiongAWuXXieJHanSZhaoS.Comparative gene expression analysis of lymphocytes treated with exosomes derived from ovarian cancer and ovarian cysts. Front Immunol2017;
8:607
123.
YinPLvHLiYDengYZhangLTangP.Exosome-mediated genetic information transfer, a missing piece of osteoblast-osteoclast communication puzzle. Front Endocrinol (Lausanne)2017;
8:336
124.
WikswoJPCurtisELEagletonZEEvansBCKoleAHofmeisterLHMatloffWJ.Scaling and systems biology for integrating multiple organs-on-a-chip. Lab Chip2013;
13:3496–511
125.
MoraesCLabuzJMLeungBMInoueMChunTHTakayamaS.On being the right size: scaling effects in designing a human-on-a-chip. Integr Biol (Camb)2013;
5:1149–61
126.
ParkDLeeJChungJJJungYKimSH.Integrating organs-on-chips: multiplexing, scaling, vascularization, and innervation. Trends Biotechnol2020;
38:99–112
127.
SinAChinKCJamilMFKostovYRaoGShulerML.The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog2004;
20:338–45
128.
HerlandAMaozBMDasDSomayajiMRPrantil-BaunRNovakRCronceMHuffstaterTJeantySSFIngramMChalkiadakiABenson ChouDMarquezSDelahantyAJalili-FiroozinezhadSMiltonYSontheimer-PhelpsASwenorBLevyOParkerKKPrzekwasAIngberDE.Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat Biomed Eng2020;
4:421–36
129.
AbaciHEShulerML.Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr Biol (Camb)2015;
7:383–91
130.
PoliniADel MercatoLLBarraAZhangYSCalabiFGigliG.Towards the development of human immune-system-on-a-chip platforms. Drug Discov Today2019;
24:517–25
131.
KimHJLiHCollinsJJIngberDE.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 A2016;
113:E7–15
132.
ZhangBRadisicM.Organ-on-a-chip devices advance to market. Lab Chip2017;
17:2395–420
133.
TourovskaiaAFauverMKramerGSimonsonSNeumannT.Tissue-engineered microenvironment systems for modeling human vasculature. Exp Biol Med (Maywood)2014;
239:1264–71
134.
WeberEJChapronAChapronBDVoellingerJLLidbergKAYeungCKWangZYamauraYHaileyDWNeumannTShenDDThummelKEMuczynskiKAHimmelfarbJKellyEJ.Development of a microphysiological model of human kidney proximal tubule function. Kidney Int2016;
90:627–37
135.
Vunjak-NovakovicGBhatiaSChenCHirschiK.HeLiVa platform: integrated heart-liver-vascular systems for drug testing in human health and disease. Stem Cell Res Ther2013;
4 Suppl 1:S8
136.
QuYFericNPallottaISinghRSobbiRVargasHM.Inotropic assessment in engineered 3D cardiac tissues using human induced pluripotent stem cell-derived cardiomyocytes in the Biowire(TM) II platform. J Pharmacol Toxicol Methods2020;
105:106886
137.
SutherlandJJJollyRAGoldsteinKMStevensJL.Assessing concordance of drug-induced transcriptional response in rodent liver and cultured hepatocytes. PLoS Comput Biol2016;
12:e1004847
138.
LowLATagleDA.Tissue chips - innovative tools for drug development and disease modeling. Lab Chip2017;
17:3026–36
139.
YeungCKKoenigPCountrymanSThummelKEHimmelfarbJKellyEJ.Tissue chips in space-challenges and opportunities. Clin Transl Sci2020;
13:8–10
